MXPA01005701A - Remedial agent for erectile dysfunction - Google Patents

Abstract

An erectile dysfunction remedy which comprises as the active ingredient a 3(2H)-pyridazinone derivative represented by formula (I) or a pharmacologically acceptable salt thereof, wherein the symbols each is the same as defined in the description.

Description

AGENT FOR THE TREATMENT OF ERECTILE DYSFUNCTION TECHNICAL FIELD The present invention relates to the use of a 3 (2H) -pyridazinone derivative having pharmaceutical activity for the treatment of erectile dysfunction.

TECHNICAL BACKGROUND In Unexamined Japanese Patent Publication No. Sho 63-301870 (U.S. Patent No. 4,978,665, European Patent No. 275997B), Japanese Patent Publication No. Hei 7-107055 (U.S. Patent No. 5,314,883, European Patent No. 482208B) and Japanese Unexamined Patent Publication No. Hei 7-252237 (U.S. Patent No. 5,750,523, European Patent No. 742211 A), preventive or therapeutic applications of the 3 (2H) -pyridazinone derivative of the compound have been described. of the present invention as an inhibitor of platelet aggregation, cardiotonic drug, vasodilator or anti-SRS-A (substances of slow reaction to anaphylaxis), for the prevention or treatment of various thrombotic diseases, ischemic diseases, hypertension, asthma or diseases immediate allergic, etc., but there is no suggestion or mention of the potential for application to the treatment of erectile dysfunction.

In addition, it has also been mentioned that the 3 (2H) -pyridazinone derivative of the compound of the present invention also has phosphodiesterase III (PDE III) inhibitory activity and phosphodiesterase V (PDE V) inhibitory activity in platelets (Jpn. Pharmacol., Vol 67 Supl. I, p 270 (1995)). However, there is no mention of the inhibitory activity on these enzymes in the corpus cavernosum. On the other hand, it has been reported that specific inhibitors of PDE III or specific inhibitors of PDE V are effective as therapeutic agents for the treatment of erectile dysfunction (Int. J. Impotence Res., Vol. 4 Suppl 2, p. (1992), J. Urol., Vol. 152, pp. 2159-2163 (1994), J. Urol., Vol. 159, pp. 1390-1393 (1998), etc.). However, there is no suggestion or mention of the case of the concomitant use of specific PDE III inhibitors and specific PDE V inhibitors, or of drugs having PDE III inhibitory activity and PDE V inhibitory activity. The inventors of the present invention unexpectedly found that the compound according to the present invention is useful in the treatment of erectile dysfunction, and that its usefulness improves comparatively with the prior art treatment methods, thereby leading to the completion of the present invention. Erectile dysfunction is caused by aging, stress or diseases such as diabetes and hyperlipidemia, and is a disease characterized by the inability to achieve or sustain an adequate erection for sexual intercourse. Its morbidity rate is increasing annually and, for example, it is estimated that there are 20 million men suffering from erectile dysfunction in the United States alone. There are several methods for the treatment of erectile dysfunction, and drug therapy is one of their established treatment methods. For example, a method is used in which prostaglandin E1 is administered intracavernously or intraurethrally. In the case of intracavernous injection, although the treatment is quick acting and has excellent efficacy, it is accompanied by pain in the penis and persistent penile rigidity. In addition, although intraurethral administration resolves the problems associated with intracavernous injection, it implies a reduction in efficacy. In addition, these treatment methods have serious problems in terms of being expensive and implying problems of convenience. In addition, although specific inhibitors are expected to PDE III typically represented by milrinone are capable of being used as therapeutic agents for erectile dysfunction, they have the problem of being difficult to dissociate them from adverse side effects on the circulatory system, such as the heart and blood vessels. In addition, although the PDE V inhibitors typically represented by zaprinast and sildenafil are effective against organic erectile dysfunction, they have the problem of being ineffective against erectile dysfunction psychogenic In addition, sildenafil has been reported to be associated with adverse side effects such as visual disturbances. Considering the present circumstances described above, there is a need for a drug that has superior safety and efficacy to be used as an agent for the treatment of erectile dysfunction. In this way, the aim of the present invention is to provide a superior agent for the treatment of erectile dysfunction.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an agent for the treatment of erectile dysfunction comprising a derivative of 3 (2H) -pyridazinone represented by the formula (I): wherein R1 represents a hydrogen atom, an alkyl group of C? -, a C3-4 alkenyl group or (CH2) nCO2R5, n represents an integer from 1 to 4, and R5 represents a hydrogen atom or an alkyl group of C? -; R represents a hydrogen atom or an alkyl group of C? -4; R3 and R4 each independently represent a hydrogen atom or a C1-3 alkyl group; A represents a single bond or a straight or branched C1-11 alkylene group in which a carbon atom in the straight chain can be substituted by an OR2 group (R2 has the same meaning as described above); X represents a chlorine atom, a bromine atom, a hydrogen atom or a cyano group; And it represents any of the subsections (1) to (13) below: (1) C02R5 (R5 has the same meaning as described above), (2) a cyano group, (3) OR6 (R6 represents a hydrogen atom, a C1-4 alkyl group or a phenyl group), (4) a thienyl group, (5) a pyridyl group, / R? (6) -CON R8 wherein R7 and R8 each independently represent a hydrogen atom, an alkyl group of C ?. ) a C3.8 cycloalkyl group, a phenyl group, a thiazolyl group or a thiadiazolyl group; or R7 and R8 combine with each other to form a straight or branched C2-s alkylene group which can be substituted by a C1-3 alkyl group or a phenyl group, or form a morpholine ring with the nitrogen atom; (7) - N-S02R9 wherein R5 has the same meaning as described above; and R9 represents a hydrogen atom, an alkyl group of C -? - 4 or a phenyl group which can be substituted by a halogen atom; wherein R10 and R11 each independently represent a hydrogen atom, a halogen atom, a C1-4 alkyl group, an acylamino group of C-, OR5 (R5 has the same meaning as described above), NHSO2R9 (R9 has the same meaning as described above) or S (0) m-R12 (wherein m is an integer from 0 to 2, and R12 represents an alkyl group of C1.4); wherein R 13 represents a hydrogen atom; R 14 represents a phenyl group; or R13 and R14 combine with each other to form an alkylene group of C2-8 which can be substituted by a straight C1-3 alkyl group; wherein R15 represents a hydrogen atom or a C1-4 alkyl group; R16 represents a C1-4 alkyl group; or R15 and R16 combine with each other to form an alkylene group of C2-β which can be substituted by a straight C1-3 alkyl group; (1 1) - N R18 wherein R17 and R18 each independently represent a group C- alkyl; OR R17 and R18 combine with each other to form an alkylene group of C2-8 which can be substituted by a straight C1.3 alkyl group; wherein p is 1 or 2, k is an integer from 0 to 3, and R19 represents a hydrogen atom or a halogen atom, or Ar represents any of subsections (1) to (5) below: wherein j is 0 or 1, R20 represents a hydrogen atom, a halogen atom or OR 2 (R12 has the same meaning as described above), (2) Z? wherein Z1 represents an oxygen atom or a sulfur atom, wherein R > 21 represents a hydrogen atom or OR (R has the same meaning as described above), wherein Z2 and Z3 each independently represent a hydrogen atom, a halogen atom, a C1-4 alkyl group, OR22 (R22 represents a hydrogen atom or an alkyl group of Ci-s), 0-A1-Y1 (A1 represents a straight or branched C1-8 alkylene group, and Y1 represents a C1-4 alkyl group or a phenyl group, which can be substituted by a halogen atom), C02R5 (R5 has the same meaning as described above) ), or R7 -CON RB wherein R7 and R8 have the same meanings described above, or wherein W forms a C1-8 alkylene group which can be substituted by a straight C1-3 alkyl group, or a pharmaceutically acceptable salt thereof as the active ingredient.

