Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-10-28
2004-03-02
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S237000
Reexamination Certificate
active
06699870
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to phthalazine compounds. More specifically, it relates to prophylactic and therapeutic agents for male erectile dysfunction, and prophylactic and therapeutic agents for female sexual dysfunction or dysmenorrhea.
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 ⅓ 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., 81, 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., 326, 90-94, 1992). However, none of the compounds employed in these studies can be satisfactorily employed clinically due to poor efficacy, etc.
An inhibitor of phosphodiesterase type V is also effective against female sexual dysfunction.
Phthalazine compounds having an inhibitory action on phosphodiesterase type V are disclosed in WO9605176 (JP-A 8-225541), but there is neither disclosure on Spiro compounds containing nitrogen atoms, or bicyclic and 6-memberred heterocyclic compounds thereof nor description on prevention and therapy for erectile dysfunction.
DISCLOSURE OF THE INVENTION
The present inventors have conducted various studies and consequently found that phthalazine compounds represented by the formula (I) show a high selectivity for phosphodiesterase type V which is an enzyme degrading cyclic GMP, and a potent inhibitory effect thereon, and exhibit a strong relaxing action on the penile cavernosum, with the increase in bioavailability and have high safety, thus completed the present invention.
The present invention relates to phthalazine compounds not specifically disclosed in JP-A 8-225541, to phthalazine compounds not suggested therein, and further to a process for producing some of the compounds.
It relates to a phthalazine compound represented by the formula (I), a pharmacologically acceptable salt thereof or a hydrate thereof:
wherein R
1
and R
2
are the same as or different from each other and represent a halogen atom, a C1 to C4 alkyl group which may be substituted with a halogen atom, a hydroxyl group, a C1 to C4 alkoxy group which may be substituted with a halogen atom or a cyano group;
X represents a cyano group, a nitro group, a halogen atom, a thiocarbamoyl group, a hydroxyimino group which may be substituted with a C1 to C4 alkyl group, an aryl C1 to C4 alkyl group or a carboxy C1 to C4 alkyl group, or a heteroaryl group which may be substituted with 1 to 3 substituent groups selected from the following substituent groups A;
Y represents:
i) a group represented by the formula (II):
wherein ring A represents a 4- to 8-memberred amine ring which may be substituted with a methyl group and may have a double bond; D represents a single bond or an oxygen atom; R
3
represents a hydrogen atom, a C1 to C4 alkyl group or a halogen atom; m represents an integer of 0 to 3; W represents an amino group, a hydroxyl group, a cyano group, a carboxyl group which may be protected, or a C1 to C4 alkoxy group;
ii) a group represented by the formula (III):
wherein ring B represents a 4- to 8-memberred amine ring which may have a double bond; and n and p are the same as or different from each other and represent an integer of 0 to 3;
iii) a group represented by the formula (IV):
wherein ring G represents a 4- to 8-memberred amine ring which may have a double bond, E represents a hydroxyl group, a halogen atom, a C1 to C4 alkyl group or a C1 to C4 alkoxy group, J is the formula —(CHR
4
)q-Q (wherein R
4
represents a hydrogen atom or a C1 to C4 alkyl group, Q represents a hydroxyl group, a halogen atom, a carboxyl group which may have a protective group, a carbamoyl group or an azolyl group not containing a heteroatom other than a nitrogen atom, q is an integer of 0 or 1 to 4), or E and J may form a 3- to 6-memberred ring together with the carbon atom to which they are bound, and the ring optionally having a heteroatom and optionally having a substituent group;
iv) a group represented by the formula (V):
wherein M represents a single bond or a C1 to C4 alkylene group which may be substituted with a hydroxyl group, carboxyl group, a C1 to C4 alkyl group or a C1 to C4 alkoxy group, ring K represents a 5- to 8-memberred amine ring formed together with M, and ring L represents a 5- to 8-memberred alkyl ring which may have a substituent group and may have an oxygen atom;
v) a group represented by the formula (VI):
wherein ring P represents a 5- to 7-memberred amine ring, and R
5
represents a hydrogen atom or a C1 to C4 alkyl group which may be substituted with a halogen atom, a hydroxyl group or a carboxyl group;
vi) an alkynyl group, an alkenyl group or an alkyl group all of which may have a substituent group;
vii) a phenyl group which may be substituted with 1 to 3 substituent groups selected from the following substituent group A; or
viii) a pyridyl group, a pyrimidyl group, a thienyl group, a thiazolyl group or a furyl group all of which may be substituted with 1 to 3 substituent groups selected from the following substituent group A;
(substituent group A) a C1 to C4 alkyl group which may be substituted with a halogen atom, a cyano group, a nitro group or a hydroxyl group; a C1 to C4 alkoxy group which may be substituted with a halogen atom, a cyano group, a nitro group or a hydroxyl group; a cyano group; a nitro group; a carboxyl group which may have a protective group; a hydroxyl group which may have a protective group; a carbamoyl group which may be substituted with a lower alkyl group; a halogen atom; and an amino group which may be substituted with a C1 to C4 acyl group, a C1 to C4 alkylsulfonyl group or an arylsulfonyl group which may have a substituent group;
l is an integer of 1 to 3;
provided that the following cases are excluded:
the case where l is 1 or 2, X is a cyano group, a nitro group or a chlorine atom, R
1
is a chlorine atom, R
2
is a methoxy group,
Adachi Hideyuki
Ishihara Hiroki
Kamada Atsushi
Kaneko Toshihiko
Karibe Norio
Bernhardt Emily
Birch & Stewart Kolasch & Birch, LLP
Eisai Co. Ltd.
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