Compounds and pharmaceutical compositions containing the same

Details Compounds and pharmaceutical compositions containing the same Compounds and pharmaceutical compositions containing the same

1999-06-04

2001-06-05

Shah, Mukund J. (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S252160, C514S258100, C544S118000, C544S262000

Reexamination Certificate

active

06242444

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel compounds, pharmaceutical compositions containing the same as well as a method for treatment of erectile dysfunction, wherein said compounds are administered.
BACKGROUND OF THE INVENTION
Erectile dysfunction is a disorder which is very common throughout the world. The recent introduction of sildenafil (the active ingredient in Viagra®) has improved the possibilities of treating this disorder significantly. Sildenafil and compounds closely related thereto are disclosed in EP 463 756, EP 702 555 and WO 98/49166 (all to Pfizer Ltd.).
However, despite the useful therapeutic properties of sildenafil, not all patients are successfully treated with this agent. Thus, there is still a great need in the art for compounds having improved therapeutic properties compared to sildenafil.
DISCLOSURE OF THE INVENTION
There are now provided novel compounds with surprisingly improved therapeutic efficiency in comparison with the prior art cited above. In summary, the present invention relates to a compound having the general formula (I):
wherein R
0
-R
6
are independently selected from at least one of a group of substituents (a)-(g) consisting of:
(a) H;
(b) straight chain, branched or cyclic saturated or unsaturated alkyl or hydroxyalkyl having 1-6 carbon atoms;
(c) O-alkyl, S-alkyl or N-(alkyl), where alkyl is as defined in (b) and n is 1 or 2;
(d) C(O)-alkyl, O—C(O)-alkyl, S—C(O)-alkyl or NH—C(O)-alkyl, where alkyl is as defined in (b);
(e) F, Cl or Br;
(f) O-aryl;
(g) NR
8
R
9
, wherein R
8
and R
9
independently is H or straight chain, branched or cyclic saturated or unsaturated alkyl, C(O)-alkyl, hydroxyalkyl or O-alkyl having 1-6 carbons atoms; wherein NR
8
R
9
optionally may form a five- or six-membered saturated or unsaturated ring;
wherein X
1
and X
2
are independently selected from a group of radicals consisting of:
—C
m
— independently substituted with the substituents (a)-(g), where m is an integer from 1 to 3 and the radical —C
m
— optionally may contain a double bond, ketone or thioketone functionality;
—O—;
—S—; and
—NR
10
—, where R
10
is H or straight chain, branched or cyclic saturated or unsaturated alkyl,
C(O)-alkyl, hydroxyalkyl or O-alkyl having 1-6 carbons atoms;
wherein Y is selected from a group of radicals consisting of:
—CR
11
═N—; —N═CR
12
—; —N═N—; —CR
13
═CR
14
—; —CR
15
R
16
CR
17
R
18
—;
—CR
19
R
20
O—; —OCR
21
R
22
—; —CR
22
R
23
NR
24
—; —NR
25
CR
26
R
27
— and
—NR
28
NR
29
—, where R
11
-R
29
are independently selected from the substituents (a)-(g);
wherein z taken together with the nitrogen atom to which it is attached forms a group selected from pyrrolidinyl, piperidinyl, morpholinyl, imidazolyl, pyridinyl, pyrrolyl and 4-N-(R
30
)-piperazinyl, whereby R
30
is selected from the substituents (a)-(g);
tautomers, solvates and radiolabelled derivatives thereof; and
pharmaceutically acceptable salts thereof.
As examples of pharmaceutically acceptable salts mention can be made of acid addition salts, e.g. a salt formed by reaction with hydrohalogen acids, such as hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, aliphatic, alicyclic, aromatic or heterocyclic sulphonic or carboxylic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, p-hydroxybenzoic acid, embonic acid, methanesulphonic acid, ethanesulphonic acid, hydroxyethanesulphonic acid, halogenbensensulphonic acid, toluenesulphonic acid and naphtalenesulphonic acid.
In a preferred embodiment of the present invention, Y is —CR
11
═N—. R
11
is preferably an n-propyl group.
Furthermore, it is preferred that Z taken together with the nitrogen atom to which it is attached forms a 4-N-(R
30
)-piperazinyl group. Preferably, R
30
is a methyl group.
Moreover, it is preferred that X