The pyridazinone compound (I) according to the present invention exhibits a potent cavernous body relaxing action and potent action that elevates intracavernosal pressure, and can be used as an agent for the treatment of erectile dysfunction. The compound (I) of piradizinone is effective for the treatment of erectile dysfunction as a result of having PDE III inhibitory activity and PDE V inhibitory activity, and demonstrates considerably improved efficacy comparatively with prior art therapeutic agents. In addition, it is a superior agent for the treatment of erectile dysfunction by being able to reduce the adverse side effects caused by excessive blood pressure, decreasing the effects attributable to PDE V inhibitors, as well as by reducing the effects on the heart observed with the PDE III inhibitors.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a diagram showing the effects of compound A on the internal pressure, duration and AUC of the penis in anesthetized dogs. Figure 2 is a diagram showing the effects that result from the concomitant use of milrinone and zaprinast on the internal pressure, duration and AUC of the penis in anesthetized dogs.

BEST WAY TO CARRY OUT THE INVENTION In the following, substituents are explained in the compound of formula (I) above with respect to the present invention, ie, R1, R2, R3, R4, X, Y, A and Ar. Specific examples of R1 may include a hydrogen atom; a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an -butyl group, a sec-butyl group, a t-butyl group; a 2-propenyl group, a 2-methyl-2-propenyl group; a carboxymethyl group, a 2-carboxyethyl group, a 3-carboxypropyl group, a 4-carboxybutyl group, a methoxycarbonylmethyl group, a 2-methoxycarbonylethyl group, a 3-methoxycarbonylpropyl group, a 4-methoxycarbonylbutyl group, an ethoxycarbonylmethyl group, a 2-ethoxycarbonylethyl group, a 3-ethoxycarbonylpropyl group, a 4-ethoxycarbonylbutyl group, an n-propoxycarbonylmethyl group, an i-propoxycarbonylmethyl group, a 2-n-propoxycarbonylethyl group, a 2-i-propoxycarbonylethyl group, a 3- group n-propoxycarbonylpropyl, a 3-i-propoxycarbonylpropyl group, a 4-n-propoxycarbonylbutyl group, a 4-i-propoxycarbonylbutyl group, a n-butoxycarbonylmethyl group, an i-butoxycarbonylmethyl group, a sec-butoxycarbonylmethyl group, a t- group butoxycarbonylmethyl, a 2-n-butoxycarbonylmethyl group, a 2-i-butoxycarbonylethyl group, a 2-sec-butoxycarbonylethyl group, a 2-t-butoxycarbonylethyl group, a 3-n-butoxycarbonylpropyl group, a 3-i-butoxycarbonylpropyl group, a 3-s group ec butoxycarbonylpropyl, a 3-i-butoxycarbonylpropyl group, a 4-n-butoxycarbonylbutyl group, a 4-i-butoxycarbonylbutyl group, a 4-sec-butoxycarbonylbutyl group, a 4-t-butoxycarbonylbutyl group, etc., preferably an hydrogen, an ethyl group and a -propyl group, more preferably a hydrogen atom. R 2 can include a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group and a t-group butyl, more preferably a hydrogen atom and a methyl group. Specific examples of R3 and R4 may include a hydrogen atom, a methyl group, an ethyl group, an n-propyl group and an i-propyl group, preferably a hydrogen atom. A represents a single bond or a straight or branched Ci-n alkylene group in which a carbon atom in a straight chain can be substituted by a hydroxyl group or a C1-4 alkoxy group, and specifically includes a single bond; methylene, hydroxymethylene, methoxymethylene, ethoxymethylene, propoxymethylene, butoxymethylene, ethylene, 1-hydroxyethylene, 2-hydroxyethylene, 1-methoxyethylene, 2-methoxyethylene, 1-ethoxyethylene, 2-ethoxyethylene, 1-propoxyethylene, 2-propoxyethylene, 1- butoxyethylene, 2-butoxyethylene, propylene, 1-hydroxypropylene, 2-hydroxypropylene, 3-hydroxypropylene, 1-methoxypropylene, 2-methoxypropylene, 3-methoxypropylene, 1-ethoxypropylene, 2-ethoxypropylene, 3-ethoxypropylene, 1-propoxypropylene, 2- propoxypropylene, 3-propoxypropylene, 1-butoxypropylene, 2-butoxypropylene, 3-butoxypropylene, butylene, 1- hydroxybutylene, 2-hydroxybutylene, 3-hydroxybutylene, 4-hydroxybutylene, 1-methoxybutylene, 2-methoxybutylene, 3-methoxybutylene, 4-methoxybutylene, 1-ethoxybutylene, 2-ethoxybutylene, 3-ethoxybutylene, 4-ethoxybutylene, 1-propoxybutylene, 2-propoxybutylene, 3-propoxybutylene, 4-propoxybutylene, 1-butoxybutylene, 2-butoxybutylene, 3-butoxybutylene, 4-butoxybutylene, pentylene, 1-hydroxypentylene, 2-hydroxypentylene, 3-hydroxypentylene, 4-hydroxypentylene, 5-hydroxypentylene, 6-hydroxypentylene, 6-hydroxyhexylene, heptylene, 7-hydroxyheptylene, octylene, 8-hydroxyoctylene, nonylene, 9-hydroxyinonylene, decanylene, 10-hydroxydecanylene, undecanylene, 11-hydroxyundecanylene, hydroxymethylmethylene, ethyl-hydroxymethylene, hydroxypropylmethylene, methoxy- methylmethylene, methylmethylene, ethylmethylene, propylmethylene, dimethylmethylene, diethylmethylene, dipropylmethylene, ethylmethylmethylene, methylpropylmethylene, 1-hydroxy-1-methylethylene, 1-ethyl-1-hydroxyethylene, 1-hydroxy-1-propyletylene, -metoxy-1-metile thylene, 1-hydroxy-2-methylethylene, 2-ethyl-1-hydroxy-ethylene, 1-hydroxy-2,2-dimethylethylene, 2,2-diethyl-1-hydroxy-ethylene, 1-methoxy-2,2-dimethylethylene, 2-hydroxy-1-methylethylene, 1-ethyl-2-hydroxyethylene, 2-hydroxy-1,1-dimethylethylene, 1,1-diethyl-2-hydroxyethylene, 2-methoxy-1,1-dimethylethylene, 1-methyl- ethylene, 1,1-dimethylethylene, 1,1-diethylethylene, 2-methylethylene, 2,2-dimethylethylene, 1,2-dimethylethylene, 2,2-diethylethylene, 1,1, 2,2-tetramethylethylene, 1-hydroxy -1-methylenepropylene, 1-methoxy-1-methylpropylene, 1-hydroxy-2-methylpropylene, 1-methoxy-2-methylpropylene, 1-hydroxy-3-methylpropylene, 1-methoxy-3-methylpropylene, 1-hydroxy -2,2-dimethylpropylene, 1-methoxy-2,2-dimethylpropylene, 2,2-diethyl-1-hydroxypropylene, 1-hydroxy-3,3-dimethylpropylene, 1-methoxy-3,3-dimethylpropylene, 3,3 -diethyl-1-hydroxypropylene, 1- hydroxy-2,2,3,3-tetramethylpropylene, 2-hydroxy-1-methylpropylene, 2-methoxy-1-methylpropylene, 2-hydroxy-2-methylpropylene, 2-methoxy-2-methylpropylene , 2-hydroxy-3-methylpropylene, 2-methoxy-3-methylpropylene, 2-hydroxy-1,1-dimethylpropylene, 2-methoxy-1,1-dimethylpropylene, 1,1-diethyl-2-hydroxyl Propylene, 2-hydroxy-3,3-dimethylpropylene, 2-methoxy-3,3-dimethylpropylene, 3,3-diethyl-2-hydroxypropylene, 2-hydroxy-1,1, 3,3-tetramethylpropylene, 3- hydroxy-1-methylpropylene, 3-methoxy-1-methylpropylene, 3-hydroxy-2-methylpropylene, 3-methoxy-2-methylpropylene, 3-hydroxy-3-methylpropylene, 3-methoxy-3-methylpropylene, 3 -hydroxy-1,1-dimethylpropylene, 3-methoxy-1,1-dimethylpropylene, 1,1-diethyl-3-hydroxypropylene, 3-hydroxy-2,2-dimethylpropylene, 3-methoxy-2,2-dimethylpropylene, 2 , 2-diethyl-3-hydroxypropylene, 3-hydroxy-3-methylpropylene, 3-hydroxy-1,1, 2,2-tetramethylpropylene, 1-methylpropylene, 1-ethylpropylene, 1-propylpropylene, 