Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
1999-11-08
2001-04-03
Dentz, Bernard (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S468000, C549S462000, C558S480000, C558S482000, C558S483000, C558S484000
Reexamination Certificate
active
06211233
ABSTRACT:
The present invention relates to drugs to be used in male impotence.
In particular it relates to drugs which are used at lower but equally effective doses than those commonly used for the treatment of said therapy, and combined with fewer side effects, in particular as far as the absence of hypotension and algogenic activity is concerned.
It is well known in the art that the available therapies for treating male impotence are based on different approaches depending on the aetiology.
In the case of impotence due to endocrine causes treatment with testosterone is used.
In the case of impotence due to vascular alterations, or following from some neurological alterations, it is used an intracavernous injection of vasoactive compounds made by the patient himself before sexual intercourse. This method of administration allows a local pharmacological activity and reduces to a minimum any interference with the other vascular areas of the body which could lead to severe side effects including vasodilation and hypotension. The drugs more frequently used with said method include the association papaverine-phentolamine and Prostaglandin E
1
(PGE
1
). This is a useful approach from the therapeutic point of view, but it has the disadvantage to presenting side effects. In fact, papaverine induces local fibrosis, prolonged erections and hepatic alterations; Prostaglandin E
1
induces pain in 20% of cases and prolonged erections in 1-2% of cases. PGE
1
is anyhow at the moment the drug most used for this type of therapy.
Besides clinical drug treatments, are well known in the art the use of prostheses and mechanical devices.
At the present time, the available drugs solve the problem only in a limited number of cases. Research is being made on the basis of various hypothesis. However, the drugs which have been proposed up to now are less active than prostaglandin-based drugs.
It was felt the need to have drugs as effective in the treatment of impotence as least as those based on prostaglandin but without presenting the side effects possessed by said known drugs as described above.
It has been surprisingly and unexpectedly found a class of drugs as herein below defined which has an improved activity than prostaglandin and the advantage of being used at lower doses with less side effects, in particular it does not cause any hypotension or algogenic activity.
It is an object of the invention the compounds, or their compositions having the general formula
A—X
1
—NO
2
(I)
for use as medicaments, in particular as drugs for the treatment of impotence, wherein:
A=R(CR
a
R
b
O)
u
(COX)
t
(II)
wherein:
t and u are integers and are equal to 0 or 1;
X=O, NH, NR
1c
wherein R
1c
is a linear or branched alkyl having from 1 to 10 carbon atoms;
R
a
and R
b
, equal or different from each other, are H, C
1
-C
3
alkyl;
R is a radical having the following formula:
where m
0
is an integer and can have a value of 0 or 1;
where the meaning of the various substituents of formula III is as follows:
when t=1, u=0 and m
0
=1;
R
1
=H; an alkyl having from 1 to 6 carbon atoms, preferably from 1 to 3, or a free valence;
R
2
=OH; O— such as to form with R
1
, when R
1
is a free valence, and with the carbon atom at position 15, a group C═O,
R
3
, R
4
, equal or different one from the other, are equal to R
1
, or one of them is a bond O—, and the other is a free valence so that with the carbon atom C
4
they form a group C═O;
R
5
, R
6
, equal or different one from the other, are equal to R
1
, in particular when both R
5
and R
3
are each a free valence, R
5
and R
3
form a double bond between C
5
and C
6
;
R
7
, R
8
, R
9
, R
10
, equal or different one from the other, have the same meaning of R
1
; when R
7
or R
9
, and at the same time R
8
or R
10