1
is —C
m
—. Preferably, m is 1. Most preferably, X
1
is —CH
2
—.
It is preferred that X
2
is —O—.
In a more preferred embodiment of the present invention, R
2
is H.
In an even more preferred embodiment, R
3
is a methyl group.
In a still even more preferred embodiment, R
4
, R
5
and R
6
are all H.
In the most preferred embodiment of the present invention, said compound is 5-[2,3-dihydro-5-(4-methylpiperazin-1-ylsulfonyl)-7-benzofuryl]-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one, the structure of which is depicted hereinbelow. This compound is hereinafter denoted 7a.
Furthermore, the present invention relates to a compound as set forth above for use as a pharmaceutical.
Accordingly, the present invention also relates to a pharmaceutical composition comprising a compound as set forth above as active ingredient in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
The pharmaceutical composition may be adapted for oral, intravenous, topical, intraperitoneal, nasal, buccal, sublingual or subcutaneous administration or for administration via the respiratory tract in the form of e.g. an aerosol or an air-suspended fine powder. Thus, the composition may be in the form of e.g. tablets, capsules, powders, micro-particles, granules, syrups, suspensions, solutions, transdermal patches or suppositories.
It should be noted that the composition according to the present invention may optionally include two or more of the above outlined compounds.
In addition, the present invention relates to a method for treatment of erectile dysfunction, wherein said method comprises administering to an animal, including human, patient of a therapeutically effective amount of a compound as outlined above.
Furthermore, it is also anticipated that the compounds according to the present invention have beneficial platelet anti-aggregatory, anti-vasospastic and vasodilatory activity. Thus, they should be useful in the treatment of a number of disorders, such as angina, hypertension, congestive heart failure, peripheral vascular disease, atherosclerosis, stroke, bronchitis, asthma, allergic rhinitis and glaucoma.
The typical dosage of the compounds according to the present invention varies within a wide range and will depend on various factors such as the individual requirement of each patient and the route of administration. The dosage is generally within the range of 0.01-100 mg/kg body weight.
The general synthetic pathway to formula (I) may be summarized as shown below (&Dgr;=heat):
Thus, the present invention also relates to a process for the preparation of a compound as set forth above, wherein a compound having the general formula (II) is reacted with a compound having the general formula (III), optionally in the presence of a solvent, wherein R
0
-R
6
and X-Z are as defined above.
The compound (II) is prepared by reacting a compound having the general formula (IV) with ClSO
3
H, optionally in the presence of a solvent.
The compound (IV) is prepared by heating a compound having the general formula (V) under basic conditions, optionally in the presence of a solvent.
The compound (V) is prepared by reacting a compound having the general formula (VI) with a compound having the general formula (VII), optionally in the presence of a solvent and a base.
As for the selection of e.g. suitable reaction and purification conditions, useful guidance is also provided by the following publications, which are incorporated herein by reference:
DeWald, H. A., Nordin, I. C., L'Italien, Y. J., Parcell, R. F.,
J. Med. Chem.,
16, 1346-1354 (1973);
Meyers, A. I., Reuman, M., Gabel., R. A.,
J. Org. Chem.,
46, 783-788 (1981);
Högberg, T., de Paulis, T., Johansson, L., Kumar, Y., Hall,. H., Ögren, S. O.,
J. Med. Chem.,
33, 2305-2309 (1990).
By guidance of known reference literature, the synthesis of the starting substances (VI) and (VII) is readily accomplished by a person skilled in the art.
The present invention is further illustrated by the following non-limiting experimental part.


REFERENCES:
patent: 0 911 333 A1 (1999-04-01), None
pa

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