2-methylpropylene, 2-ethylpropylene , 2-propylpropylene, 3-methylpropylene, 3-et ilpropylene, 3-propylpropylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 3,3-dimethylpropylene, 1,1-diethylpropylene, 2,2-diethylpropylene, 3,3-diethylpropylene, 1,1-dipropylpropylene, 2, 2-dipropylpropylene, 3,3-dipropylpropylene, 2,2-dimethyl-1-hydroxybutylene, 2,2-dimethyl-1-methoxybutylene, 3,3-dimethyl-1-hydroxybutylene, 3,3-dimethyl-1-methoxybutylene, 4,4-dimethyl-1-hydroxybutylene, 4,4-dimethyl-1-methoxybutylene, 1,1-dimethyl-2-hydroxybutylene, 1,1-dimethyl-2-methoxybutylene, 3,3-dimethyl-2-hydroxybutylene, 3,3-dimethyl-2-methoxybutylene, 4,4-dimethyl-2-hydroxybutylene, 4,4-dimethyl-2-methoxybutylene, 1,1-dimethyl-3-hydroxybutylene, 1,1-dimethyl-3- methoxybutylene, 2,2-dimethyl-3-hydroxybutylene, 2,2-dimethyl-3-methoxybutylene, 4,4-dimethyl-3-hydroxybutylene, 4,4-dimethyl-3-methoxybutylene, 1,1-dimethyl-4- hydroxybutylene, 1,1-dimethyl-4-methoxybutylene, 2,2-dimethyl-4-hydroxybutylene, 2,2-dimethyl-4-methoxybutylene, 3,3-dimethyl-4-hydroxybutylene, 3,3-dimethyl- 4-methoxybutylene, 5,5-dimethylpentylene, 6,6-dimethylhexylene, 7,7-dimethylheptylene, 8,8-dimethyloctylene, etc., preferably an alkylene group of C 1-5 and a? -dialkyl- or? -hydroxy group -alkylene in the carbon chain thereof. Specific examples of Y may include a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an i-propoxycarbonyl group, an n-butoxycarbonyl group, an i-butoxycarbonyl group, a sec-butoxycarbonyl group, a group t-butoxycarbonyl; a 2-thienyl group, a 3-thienyl group, a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group; a cyano group; a hydroxyl group, a methoxy group, an ethoxy group, an n-propoxy group, a -propoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, a t-butoxy group; a phenoxy group; a carbamoyl group, an N-methylaminocarbonyl group, an N-ethyl-aminocarbonyl group, a N-propylaminocarbonyl group, a Ni-propylaminocarbonyl group, a N-butylaminocarbonyl group, a Ni-butylaminocarbonyl group, an N-sec-butylaminocarbonyl group, an Nt-butylaminocarbonyl group; an N-cyclopropylaminocarbonyl group, a N-cyclobutylaminocarbonyl group, a N-cyclopentylaminocarbonyl group, a N-cyclohexylaminocarbonyl group, a N-cycloheptylaminocarbonyl group, a cyclooctylaminocarbonyl group; an N-phenylaminocarbonyl group, an N-2-thiazolylaminocarbonyl group, a N-4-thiazolylaminocarbonyl group, a N-5-thiazolylaminocarbonyl group, a N-2-thiadiazolylaminocarbonyl group, a N-5-thiadiazolylaminocarbonyl group, a group 1 aziridinocarbonilo group, a 1-azetidinocarbonilo, a 1-pyrrolidinocarbonyl group, a 1-piperidinocarbonyl a homopiperidinocarbonilo group, a 1- (2,5-dimethyl) pyrrolidinocarbonyl, a 1- (2,6-dimethyl) piperidinocarbonyl, a 1- (3-phenyl) pyrrolidinocarbonyl group, a group, 1- (4-phenyl) piperidinocarbonyl, a 1-morpholinocarbonyl group, an N-methyl-sulfonylamino group, an N-ethyl-sulfonylamino group, an N-propyl group alkylsulfonylamino group, a Ni-propyl-sulfonylamino, Nn-butyl-sulfonylamino group, a sulfonylamino Ni-butyl group, a sec-butyl-N-sulfonylamino group, a sulfonylamino Nt-butyl group, an N-phenyl group -sulfonylamino, a phenylsulfonylamino group, in which an ortho position, a meta position or a para position on the benzene ring is substituted by a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a t-butyl group, a fluorine atom, a chlorine atom, a t-butyl group as bromine or an iodine atom; a phenyl group or a mono- or di-substituted phenyl group, in which an arbitrary position on the benzene ring is independently substituted by 1 or 2 substituents selected from a methyl group, an ethyl group, an n-propyl group, a i-propyl group, an n-butyl group, a -butyl group, a sec-butyl group, a t-butyl group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an formylamino group, an acetylamino group, a propionylamino group, a butyrylamino group, a methylsulfonylamino group, an ethylsulfonylamino group, a n-propylsulfonylamino group, an i-propylsulfonylamino group, a n-butylsulfonylamino group, an i-butylsulfonylamino group, a sec - butylsulphonylamino, a t-butyl-sulfonylamino group, a phenylsulfonylamino group, a hydroxyl group, a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, a n-butoxy group, a group i- butoxy, a sec-butoxy group, a t-butoxy group, a methylthio group, an ethylthio group, an n-propylthio group, an i-propylthio group, an n-butylthio group, an i-butylthio group, a sec- butylthio, t-butylthio group, one methylsulfoxy group, an ethylsulfoxy group, a n-propilsulfoxi group, an i-propilsulfox¡, an n-butylsulfoxy group, an i-butylsulfoxy, a sec-butylsulfoxy group, a t -butilsulfoxi, a methylsulfonyl group, an ethylsulfonyl group, a n-propylsulfonyl group, an i-propylsulfonyl, n-butylsulfonyl group, an i-butylsulfonyl, sec-butiisulfonilo group and t-butylsulfonyl group; a benzoylamino group, a 1- (2-oxo) azetidinyl group, a 1- (2-oxo) pyrrolidinyl group, a 1- (2-oxo) piperidinyl group, a 1- (2-oxo) homopiperidinyl group, a group 1- (2-Oxo-3,3-dimethyl) -pyrrolidinyl, a 1- (2-oxo-4,4-dimethyl) pyrrolidinyl group a 1- (2-oxo-5,5-dimethyl) pyrrolidinyl group, a N-methoxycarbonylamino, N-ethoxycarbonylamino group, a-propoxycarbonylamino Ni, one-butoxycarbonylamino Ni, un-sec-butoxycarbonylamino group N Nn-butoxycarbonylamino group, an Nt-butoxycarbonylamino group Nn-propoxycarbonylamino group, a 3- (2-Oxo) oxazolidinyl group, a 3- (2-oxo-5,5-dimethyl) oxazolidinyl group, a 3- (2-oxo-4,4-diethyl) oxazolidinyl group, a 3- (2-group -oxo-5,5-diethyl) oxazolidinyl; a N, N-dialkyl substituted amino group in which a methyl group, an ethyl group, an n-propyl group, a -propyl group, an n-butyl group, an -butyl group, a sec-butyl group and a t-butyl group are substituted in a combination arbitrary a 1-azetidino group, a 1-pyrrolidino group, a 1-piperidino group, a 1- (2,5-dimethyl) pyrrolidino group, a 1- (3,4-dimethyl) pyrrolidino group, a 1- group (4,4-dimethyl) piperidino, a 1- (4-benzyl) piperazino group, a 1- (4-diphenylmethyl) piperazino group, a 1- (4-substituted benzylpiperazinyl) group or a 1- (phenylmethylpiperazinyl) group 4-disubstituted), in which an ortho position, a meta position or a position in the benzene ring is replaced by a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; a phenylaminocarbonyloxy group, or a N, N-disubstituted aminocarbonyl group, in which the N-substituted aminocarbonyl groups explained above are substituted by a cyclic or chain alkyl group, a phenyl group, a thiazolyl group or a thiadiazolyl group in a combination arbitrary or an N-alkyl-alkylsulfonylamino group, an N-alkyl-phenylsulfonylamino group, or an N-alkyl-alkoxycarbonylamino group, in which the nitrogen atom of the alkylsulfonylamino group, the phenylsulfonylamino group or the alkoxycarbonylamino group