CA2714160A1 - A method of administering a pde3 inhibitor via titration for the treatment of peripheral arterial disease - Google Patents

Abstract

The present invention includes a method of administering a type III
phosphodiesterase (PDE3) inhibitor via titration.
For example, the method comprises administering to a mammal multiple doses of the PDE3 inhibitor, wherein one or more doses are administered in an initial dosage amount and one or more doses are subsequently administered in an end dosage amount, and the initial dosage amount is less in amount than the end dosage amount.
Preferably, the PDE3 inhibitor is also a TXA2 synthase inhibitor.

Description

FOR THE TREATMENT OF PERIPHERAL ARTERIAL DISEASE

CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application No.
61/024,445, filed on January 29, 2008 and entitled "A METHOD OF ADMINISTERING A PDE3 VIA TITRATION
FOR THE TREATMENT OF PERIPHERAL ARTERIAL DISEASE", the content of which is herein incorporated by reference in its entirety for all purposes. This application is also related to U.S. Patent Nos. 5,314,883; 5,798,357; 5,942,249; 6,284,758; 6,369,061; and 6,407,298; U.S.
Application Publication Nos. 2007/0117806 and 2007/0161642; and International Application Publication No. WO 2007/023729, the content of which are herein incorporated by reference in their entirety for all purposes.

FIELD OF THE INVENTION

[0002] The present invention relates to a method of administering a type III
phosphodiesterase (PDE3) inhibitor via titration for the treatment of peripheral arterial diseases.
BACKGROUND OF THE INVENTION

[0003] Peripheral artery disease (PAD), also known as peripheral artery occlusive disease (PAOD) or peripheral vascular disease (PVD), is a collective name for all diseases caused by the obstruction of large peripheral arteries, which can result from atherosclerosis, inflammatory processes leading to stenosis, an embolism or thrombus formation. For example, PAD includes peripheral arterial obstructive disease with intermittent claudication also know as chronic arterosclerosis obliterans (See Burns et al., "Management of PAD in primary care" British Medical Journal, 2003, 326, 584-588 and Medline-plus Medical Encyclopedia).
That is, arteriosclerosis obliterans, also known as arteriosclerosis of the extremities, is one type of PAD.
Patients with PAD may suffer severe pain or even loss of sensation in the affected limb, and are at high risk for cardiovascular morbidity and mortality. PAD is associated with substantial functional disability due to impaired walking performance, which is commonly known as intermittent claudication including intermittent claudication associated with arteriosclerosis obliterans. PAD can also cause acute or chronic ischemia. The prevalence of PAD in people aged over 55 years is about 10% to about 25%. The incidence of symptomatic PAD
increases with age, from about 0.3% per year for men aged 40-55 years to about 1 % per year for men aged over 75 years. In the United States, peripheral arterial disease affects 12-20 percent of Americans age 65 and older.

[0004] Dependent on the severity of the disease, PAD therapy includes both moderate measures, such as exercise rehabilitation and smoking cessation, and invasive methods, such as agioplasty, bypass grafting, and sympathectomy. When gangrene of toes has set in, amputation is often a last resort to stop infected dying tissues from causing septicemia. In general, strategies to reduce systemic cardiovascular risk are the cornerstone of PAD therapy. Despite its prevalence and cardiovascular risk implications, only 25 percent of PAD patients are undergoing treatment partially due to the lack of efficacious medicines with tolerable side effects. Thus, there is still a strong need to research and develop new PAD therapy.

[0005]

SUMMARY OF THE INVENTION

[0006] In one aspect, the present invention provides a method of administering a PDE3 inhibitor.
The method comprises administering to a mammal multiple doses of the PDE3 inhibitor, wherein one or more doses are administered in an initial dosage amount and one or more doses are subsequently administered in an end dosage amount, and the initial dosage amount is less in amount than the end dosage amount. Preferably, the PDE3 inhibitor is also an inhibitor of human platelet thromboxane A2 (TXA2) synthase.

