Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclopentanohydrophenanthrene ring system containing
Reexamination Certificate
2000-04-14
2001-08-07
Dees, Jose G (Department: 1616)
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclopentanohydrophenanthrene ring system containing
C540S107000, C540S113000, C540S114000, C540S117000, C540S120000
Reexamination Certificate
active
06271403
ABSTRACT:
This invention relates to substituted 7&agr;-(&egr;-aminoalkyl)-estratrienes of general formula I
in which
side chain SK is a radical of partial formula
whereby m is 4, 5 or 6,
n is 0, 1 or 2,
x is 0, 1 or 2,
A is a hydrogen atom or a C
1-5
alkyl group,
B and C each are a hydrogen atom, or
A and B together are an alkylene group —(CH
2
)
p
— with p=2, 3, 4 or 5, and C is a hydrogen atom or
A and C together are an alkylene group —(CH
2
)
q
— with q=2, 3 or 4, and B is a hydrogen atom, and
E is an unsubstituted ethyl radical or a 1x to 5x fluorinated ethyl directly adjacent to or linked by up to three methylene groups to the sulfur atom,
R
3
is a hydrogen atom, a hydrocarbon radical with up to 8 carbon atoms or a radical of partial formula R
3′
—C(O)—, in which R
3′
is a hydrogen atom or a hydrocarbon radical with up to 8 carbon atoms or a phenyl radical,
R
11
is a hydrogen atom, a halogen atom or a nitroxy group —O—NO
2
,
R
14
, R
15&agr;
, R
15&bgr;
, R
16&agr;
and R
16&bgr;
each are a hydrogen atom or
R
14
and R
15&agr;
are an additional bond or a methylene bridge, or
R
15&bgr;
is a methyl group and R
15&agr;
is a hydrogen atom, or
R
15&agr;
and R
15&bgr;
in each case are a methyl group, or
R
15&bgr;
and R
16&bgr;
together are a methylene bridge, or
R
16&agr;
or R
16&bgr;
is a halogen atom or
R
16&agr;
and R
16&bgr;
together are a methylidene group
and the others of substituents R
14
, R
15&agr;
, R
15&bgr;
, R
16&agr;
and R
16&bgr;
are each a hydrogen atom,
R
17′
in &agr;- or &bgr;-position is a hydrogen atom, a C
1-5
alkyl, C
2-5
alkenyl or C
2-5
alkinyl group or a trifluoromethyl group and
R
17″
is a hydrogen atom or a radical of partial formula R
17″
—C(O)—, in which R
17″
is a hydrogen atom or a hydrocarbon radical with up to 8 carbon atoms, or, if R
17′
is in &agr;-position, R
17′
together with R
14
means an ethano bridge,
provided that unless A and B together stand for —(CH
2
)
p
— or A and D together stand for —(CH
2
)
q
— at least one of substituents R
11
, R
14
, R
15&agr;
, R
15&bgr;
, R
16&agr;
and R
16&bgr;
is not a hydrogen atom,
as well as their physiologically compatible addition salts with organic and inorganic acids.
In addition, this invention relates to these compounds of general formula I as well as their physiologically compatible addition salts with pharmaceutical preparations that contain organic and inorganic acids as well as their use for the production of pharmaceutical agents.
In the compounds of general formula I, the nitrogen atom in the side chain is preferably separated by 5 methylene groups from carbon atom 7 of the steroid skeleton.
If A stands for an alkyl group with up to 5 carbon atoms, this is a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, or neopentyl group; a methyl group is preferred as A.
Index n can assume the value 0, 1 or 2, whereby if A is a hydrogen atom or an alkyl group with up to 5 carbon atoms, value 1 is preferred for n, so that the nitrogen atom and the sulfur atom are separated by 3 methylene groups.
The nitrogen atom can be a component of a 4- to 7-membered or 5- to 7-membered heterocycle, which is substituted in 2- or 3-position with the radical of side chain —(CH
2
)
n
—SO
x
—(CH
2
)
3
E.
Preferably, A and B together are a trimethylene group, i.e., together with the nitrogen atom and its adjacent carbon atom, they form a pyrrolidine ring that is substituted in 2-position.
In the latter case, value 0 is preferred for n and value 0 is preferred for x.
The sulfur atom in the side chain can be present as a simple sulfur bridge (sulfide), as sulfone or sulfoxide. The sulfides are preferred.
As radical E, an unsubstituted ethyl radical or a 1x to 5x fluorinated ethyl radical is suitable; the perfluorine radical is preferred for E.