explained above, is further substituted by a straight or branched C1-4 alkyl group. Specific examples of X may include a hydrogen atom, a chlorine atom, a bromine atom and a cyano group, preferably a chlorine atom, a bromine atom and a cyano group. Specific examples of Ar may include a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a substituted 2-pyridyl group, a 3-pyridyl group or a 4-pyridyl group in which the 2- position, 3-, 4-, 5- or 6 in the pyridine ring is replaced by a fluorine atom, a chlorine atom, an atom of bromine, an iodine atom, a methoxy group, an ethoxy group, an n-propoxy group, a -propoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group or a t-butoxy group; a group in which the pyridyl group or the substituted pyridyl group explained above is replaced by an N-oxidopyridyl group, a 2-furyl group, a 3-furyl group, a 2-thienyl group, a 3-thienyl group, a group 1-naphthyl or a 2-naphthyl group; a 1-naphthyl group or a 2-naphthyl group in which an arbitrary position in the naphthalene ring is replaced by a hydroxyl group, a methoxy group, an ethoxy group, a n-propoxy group, an i-propoxy group, a n-butoxy group, an i-butoxy group, a sec-butoxy group or a t-butoxy group; and a phenyl group substituted by the following 1 or 2 substituents in an arbitrary position and arbitrary combination. Specific examples of the substituent may include a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethyl group, an n-propyl group, an i-propyl group , a n-butyl group, an i-butyl group, a sec-butyl group, a t-butyl group, a hydroxyl group, a straight or branched Ci-β alkoxy group; a methylenedioxy group, an ethylenedioxy group or a propylenedioxy group, in which two adjacent substituents are combined with each other; or a group 0-A1-Y1. Here, A1 represents an alkylene group of straight or branched Ci-β, and Y1 represents a phenyl group, a substituted phenyl group in which an ortho position, a meta position or a para position on the benzene ring is replaced by a group methyl, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an -butyl group, a sec-butyl group, a t-butyl group, a fluorine atom, an chlorine, a bromine atom or an iodine atom; a carboxyl group, an alkoxycarbonyl group, a 1-cyclic aminocarbonyl group, a 1-morpholinocarbonyl group explained in the Y item; a carbamoyl group, in which two substituents selected from a hydrogen atom, a straight, branched or cyclic alkyl group, a phenyl group, a thiazolyl group and a thiadiazolyl group are attached to a nitrogen atom in an arbitrary combination, a group N-substituted or N, N-disubstituted aminocarbonyl. Among them, the preferred groups may include a 3-pyridyl group and one of the 3-substituted 4-methoxyphenyl type, but the present invention is not limited to these specific examples. In the above explanation, n means normal, i means iso, sec means secondary and t means tertiary. The preferred compounds represented by the formula (I) for use in the present invention may include the following compounds. (1) An agent for the treatment of erectile dysfunction represented by formula (I), wherein R 1 is a hydrogen atom, X is a chlorine atom or a bromine atom, and R 3 and R 4 are both hydrogen atoms . (2) The agent for the treatment of erectile dysfunction described in subsection (1) above, wherein Ar is a pyridyl group, an N-oxypyridyl group or a phenyl group represented by the formula: wherein Z2 and Z3 each independently represent a hydrogen atom, a halogen atom, a C1-4 alkyl group or OR22 (R22 represents a hydrogen atom or an alkyl group of C-i-β). (3) The agent for the treatment of erectile dysfunction described in any of items (1) to (2) above, wherein Y is a carbamoyl group represented by the formula: / R7 -CON wherein R7 and R8 each independently represent a hydrogen atom, a C1-4 alkyl group, a C3-cycloalkyl group or a phenyl group, or R7 and R8 combine with each other to form an alkylene group of C2-8 which may be substituted by a C1-3 alkyl group or a phenyl group to form a morpholine ring with a nitrogen atom; or a phenyl group represented by the formula: wherein R10 and R11 each independently represent a hydrogen atom, a halogen atom, a C1-4 alkyl group, a C1-4 acylamino group, OR5 (R5 represents a hydrogen atom or a C1- alkyl group) 4), NHS02R9 (R9 represents a hydrogen atom or a phenyl group which can be substituted by an alkyl group of C? -4 or a halogen) or S (0) m-R12 (m is an integer from 0 to 2 and R12 represents a C1-4 alkyl group). (4) The agent for the treatment of erectile dysfunction described in any of items (1) to (3) above, wherein Ar is a pyridyl group, an N-oxypyridyl group or a phenyl group which can be substituted by OR22 (R22 represents a C1-4 alkyl group). (5) The agent for the treatment of erectile dysfunction described in any of items (1) to (4) above, wherein A is a straight or branched C1-8 alkylene group, wherein the carbon atom in the Straight chain can be substituted by a hydroxyl group (-OH). (6) The agent for the treatment of erectile dysfunction described in any of items (1) to (5) above, wherein Y is a phenyl group represented by the formula: wherein R10 and R11 each independently represent a hydrogen atom, a halogen atom, a C1-4 alkyl group, a C1-4 acylamino group, OR5 (R5 represents a hydrogen atom or a C1- alkyl group) 4), NHSO2R9 (R9 represents a hydrogen atom, a C1- alkyl group or a phenyl group which can be substituted by a halogen atom) or S (0) m-R12 (m is an integer from 0 to 2 , and R12 represents a C1-4 alkyl group). (7) The agent for the treatment of erectile dysfunction described in subsection (6) above, wherein Y is a phenyl group which can be substituted by a halogen atom. (8) The agent for the treatment of erectile dysfunction described in any of items (4) to (7) above, wherein Ar is a 3-pyridyl group. (9) The agent for the treatment of erectile dysfunction described in formula (I), wherein the compound represented by formula (I) is 4-bromo-6- [3- (4-chlorophenyl) propoxy] -5 - (3-pyridylmethylamino) -3 (2H) -pyridazinone or 4-bromo-6- [3- (4-chlorophenyl) -3-hydroxypropoxy] -5- (3-pyridylmethyl) -3 ( 2H) -pyridazinone. Stereoisomers and optical isomers are also included in the compound (I) of pyridazinone and its pharmacologically acceptable salt of the present invention. The compound (I) of pyridazinone and its pharmacologically acceptable salt are known compounds, and these compounds can be produced in accordance with the methods described, for example, in Unexamined Japanese Patent Publication No. Sho 63-301870 (US Pat. No. 4,978,665, European Patent No. 275997B), Japanese Patent Publication No. Hei 7-107055 (US Patent No. 5,314,883, European Patent No. 482208B) and Japanese Unexamined Patent Publication No. Hei 7-252237 (Patent No. 5,750,523, European Patent No. 742211 A).

