Steroid esters and amides, process for their production and...

Details Steroid esters and amides, process for their production and... Steroid esters and amides, process for their production and...

1997-08-19

2003-07-22

Badio, Barbara P. (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

C514S176000, C552S510000, C540S047000

Reexamination Certificate

active

06596713

ABSTRACT:

The invention relates to steroid esters and amides, . . . as well as their use as adjuvants for pharmacological studies and as pharmaceutical substances.
The invention relates to steroid esters and amides of formula I
in which
R
1
means a C
1
-C
3
alkyl radical in &agr;- or &bgr;-position,
Sk means —C≡C—(CH
2
)
r
—R
2
, (E) or (Z)—CH═CH—(CH
2
)
r
—R
2
, —(CH
2
)
2
—(CH
2
)
r
—R
2
,
r means 1, 2 or 3,
R
2
means —O—(X
i
1
—X
i
2
—X
i
3
— . . . —X
i
p
)—R
5
, —C(═O)—(Y
i
1
—Y
1
2
—Y
i
3
— . . . —Y
i
p
)—OR
5
, —OC(═O)R
3
, —NHC(═O)R
3
,
R
3
means —L—R
4
,
L means an n-membered, straight- or branched-chain alkylene group,
n, if St stands for an ABC-ring system of partial formula B, R
1
stands for a methyl group in &agr;-position, Sk stands for a radical of formula —(CH
2
)
3
—O—C(═O)—L—R
4
and R
4
stands for a hydrogen atom, n means an integer from 11 to 20; if St stands for an ABC-ring system of partial formula B, R
1
stands for a C
1
-C
2
alkyl radical in &bgr;position, Sk stands for a radical of formula —CH═CH—CH
2
—O—C(═O)—L—R
4
and R
4
stands for a hydrogen atom, n means an integer from 9 to 20; and in all other cases in which St stands for B, R
2
stands for —OC(═O)R
3
and R
4
stands for a hydrogen atom, n means an integer from 5 to 20, or if St stands for an ABC-ring system of partial formula A, Sk stands for a radical of formula (E) or (Z)—CH═CH—(CH
2
)
r
—O—C(═O)—L—R
4
and R
4
stands for a hydrogen atom, n means an integer from 5 to 20; if St stands for an ABC-ring system of partial formula A, Sk stands for a radical of formula —(CH
2
)
2
—(CH
2
)
r
—O—C(═O)—L—R
4
and R
4
stands for a hydrogen atom, n means an integer from 11 to 20 or if St stands for an ABC-ring system of partial formula C, R
2
stands for —OC(═O)R
3
and R
4
stands for a hydrogen atom, n means an integer from 5 to 20; and in all other cases, n means an integer from 2 to 20,
p means an integer from 1 to 6,
R
4
means hydrogen, —O—(X
1
1
—X
i
2
—X
i
3
— . . . —X
i
p
)—R
5
, —C(═O)—(Y
i
1
—Y
i
2
—Y
i
3
— . . . —Y
i
p
)—OR
5
, —OR
5
, a C
3
-C
10
cycloalkyl radical, —C(═O)R
5a
,
R
5
means hydrogen, a C
1
-C
10
alkyl radical,
R
5a
means hydrogen, a C
1
-C
10
alkyl radical, a C
1
-C
10
alkoxy radical,
X
i
1 . . . p
are the same or different and mean —[—C(O)—W—NH—]—═X, and X as HO—X—H is an &agr;-, &bgr;- or &ggr;-amino acid that is linked on its C-terminal end,
Y
i
1 . . . p
are the same or different and mean —[—NH—W—C(O)—]—═Y, and Y as H—Y—OH is an &agr;-, &bgr;- or &ggr;-amino acid that is linked on its N-terminal end,
St represents one of the steroidal ABC-ring systems of partial formula A, B or C
R
6
means hydrogen, C
1
-C
4
alkyl, halogen,
R
7
means hydrogen, C
1
-C
4
alkyl, halogen, and further an additional bond can be contained between carbon atoms 6 and 7 of ring systems A, B and C,
R
8
means a group Z or an aryl radical optionally substituted several times by a group Z,
Z means hydrogen, halogen, —OH, —NO
2
, —N
3
, —CN, —NR
9a
R
9b
, —NHSO
2
R
9
, —CO
2
R
9
, C
1
-C
10
alkyl, C
1
-C
10
alkoxy, C
1
-C
10
acyloxy, C
1
-C
10
acyl,
R
9a,b
are the same or different and have one of the meanings mentioned under R
9
,
R
9
means hydrogen or C
1
-C
10
alkyl and, if R
9
is hydrogen, further their physiologically compatible salts with bases (Z=—CO
2
H) or acids (Z=—NR
9a
R
9b
)
The wavy lines that start from carbon atom 17 on the two substituents OH and Sk (side chain) mean that the respective substituent OH or Sk can be present both in &agr;-position and &bgr;-position.
As alkyl groups R
5
, R
5a
, R
6
, R
7
, R
8
and R
9