In case of the terminal substituent —(CH
2
)
3
-E in the side chain being replaced by an optionally substituted aryl or heteroaryl residue directly adjacent to or linked by up to three methylene groups to the sulfur atom; for the aryl residue a phenyl residue is preferred; in the case of a heteroaryl residue a 2-furyl- or 2-thienyl residue is preferred. As a substituent on this aryl or heteroaryl residue, for example, a pentafluoroethyl or trifluoromethyl group is possible; a trifluoromethyl group is preferred, preferably in the 4-position of a phenyl residue. In the case of a heteroaryl a 2-furyl- or 2-thienyl residue is spaced by one methylene group from the sulfur atom.
Substituent R
3
at the 3-oxygen atom is primarily a hydrogen atom. The hydroxy group can also, however, be etherified with a straight-chain or branched-chain, saturated or unsaturated hydrocarbon radical with up to 8 carbon atoms, such as, e.g., a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl or octyl radical or esterified with an acyl radical R
3′
—C(O)—, in which R
3′
is a hydrogen atom or a hydrocarbon radical with up to 8 carbon atoms or a phenyl radical.
Substituents R
11
can be a hydrogen atom, a halogen atom (F, Cl, Br, I) or a nitroxy group; a fluorine atom is preferred.
If R
11
stands for a hydrogen atom or if A and B together do not stand for —(CH
2
)
p
— or if A and D together do not stand for —(CH
2
)
q
—, the D-ring exhibits a substitution from the group 14,15-double bond, 14&agr;,15&agr;-methylene, 15&bgr;-methyl, 15,15-dimethyl, 15&bgr;,16&bgr;-methylene, 16&agr;- or 16&bgr;-halogen and of these especially 16&agr;-fluorine, 16-methylidene or 14&agr;,17&agr;-ethano. A 15&bgr;-methyl group or 16&agr;-fluorine atom preferably can be mentioned.
R
17′
can be in &agr;- or &bgr;-position.
In the case of a C
1-5
alkyl group, this is a methyl, ethyl, propyl, isopropyl butyl isobutyl, tert-butyl, pentyl isopentyl or neopentyl group. As a C
2-5
alkenyl group, for example, the vinyl or allyl radical can be mentioned. Typical representatives of a C
2-5
alkinyl group are the ethinyl and 1-propinyl radicals.
If R
17′
is in &agr;-position, especially a hydrogen atom, a methyl or trifluoromethyl group or an ethano bridge that is formed together with R
14
stands for this.
For R
17′
in &bgr;-position, primarily a hydrogen atom and a methyl group can be mentioned.
Especially those compounds of general formula I are preferred in which side chain SK is either a radical of partial formula —(CH
2
)
5
—N(CH
3
)—(CH
2
)
3
—SO
x
—(CH
2
)
3
—C
2
F
5
with x=0, 1 or 2 or —(CH
2
)
5
—N(A)—(CHB)—CH
2
—S—(CH
2
)
3
—C
2
F
5
with A+B=—(CH
2
)
3
—. In the latter case, the compounds preferably exhibit a 17&agr;-hydrogen atom.
Inorganic and organic acids, as they are known to one skilled in the art for forming physiologically compatible salts, are suitable for forming acid addition salts. As addition salts with acids, especially hydrochlorides and methanesulfonates can be mentioned.
The compounds below are especially preferred according to the invention:
14,17-Ethano-7&agr;- {5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)-propylamino]-pentyl}-estra- 1,3,5(10)-triene-3,17&bgr;-diol
14,17-ethano-7&agr;-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfinyl)-propylamino]-pentyl}-estra- 1,3,5(10)-triene-3,17&bgr;-diol
3,17&bgr;-diacetoxy-14&agr;,17&agr;-ethano-7&agr;- {5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)-propylamino]-pentyl}-estra-1,3,5(10)-triene
14,17-ethano-7&agr;-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfonyl)-propylamino]-pentyl}-estra-1,3,5(10)-triene-3,17&bgr;-diol
17&agr;-trifluoromethyl-7&agr;-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)-propylamino]-pentyl}-estra-1,3,5(10)-triene-3,17&bgr;-diol
15&bgr;,16&bgr;-methano-17&agr;-methyl-7&agr;-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)-propylamino]-pentyl}-estra-1,3,5(10)-triene-3,17&bgr;-diol
15&bgr;,16&bgr;-methano-17&agr;-methyl-7&agr;-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentane
Bittler Dieter
Bohlmann Rolf
Hegele-Hartung Christa
Heindl Josef
Heinrich Nikolaus
Dees Jose G
Millen White Zelano & Branigan
Pryor Alton
Schering Aktiengesellschaft
LandOfFree
7&agr;-(xi-aminoalkyl)-estratrienes, process for their... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 7&agr;-(xi-aminoalkyl)-estratrienes, process for their..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 7&agr;-(xi-aminoalkyl)-estratrienes, process for their... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2444810