The derivative (I) of pyridazinone and its pharmacologically acceptable salt of the present invention have superior treatment effects on erectile dysfunction in mammals such as men, dogs, cows, horses, rabbits, mice and rats. The dose of the derivative (I) of pyridazinone or its pharmacologically acceptable salt according to the present invention can be suitably selected according to the patient's age and body weight and the degree of the symptoms, and the dose for adult humans is usually from 0.001 mg to 5 g per day, and preferably from 0.005 to 1000 mg per day administered thereto from one to several times per day. Examples of administration forms of the derivative (I) of pyridazinone or a pharmacologically acceptable salt thereof according to the present invention, include forms of parenteral administration such as injections (subcutaneous, intravenous, intramuscular and intraperitoneal injections), ointments, suppositories and aerosols , as well as oral administration forms such as tablets, capsules, granules, pills, powders, troches, chewable preparations, syrups, liquids, emulsions and suspensions. Oral administration is preferred. The compound according to the present invention is formulated for administration by routine means for preparation. Tablets, capsules, granules, pills, powders, troches and chewable preparations for oral administration can be prepared by routine means using a vehicle (eg, sucrose, lactose, glucose, starch or mannitol), binder (eg, syrup, gum arabic, gelatin, sorbitol, tragacanth, methylcellulose or polyvinylpyrrolidone), disintegrating agent (eg, starch, carboxymethyl cellulose or its calcium salt, microcrystalline cellulose or polyethylene glycol), lubricant (eg, talc, magnesium stearate, calcium stearate or silica), homogenizing agent (eg, sodium laurate or glycerin), etc. In addition, injections, aerosols, syrups, liquids, emulsions, suspensions, etc., are prepared by routine means using a solvent (eg, water, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycol or polyethylene glycol) of the ingredient active, surfactant (for example, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene ester of hydrogenated castor oil or lecithin), suspending agent (for example, carboxymethyl sodium, cellulose derivatives such as methyl cellulose, or natural rubbers such as tragacanth or gum arabic), preservative (for example, an ester of paraoxybenzoic acid, benzalkonium chloride or sorbates), etc. Suppositories are produced by routine methods using, for example, cocoa butter, polyethylene glycol, lanolin, fatty acid triglycerides, coconut oil, etc. White petrolatum, liquid paraffin, higher alcohols, macrogol ointment, hydrophilic ointment, aqueous gel base, etc., are used for ointments used as preparations that are absorbed through the skin.