are each a free valence, there is a double bond between C
13
and C
14
;
R
11
=R
1
;
R
12
=R
11
or OH;
R
13
, R
14
, R
15
, R
16
, equal or different one from the other, are equal to R
1
; when R
13
or R
15
, and at the same time R
14
or R
16
, are each a free valence, there is a double bond between C
1
and C
2
;
R
17
, R
18
, equal or different one from the other, are equal to R
1
;
R
19
, R
20
, equal or different one from the other, are equal to R
1
; when R
6
or R
5
is a free valence, and at the same time R
19
or R
20
is a free valence, there is a double bond between C
4
and C
5
;
R
21
, R
22
, R
23
, R
24
, equal or different one from the other, are equal to R
1
;
R
25
, R
26
, equal or different one from the other, are equal to R
1
, but both R
25
and R
26
cannot be a free valence;
R
27
is a linear or whenever possible branched alkyl having from one to six carbon atoms;
B is equal to the group O═ (a keto group with the carbon atom at position 9 of the prostaglandin molecule), OH or —O—;
when no aliphatic chain C
7
-C
2
is found attached at position 8, in its place there is the alkylaromatic residue:
wich is bound to formula (III) (B=—O—) in the following way:
wherein m
1
is an integer from 1 to 6, preferably from 1 to 3;
R
a
and R
b
, equal or different from each other, are as above defined;
when t=0, u=1 and m
0
=1 the meanings of the various substituents are as above defined;
when t=0, u=0 and m
0
=0 the meanings of the various substituents are as above defined and
C
16
is bound, optionally by a bridging group —O—, to an aromatic radical or an alkyl-aril radical, where the aryl can be substituted, preferably with halogens, preferably with Cl, F; said aryl radical can also contain heteroatoms, such as O, N; the alkyl of the alkyl-aril radical is an aliphatic chain from 1 to 3 carbon atoms, preferably —CH
2
—;
X
1
of formula A—X
1
—NO
2
is a bivalent connecting bridge, chosen from the following:
—Y
Y is a linear or whenever possible branched C1-C20 alkylene oxygen terminated, preferably having from 2 to 5 carbon atoms or is a C5-C7 cycloalkylene oxygen terminated optionally substituted;
where n
3
is an integer from 0 to 3;
where nf′ is an integer from 1 to 6, preferably from 2 to 4;
where R
1f
=H, CH
3
and nf is an integer from 1 to 6, preferably from 2 to 4.
When in formula (II) t=1 u=0 and in formula (III) m
0
=1, the preferred prostaglandin residues R are the following:
when B is O═ (keto group with C
9
); R
7
, R
8
, R
9
and R
10
are such as to give a double bond between C
13
and C
14
; R
2
is OH; R
27
is CH
3
; the substituents of the carbon atoms of the C
2
-C
7
and C
16
-C
19
aliphatic chains are H; R thus defined is known as the residue of Prostaglandin E
1
;
or, by putting in the formula of Prostaglandin E
1
R
2
=CH
3
and R
3
, R
4
, R
5
, R
6
such as to give a double bond between C
5
and C
6
;
R thus defined it is known as the residue of Arbaprostil;
or, by putting in the formula of Arbaprostil R
7
=R
9
=R
9
=R
10
=H; R
1
and R
2
are such as to form the group C═O with C
15
; B is OH; R
27
=C
3
H
7
, R thus defined it is known as the residue of Unoprostone;
or, by putting in the formula of Arbaprostil R
11
=R
12
=CH
3
;
R
1
=H, R thus defined it is known as the residue of Trimoprostil;
or, when in the formula of Arbaprostil B is OH; R
1
=H; R thus defined it is known as the residue of Prostaglandin F
2&agr;
;
or, when in the formula of Prostaglandin R
2&agr;
B is O═ (keto group with C
9
), R thus defined it is known as the residue of Prostaglandin E
2
;
or, when in the formula of Arbaprostil B is OH; R thus defined it is known as the residue of Carboprost;
or, by putting in the formula of Arbaprostil R
1
=H; R
17
=H; R
19
=CH
3
; R
3
=R
4
=R
5
=R
6
=H; R
27
=C
2
H
5
; R
13
=R
16
=H and R
14
=R
15
being free valences such as to form a double bond between C2 and C3; R thus defined it is known as the residue of Limaprost;
or, by putting in the formula of Trimoprostil R
Arent Fox Kintner Plotkin & Kahn
Dentz Bernard
Nicox S.A.
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