Remedy for erection failure comprising fused pyridazine...

Details Remedy for erection failure comprising fused pyridazine... Remedy for erection failure comprising fused pyridazine...

1999-02-16

2001-09-11

Travers, Russell (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S252010, C514S253030, C514S234500

Reexamination Certificate

active

06288064

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Technical Field
The present invention relates to remedies for erectile dysfunction which contain as the active ingredient novel fused pyridazine compounds.
2. Prior Art
It is said that the number of latent patients with erectile dysfunction amounts to about 3,000,000 in Japan. In U.S.A., it is reported that the number of patients with erectile dysfunction reaches 20,000,000 and 15% of males in the fifties and about {fraction (1/3+L )} of those in the sixties suffer from this disease. In this aging society, sexual intercourse is regarded as a pleasant and emotional behavior. With the needs for the improved quality of life, it is anticipated that erectile dysfunction will raise not only a medical problem but also a social problem in future. This disease is classified into organic impotence caused by disorders in the nerves, blood vessels or muscles in the penis per se or sexual hormones and functional (psychic) impotence caused by mental or psychologic troubles. There are three factors necessary for erection, i.e., an increase in the penile arterial blood flow, the regulation of blood leakage from the penile veins, and the relaxation of the cavernous tissue. Erectile dysfunction arises when at least one of these conditions is inhibited.
The urological treatments for erectile dysfunction effected today involve drug therapy and operative penile prosthesis with the use of penile prosthetic appliances.
As the drug therapy, it is possible to inject papaverine hydrochloride or prostaglandin E1 into the penile cavernous tissue. However, this treatment is scarcely performed today, since it is not allowed in Japan that a patient gives an injection to himself and it is impossible in practice to go for a doctor every time he has coitus. In addition, the injection of papaverine hydrochloride would cause, though exceptionally, a painful symptom called priapism. Thus, the treatments with the existing drugs are not practically usable. Accordingly, it has been urgently desired to develop a drug therapy therefor which is clinically efficacious in practice.
In 1984, Bowman and Drummond reported that a selective cyclic GMP phosphodiesterase inhibitor M&B22948 (zaprinast) increased cyclic GMP in the tissue and relaxed the bovine retractor penis muscle (Cyclic GMP mediates neurogenic relaxation in the bovine retractor penis muscle, Br. J. Pharmacol., RI, 665-674, 1984). Subsequently, other workers have reported one after another the relaxation of the penis cavernosum by increasing cyclic GMP in the tissue (Int. J. Impotence Res., 4, 85-93, 1992; J. Urol., 147, 1650-1655, 1992; and N. Engl. J. Med., 32S, 90-94, 1992). However, none of the compounds employed in these studies can be satisfactorily employed clinically due to poor efficacy, etc.
DISCLOSURE OF THE INVENTION
Under these circumstances, the present inventors have conducted extensive studies and consequently found out that fused pyridazine compounds represented by the formula (I), which are disclosed in WO96/05176 show a high selectivity for phosphodiesterase type v which is an enzyme capable of degrading cyclic GMP and a potent inhibitory effect, thus completing the present invention:
(wherein the ring C represents an unsaturated 5 or 6 membered ring optionally having hetero atom(s); n is 0 or an integer of from 1 to 4; R
1
represents a halogen, an optionally substituted lower alkyl, an optionally substituted lower alkoxy, an optionally substituted cycloalkyl, a nitro, a cyano, a group represented by the formula —NR
2
R
3
(wherein R
2
and R
3
are the same as or different from each other and represent a hydrogen, an optionally substituted lower alkyl, an acyl, an optionally substituted arylalkyl or an optionally substituted heteroarylalkyl, or R
2
and R
3
together with the nitrogen atom to which they are bonded may form a ring, and the ring may be substituted), a group represented by the formula —O—R
9
(wherein R
9
represents a hydrogen, an optionally substituted lower alkyl, an acyl, an optionally substituted arylalkyl or an optionally substituted heteroarylalkyl), a group represented by the formula —S—R
10
(wherein R
10
represents a hydrogen, an optionally substituted lower alkyl, an acyl, an optionally substituted arylalkyl, or an optionally substituted heteroarylalkyl), a group represented by the formula;
(wherein R
11
represents a hydrogen, a lower alkyl or an amino; and m is 0 or an integer of 1 or 2) or an optionally protected carboxy, provided that when n is 2 to 4, then R
1
s may independently represent the above substituents;
A represents a hydrogen, a halogen, a group represented by the formula —NR
4
R
5
(wherein R
4
and R
5
are the same as or different from each other and represent a hydrogen, an optionally substituted lower alkyl, an acyl, an optionally substituted arylalkyl or an optionally substituted heteroarylalkyl, or R
4
and R
5
together with the nitrogen atom to which they are bonded may form a ring, and the ring may be substituted), an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted arylalkyl or an optionally substituted heteroarylalkyl;
X represents a group represented by the formula —NR
6
— (wherein R
6
represents a hydrogen, an optionally substituted lower alkyl, an optionally substituted arylalkyl or an optionally substituted heteroarylalkyl) or a group represented by the formula —N═;
Y represents a group represented by the formula —CO— or —C(B)═ [wherein B represents a hydrogen, a halogen, a group represented by the formula —NR
7
R
8
(wherein R
7
and R
8
are the same as or different from each other and represent a hydrogen, an optionally substituted lower alkyl, an acyl, an optionally substituted arylalkyl or an optionally substituted heteroarylalkyl, or R
7
and R
8
together with the nitrogen atom to which they are bonded may form a ring, and the ring may be substituted), a group represented by the formula —O—R
12
(wherein R
12
represents a hydrogen, an optionally substituted lower alkyl, an acyl, an optionally substituted arylalkyl or an optionally substituted heteroarylalkyl), —S—R
13
(wherein R
13
represents a hydrogen, an optionally substituted lower alkyl, an acyl, an optionally substituted arylalkyl or an optionally substituted heteroarylalkyl), an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted arylalkyl or an optionally substituted heteroarylalkyl]; and
represents a double or single bond; provided that when the ring C is a benzene ring, then the case where n is 0 is excluded}.
In addition to the remedies (1) as described above, the present invention further provides: (2) remedies for female sexual dysfunction, dysmenorrhea or premature birth comprising as the active ingredient the above fused pyridazine compounds or pharmacologically acceptable salts thereof; (3) medicinal compositions comprising a therapeutically effective dose of the above fused pyridazine compounds or pharmacologically acceptable salts thereof and pharmacologically acceptable carriers; (4) a method for treating erectile dysfunction, female sexual dysfunction, dysmenorrhea or premature birth which comprises administering a therapeutically effective dose of the above fused pyridazine compounds or pharmacologically acceptable salts thereof to a patient with erectile dysfunction, female sexual dysfunction or dysmenorrhea or a patient giving premature birth; and (5) use of the above fused pyridazine compounds or pharmacologically acceptable salts thereof for producing remedies for erectile dysfunction, female sexual dysfunction, dysmenorrhea or premature birth.
In the definition given herein, as the unsaturated 5 or 6 membered ring optionally having hetero atom(s) represented by the ring C, benzene, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, imidazole, pyrazole, thiophene and furan rings may be proposed.
In the definition represented by the above formula (I), the lower alkyl in the “optionally substituted lower alkyl” as used in the definition of R
1
, R
1a
, R
1b

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