EXAMPLES AND EXPERIMENTAL EXAMPLES The present invention will be described in detail by the following examples and experimental examples, but in no way is the present invention limited thereto. Compounds A (4-bromo-6- [3- (4-chlorophenyl) propoxy] -5- (3-pyridylmethylamino) -3 (2H) -pyridazinone hydrochloride) and compound B (hydrochloride 4) were used as reagents. -bromo-6- [3- (4-chlorophenyl) -3-hydroxy-propoxy] -5- (3-pyridylmethylamino) -3 (2H) -pyridazinone) produced in accordance with the conventional manner. Commercially available products were used for the other reagents.

EXPERIMENTAL EXAMPLE 1 Activity on intracavernous pressure by intracavernous injection to anesthetized dogs Male penny dogs having body weights of approximately 10 kg were anesthetized by intravenous administration of pentobarital sodium at 35 mg / kg, followed by immobilization of the animals in the dorsal position on a heating mat (SMS-2000 J, Medical System Inc .), and inserting a cannula into the trachea. A 23G winged needle to measure internal pressure was inserted into the right cavernous body of the penis, and the intracavernous pressure was measured with a amplifier for blood pressure measurement (AP-641G, Nihon Koden) by means of a pressure transducer (Statham P-50, Gould Co.). In addition, a 23G winged needle for drug administration was inserted into the right cavernous body of the penis, followed by intracavemosal injection of sodium ferrocyanide (SNP, 10"4 or 10" 3 moles / I, 0.5 ml), followed by the administration of drug in the stage, and an increase in intracavernosal pressure was confirmed. It should be noted that compound A and milrinone were prepared with dimethyl sulfoxide-ethanol-physiological saline solution (1: 2: 30). Zaprinast was used after dissolution in 1 mol / l of aqueous solution of sodium hydroxide and adjusting the pH to the vicinity of 9.5 with 1 mol / l of hydrochloric acid. The activity of compound A was evaluated directly by administration at a volume of 0.5 ml starting from the lowest dose level at 0.243, 0.729, 2.43, 7.29, 24.3 and 72.9 μg / body (10"6, 3 x 10 -6, 10"5, 3 x 10-5, 10-4 and 3 x 10-4 moles / l). The effect of milrinone and zaprinast was evaluated by concomitant administration of milrinone at 106 μg / body (10'3 moles / l) and zaprinast at 136 μg / body (10"3 moles / l) using a dose volume of 0.5 ml The intratravenous pressure was fed into a polygraph (RM-6000, Nihon Koden), and together recording continuously in a thermal pen recorder, it was recorded and sampled in an external storage device (hard disk) of a computer (Macintosh Performa 5260, Apple) using a circulation kinetics analysis system (MP100WS, BIOPAC System) using a circulation kinetics analysis program (MP? AS 3 Ver. 1.0 beta 4.2, Physio-Tech Co., Ltd.). The maximum rate of change, duration and area under the curve (AUC) of the intracavernosal pressure were calculated using the circulation kinetics analysis program based on the obtained data. The resulting values were expressed as the mean ± standard error (S.E.), and subjected to the statistical processing indicated below. The effect of compound A was tested in accordance with Dunnett's method using the solvent group as a control. The concomitant effect of milrinone and zaprinast was analyzed by bidirectional analysis of variance. One level of p < 0.05 was considered statistically significant in all tests. The results are shown in figures 1 and 2. i) Direct effect on intracavernosal pressure Compound A increased the intracavernosal pressure in a dose-dependent manner from 0.243 to 72.9 μg / body (10.6 to 3 x 10.4 mol / l). Significant effects were observed with respect to to the duration and maximum speed of change to 2.43 μg / body (10"5 moles / l) and higher values. As a result, similar effects were also observed for AUC (Fig. 1).

It should be noted that in Figure 1, the asterisks (*) indicate the presence of a significant difference at p < 0.05, as a result of performing the Dunnett test using the solvent group as a control. In addition, in Figure 1, the double asterisks (**) indicate the presence of a significant difference at p < 0.01 as a result of performing the Dunnett test using the solvent group as a control.

I) Effect of concomitant administration of milrinone and zaprinast Concomitant administration of milrinone at 106 μg / body (10"3 moles / l) and zaprinast at 136 μg / body (10" 3 moles / l) markedly increased the intracavemose pressure compared to the administration of the drug alone, and significant synergistic effects were observed with respect to duration and AUC ( Fig. 2). It should be noted that in Figure 2, double asterisks (**) indicate the presence of a significant difference at p < 0.01 as a result of administering milrinone or zaprinast alone and performing a bidirectional analysis of variance.

EXPERIMENTAL EXAMPLE 2 Relaxation on norepinephrine-induced contraction in the corpus cavernosum isolated from rabbits The rabbits were sacrificed by phlebotomy after separating the carotid artery under anesthesia with sodium pentobarbital. The penis was immediately isolated and transferred in Krebs-Henseleit solution (composition (mmol / l): NaCl 118.4, KCl 4.7, CaCl2 2.5, MgSO4 1.2, KH2P04 1.2, NaHCO3 25.0, glucose 11.1), which was adequately ventilated with 95 % of 02/5% of CO2 After separating the connective tissue, the penis was separated longitudinally into two sections, so that half of the urethra was present in each section using an extension of the midline as the limit. Each preparation was suspended from a FD sensor device (TB-611T, Nihon Koden) at a resting voltage of 0.5 g (approximately 5 mN) for loading into a nutrient solution consisting of 20 ml of organ bath maintained at room temperature. 37 ° C. The contraction was recorded as the isometric contraction in a thermal pen writing record apparatus (WT-685G, Nihon Koden) after amplification by a vehicle amplifier (AP-621 G, Nihon Koden). After replacing the nutrient solution twice every 20 minutes and allowing it to equilibrate, the radioactivity was confirmed for each preparation by observing the contraction up to 1 μmol / l of norepinephrine. After the contraction stabilized, the preparation was washed replacing the nutrient solution, after which the solution was additionally replaced twice every 20 minutes, and acceptable to balance. To begin with, each preparation was contracted by norepinephrine (final concentration: 1 μmol / l). The preparation for which the stable station was obtained at this time was used in the experiment. Each drug was cumulatively administered in 10-fold ratios, followed by observation of the reaction. The maximum relaxation reaction was determined by the application of papaverine hydrochloride final concentration: 100 μmol / l). The rate of inhibition at each concentration was calculated considering the tension during the addition of norepinephrine to represent a rate of inhibition of 0%, and the tension during the maximum relaxation reaction induced by the addition of papaverine hydrochloride to represent a rate of inhibition. of 100%, followed by the calculation of the concentration value at which the inhibition rate was 50% (IC5o). The results are shown in tables 1 and 2. i) Direct relaxation on the norepinephrine-induced contraction in the isolated cavernous body of rabbits All drugs demonstrated dose-dependent relaxation action. The IC50 values of each compound were as shown in the following table. The action of compound A was the most potent.

TABLE 1 IC50 (Emoles / I) Compound A 0.33 Compound B 1.59 Milrinone 5.8 Zaprinast 5.5 I) Relaxation on norepinephrine-induced contraction in the corpus cavernosum isolated from rabbits in the presence of SNP and N-omega-nitro-L-arginine methyl ester (L-NAME) The action of compound A increased approximately twice by pretreatment with SNP (1 nmol / l), and decreased approximately half by pretreatment with L-NAME (1 mmol / l). On the other hand, the action of zaprinast was attenuated to 1/18 or less by pre-treatment with L-NAME (1 mmol / l).