, straight-chain or branched-chain alkyl groups with 1-10 carbon atoms can be considered, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl as well as the appropriate unsaturated radicals (up to 3 double bonds), such as, for example, vinyl, propenyl, isopropenyl, butenyl, isobutenyl, butadienyl, hexenyl, etc.
Alkyl group R
1
is a straight-chain or branched-chain alkyl group with 1-3 carbon atoms, namely a methyl, ethyl, propyl or isopropyl group.
Alkyl groups R
5
, R
5a
, R
6
, R
7
, R
8
and R
9
can be substituted by 1-3 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, heteroaryl radicals, such as furyl, benzofuryl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, further di-(C
1
-C
4
)-alkylamine and tri-(C
1
-C
4
)-alkylammonium. Possible alkyl groups are those mentioned above; those alkyl groups that are not substituted or are singly substituted are preferred. As substituents, there can be mentioned, for example, halogens, such as fluorine, chlorine or bromine atoms, phenyl, dialkylamines, such as dimethylamino, diethylamino, C
1
-C
4
alkoxy, such as methoxy, ethoxy. The C
6
-C
12
aryl groups can also be substituted by the halogen atoms fluorine, chlorine or bromine.
As preferred alkyl group R
1
, a methyl group can be cited, and as preferred alkyl groups R
5
, R
5a
, R
6
, R
7
, R
8
and R
9
, those with 1-5 carbon atoms, such as, e.g., methyl, ethyl, propyl, isobutyl, butyl, tert-butyl can be mentioned.
Cycloalkyl groups R
4
can contain 3-10, preferably 3-6 carbon atoms in the ring. Ring R
4a
can be substituted by straight-chain or branched alkyl groups with 1-4 carbon atoms. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopentyl, methylcyclohexyl can be mentioned.
Of side chains Sk that have the characteristic functional group R
2
, all lead to good results, but in particular an esterified {overscore (&ohgr;)}-hydroxyprop-1-enyl and but-1-enyl chain as well as an esterified 3-hydroxypropyl chain are to be emphasized.
For radical R
2
, one of groups —O—(X
i
1
—X
i
2
—X
i
3
— . . . —X
i
p
), —C(═O)—(Y
i
1
—Y
i
2
—Y
i
3
— . . . —Y
i
p
) or —OC(═O)R
3
is preferred.
p preferably has the value 1, i.e., side chain Sk is then terminally esterified preferably with an amino acid or the carboxylic acid amide represents an amino acid.
The alkoxy groups that are contained in R
5a
, R
8
or Z in general formula I are to contain 1 to 10 carbon atoms in each case, and methoxy, ethoxy, propoxy, isopropoxy and t-butyloxy groups are preferred.
In the C
1
-C
10
acyl or C
1
-C
10
acyloxy radical under definition Z, this is a C
1
-C
10
alkanoyl(oxy) or benzoyl(oxy) radical, preferably a formyl, acetyl, propionyl or isopropionyl group.
Preferably one of the 17-substitutents in the compounds according to this invention stands for a free hydroxy group, as is evident from general formula I. It is also possible within the scope of this invention, however, that this free hydroxy group is etherified with one of the radicals mentioned under the definition of alkyl groups R5, R
5a
, R
6
, R
7
, R
8
and R
9
or is esterified with a C
1
-C
10
acyl radical as mentioned under Z.
In the definitions for R
6
, R
7
and Z, halogen means fluorine, chlorine, bromine or iodine.
If R
8
is a group Z, this is preferably a dialkylamino group —NR
9a
R
9b
, especially the dimethylamino group, a C
1
-C
10
alkoxy group, especially the methoxy group or a C
1
-C
10
acyl radical, in particular the formyl or acetyl radical.
As an aryl radical R
8
that is optionally substituted with a group Z, carbocyclic or heterocyclic aryl radicals, such as, e.g., phenyl, naphthyl, furyl, benzofuryl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, are suitable.
Preferred aryl radicals are phenyl, naphthyl, furyl, benzofuryl, thienyl, pyridyl; as substituted aryl radical R
8
, first of all the 4-cyanophenyl radical and a 4-halophenyl radical, especially the 4-fluorophenyl radical, can be cited.
In compounds that are preferred according to the invention, substituents R
6
and R
7
respectively stand for a hydrogen atom.
A C—C single bond is preferably present between carbon atoms 6 and 7.
Amino acids HO—X—H or H—Y—OH c

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