TABLE 2 IC50 (μmoles / l) Compound A 0.33 Compound A + SNP 0.15 Compound A + L-NAME 0.77 Zaprinast 5.5 Zaprinast + L-NAME > 100 EXPERIMENTAL EXAMPLE 3 Relaxation on norepinephrine-induced contraction in thoracic aorta isolated from rabbits The procedure was carried out in the same manner as Experimental Example 2, except that the thoracic aorta was isolated and prepared in the form of a spinal strip, and using 1 g (approximately 10 mN) of resting tension for loading. The results are shown in tables 3 and 4. i) Direct relaxation on norepinephrine-induced contraction in thoracic aorta isolated from rabbits Compound A exhibited relaxation action dependent on the dose, and its IC5o value was 2.65 μmoles / l. When compared with the action on the corpus cavernosum in experimental example 2, the action on the cavernous body was approximately 8 times more powerful than that on the aorta.

TABLE 3 IC50 (Emoles / I) Aorta 2.65 Corpora cavernoso 0.33 (I) Relaxation on norepinephrine-induced contraction in thoracic aorta isolated from rabbits in the presence of SNP The action of compound A was not affected by pretreatment with SNP (1 nmol / l), and results were obtained that differed from the action on the corpus cavernosum in experimental example 2.

TABLE 4 IC50 (Emoles / I) Corpora cavernosa Aorta Compound A 0.33 2.65 Compound A + SNP 0.15 2.71 EXPERIMENTAL EXAMPLE 4 Action on isolated cardiac muscle of guinea pigs After sacrificing male Hartley guinea pigs by phlebotomy, the heart was isolated and transferred to Krebs-Henseleit solution, and adequately ventilated with 95% 02/5% C02. After rapidly separating the heart in the atria and ventricles, a papillary muscle preparation was obtained from the right ventricle and the right atrium. Each preparation was suspended from an FD sensor device (TB-611T, Nihon Koden) at a resting voltage of 0.5 g (approximately 5 mN) for loading into a nutrient solution consisting of an organ bath maintained at 31 ° C. The automatic contraction of the right atrium was amplified by a vehicle amplifier (AP-600G, Nihon Koden) followed by voltage recording, and the number of beats was recorded by an instantaneous heart rate counter (AT600G, Nihon Koden). For the papillary muscle, a rectangular-wave electric stimulus was applied by an electrical stimulator (SEN-3201, Nihon Koden) through bipolar platinum electrodes, followed by amplification of the resulting voltage by means of a vehicle amplifier (AP-600G, Nihon Koden), and registration in a recording device. The right atrial preparations were balanced by replacing the nutrient solution twice every 20 minutes, followed by confirmation of the reactivity of each preparation by observing the number of beats in the presence of 0.1 μmol / l of isoproterenol. Once the number of beats had stabilized, the preparations were washed by replacing the nutrient solution, and additionally balanced by replacing the nutrient solution twice every 20 minutes. Each drug was administered cumulatively, followed by observation of the reaction. The action of the drug was evaluated by determining the rate of change caused by the drug by taking the difference between the maximum reaction induced by isoproterenol and that before drug administration as 100%, and then calculating the EC30 value as the concentration at which the action of the drug was 30% with respect to the number of beats based on this rate of change. The papillary muscle preparations were balanced by replacing the nutrient solution twice every 20 minutes, followed by the cumulative administration of isoproterenol (final concentration: 0.03 μmol / l) and observation of the strength of concentration to confirm the reactivity of each preparation. After repeating the same procedure again, the preparations were further balanced by replacing the nutrient solution twice every 20 minutes. Each drug was administered cumulatively, followed by observation of the reaction. The action of the drug was evaluated by determining the rate of change caused by the drug by taking the difference between the maximal reaction induced by the second administration of so soproterenol and that before administration of the drug as 100%, and then calculating the EC30 value as the concentration at which the action of the drug was 30% with respect to the contraction force based on this rate of change. The results are shown in table 5. i) Action on cardiac muscle isolated from guinea pigs Compound A did not increase the heart rate or contraction force up to 30% or more at concentrations up to 30 μmoles / l. On the other hand, the values of EC30 with respect to the number of beats and force of Contraction of milrinone were 11.7 μmol / l and 33.9 μmol / l, respectively, and the effects on the heart were observed. When compared to the action on the corpus cavernosum in experimental example 2, in contrast to the action of milrinone on the heart being about half the action on the corpus cavernosum, the action of compound A on the heart was less than 1/90 than the action on the corpus cavernosum.

TABLE 5 EC30 (Emoles / I) Heart rate Coronary contraction force Compound A > 30 > 30 Milrinona 11.7 33.9 The following findings were determined based on the previous experimental results. Since the pyridazinone compound (I) according to the present invention increased intracavernosal pressure during intracavernosal injection to anesthetized dogs, and exhibited relaxation on the cavernous body isolated in rabbits, it was suggested that it is effective for the treatment of erectile dysfunction. . Synergistic effects resulting from the concomitant use of the PDE III inhibitor, milrinone, and the PED inhibitor V, zaprinast, were observed in anesthetized dogs. Based on this finding, the suggestion was made Possibility that the inhibitory activity on PDE III and PDE V is involved in the potent action of the compound (I) of pyridazinone according to the present invention, which causes an increase in the intracavernosal pressure. In addition, it was also clearly demonstrated that concomitant therapy with PDE III and PDE V inhibitors results in a considerable improvement in efficacy. Since the pyridazinone compound (I) according to the present invention is less susceptible to the effect of the nitrogen monoxide synthesis inhibitor, L-NAME, than the PDE inhibitor V, zaprinast, the possibility was also suggested that It is effective for psychogenic dysfunction for which PDE V inhibitors are minimally effective. Although the action of the compound (I) of pyridazinone according to the present invention is enhanced in the corpus cavernosum during concomitant use with the nitrogen monoxide donor, SNP, which has the ability to activate the guanylate cyclase, since it does not intensified effects are observed in the aorta, it was suggested that it is able to alleviate the adverse side effects attributable to the excessive decrease in blood pressure associated with the PDE V inhibitors. It was observed that the compound (I) of pyridazinone from In accordance with the present invention, it has hardly any effect on the heart, and effects on the heart such as Increased heart rate and contraction force, as seen with PDE III inhibitors.

INDUSTRIAL APPLICATION The pyridazinone compound (I) according to the present invention has PDE III and PDE V inhibitory activity, is useful as a therapeutic agent for erectile dysfunction, and has improved utility in comparison with the prior art therapeutic methods.

Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1. - An agent for the treatment of erectile dysfunction, characterized in that it comprises a derivative of 3 (2H) -pyridazinone represented by the formula (I): wherein R1 represents a hydrogen atom, a C1-4 alkyl group, a C3-4 alkenyl group or (CH2) nC? 2R5, n represents an integer from 1 to 4, and R5 represents a hydrogen atom or a C1-4 alkyl group; R 2 represents a hydrogen atom or a C 1-4 alkyl group; R3 and R4 each independently represent a hydrogen atom or an alkyl group of C1.3; A represents a single bond or a straight or branched Ci-n alkylene group in which a carbon atom in the straight chain can be substituted by an OR2 group (R2 has the same meaning as described above); X represents a chlorine atom, a bromine atom, a hydrogen atom or a cyano group; And it represents any of the items (1) to (13) below: (1) CO2R5 (R5 has the same meaning as described above), (2) a group cyano, (3) OR6 (R6 represents a hydrogen atom, an alkyl group of C- or a phenyl group), (4) a thienyl group, (5) a pyridyl group, wherein R7 and R8 each independently represent a hydrogen atom, an alkyl group of C-, a C3-8 cycloalkyl group. a phenyl group, a thiazolyl group or a thiadiazolyl group; or R7 and R8 combine with each other to form a straight or branched C2-s alkylene group which can be substituted by an alkyl group of C-? -3 or a phenyl group, or form a morpholine ring with the nitrogen, wherein R5 has the same meaning as described above; and R9 represents a hydrogen atom, a C1-4 alkyl group or a phenyl group which can be substituted by a halogen atom; wherein R10 and R11 each independently represent a hydrogen atom, a halogen atom, a C1-4 alkyl group, a C1-4 acylamino group, OR5 (R5 has the same meaning as described above), NHSO2R9 (R9 has the same meaning as described above) or S (0) m-R12 (wherein m is an integer from 0 to 2, and R 2 represents a C 1-4 alkyl group); wherein R 13 represents a hydrogen atom; R 14 represents a phenyl group; or R13 and R14 combine with each other to form an alkylene group of C2-8 which can be substituted by a straight C1-3 alkyl group; wherein R15 represents a hydrogen atom or a C1-4 alkyl group; R16 represents a C1-4 alkyl group; or R15 and R16 combine with each other to form an alkylene group of C2-8 which can be substituted by a straight C1-3 alkyl group;

/ R17 (11) - NR18 wherein R17 and R18 each independently represent a C1-4 alkyl group; or R17 and R18 combine with each other to form an alkylene group of C2-8 which can be substituted by a straight C1-3 alkyl group; wherein p is 1 or 2, k is an integer from 0 to 3, and R19 represents a hydrogen atom or a halogen atom, or

Ar represents any of subsections (1) to (5) below: wherein j is 0 or 1, R20 represents a hydrogen atom, a halogen atom or OR12 (R12 has the same meaning as described above), wherein Z1 represents an oxygen atom or a sulfur atom, wherein R > 21 represents a hydrogen atom or OR (R has the same meaning as described above), wherein Z2 and Z3 each independently represent a hydrogen atom, a halogen atom, an alkyl group of C-? -4, OR22 (R22 represents a hydrogen atom or an alkyl group of d-β), O-A1 -Y1 (A1 represents an alkylene group of straight or branched Cis, and Y1 represents a alkyl group of C? -4 or a phenyl group, which can be substituted by a halogen atom), CO2R5 (R5 has the same meaning as described above), or R7 -CON wherein R7 and R8 have the same meanings described above, or wherein W forms an alkylene group of C? -8 which can be substituted by a straight C? -3 alkyl group, or a pharmaceutically acceptable salt thereof as the active ingredient. 2. The agent for the treatment of erectile dysfunction according to claim 1, further characterized in that R1 is a hydrogen atom, X is a chlorine atom or a bromine atom, and R3 and R4 are both hydrogen atoms . 3. The agent for the treatment of erectile dysfunction according to claims 1 or 2, further characterized in that Ar is a pyridyl group, an N-oxypyridyl group or a phenyl group represented by the formula: wherein Z2 and Z3 each independently represent a hydrogen atom, a halogen atom, a C1-4 alkyl group or OR22, wherein R22 represents a hydrogen atom or an alkyl group of d-β. 4. The agent for the treatment of erectile dysfunction according to any of claims 1 to 3, further characterized in that Y is a carbamoyl group represented by the formula:

/ R? -CON NR8 wherein R7 and R8 each independently represent a hydrogen atom, a C1-4 alkyl group, a C3-8 cycloalkyl group or a phenyl group, or R7 and R8 combine with each other to form an alkylene group of C2-8 which can be substituted by an alkyl group of C -? - 3 or a phenyl group, or form a morpholine ring with the nitrogen atom, or a phenyl group represented by the formula: wherein R 10 and R 11 each independently represent a hydrogen atom, a halogen atom, a C 1-4 alkyl group, a C 1-4 acylamino group, OR 5, wherein R 5 represents a hydrogen atom, or an alkyl group of C? -4, NHSO2R9, wherein R9 represents a hydrogen atom, an alkyl group of C? -4 or a phenyl group which can be substituted by a halogen atom, or S (O) m-R12, in where m is an integer from 0 to 2, and R12 represents a C1-4 alkyl group.

5. - The agent for the treatment of erectile dysfunction according to claim 3, further characterized in that Ar is a pyridyl group, an N-oxypyridyl group or a phenyl group which can be substituted by OR22, wherein R22 represents an alkyl group of C1-4.

6. The agent for the treatment of erectile dysfunction according to any of claims 1 to 5, further characterized in that A is an alkylene group of straight or branched in which a carbon atom in the straight chain can be substituted by a hydroxyl group (-OH).

7. The agent for the treatment of erectile dysfunction according to any of claims 4 to 6, further characterized in that Y is a phenyl group represented by the formula: wherein R 10 and R 11 each independently represent a hydrogen atom, a halogen atom, an alkyl group of C-, an acylamino group of C 1-4, OR 5, wherein R 5 represents a hydrogen atom, or an alkyl group of CM, NHS02R9, wherein R9 represents a phenyl group which can be substituted by a hydrogen atom, a C1-4 alkyl group or a halogen atom, or S (0) m -R12, where m is an integer from 0 to 2, and R12 represents a C1-4 alkyl group.

8. - The agent for the treatment of erectile dysfunction according to claim 7, further characterized in that Y is a phenyl group which can be replaced by a halogen atom.

9. The agent for the treatment of erectile dysfunction according to any of claims 5 to 8, further characterized in that Ar is a 3-pyridyl group.

10. The agent for the treatment of erectile dysfunction according to claim 1, further characterized in that the compound represented by the formula (I) is 4-bromo-6- [3- (4-chlorophenyl) propoxy] -5 - (3-pyridylmethylamino) -3 (2H) -pyridazinone or 4-bromo-6- [3- (4-chlorophenyl) -3-hydroxypropoxy] -5- (3-pyridomethylamino) -3 ( 2H) -pyridazinone, or a pharmaceutically acceptable salt thereof.