DETAILED DESCRIPTION OF THE INVENTION

[0007] The present invention includes a method of administering a PDE3 inhibitor in which a reduced dosage is administered to a patient initially for a period of time followed by an increase in dose (up titration). The later increased dosage may be again reduced (down titration) depending on the patient's reaction and tolerability to later increased dosage. The purpose of this method of administration is to ameliorate mechanism based side effects of the drug product and increase the tolerability of the drug among patients. Some patients currently receiving the recommended dose of PDE3 inhibitor find the mechanism based side effects to be intolerable and discontinue the medication. By increasing the dose administration over a period of time and therefore reducing the observed side effects, a greater percentage of patients can tolerate the recommended dose for effective treatment.

[0008] In one embodiment of the present method, multiple doses of a PDE3 inhibitor are administered to a mammal, wherein one or more doses are administered in an initial dosage amount and one or more doses are subsequently administered in an end dosage amount, and the initial dosage amount is less in amount than the end dosage amount. It is preferred that the PDE3 inhibitor is also a TXA2 synthase inhibitor. It is also preferred that the mammal is a human. In one embodiment of the present invention, the initial dosage amount is about 75% of the end dosage amount or less. In another embodiment of the present invention, the initial dosage amount is about 50% of the end dosage amount or less. In another embodiment of the present invention, the initial dosage amount is about 25% of the end dosage amount or less.

[0009] In one embodiment of the present method, at least one of the multiple doses of the PDE3 inhibitor is administered in at least one intermediate dosage amount which is more in amount than the initial dosage amount and less in amount than the end dosage amount.
In another embodiment of the present method, some of the multiple doses of the PDE3 inhibitor are administered with multiple intermediate dosage amounts which are more in amount than the initial dosage amount and less in amount than the end dosage amount, wherein the multiple intermediate dosage amounts are applied in a manner of subsequently increasing amounts.

[0010] Depending on the patient's reaction and tolerability to the intermediate dosage amount, the subsequent intermediate dosage amount or end dosage amount may be less in amount than the intermediate amount. For example, if the intermediate dosage amount causes side effects intolerable to the patient, the subsequent intermediate dosage amount or end dosage amount can be reduced. In other words, the titration administration method of the present invention can be up titration or down titration. Preferably, the patient is a mammal. More preferably, the patient is a human.

[0011] Besides the patient's reaction and tolerability to the PDE3 inhibitor, a physician can adjust the dosage amount of the initial dosage, one or more intermediate dosages, and end dosage according to the patient's age, bodyweight, and severity of the disease. The up or down titration is to find an end dosage amount which can treat the patient's condition efficaciously and yet be tolerated by the patient for continuous or long-term treatment.

[0012] In one embodiment of the present invention, the initial dosage amount is from about 0.005 mg/kg to about 0.035 ng/kg. In another embodiment of the present invention, the initial dosage amount is from about 0.01 ng/kg to about 0.03 ng/kg. In another embodiment of the present invention, the initial dosage amount is from about 0.015 ng/kg to about 0.025 ng/kg. In yet another embodiment of the present invention, the initial dosage amount is from about 1 mg to about 7 mg. In yet another embodiment of the present invention, the initial dosage amount is from about 1.5 mg to about 6.5 mg. In yet another embodiment of the present invention, the initial dosage amount is from about 2 mg to about 6 mg.

[0013] Besides the patient's reaction and tolerability to the PDE3 inhibitor, a physician can adjust the dosing intervals and treatment duration according to the patient's age, bodyweight, and severity of the disease. In one embodiment of the present method, the multiple doses of the PDE3 inhibitor are administered at a time interval of about 8 hours or more per dose. In another embodiment of the present method, the multiple doses of the PDE3 inhibitor are administered at a time interval of about 12 hours or more per dose. In one embodiment of the present method, the multiple doses of the PDE3 inhibitor are administered at a time interval of about 24 hours or more per dose. In one embodiment of the present method, the multiple doses of the PDE3 inhibitor are administered for a period of about one week or more. In one embodiment of the present method, the multiple doses of the PDE3 inhibitor are administered for a period of about two weeks or more. In one embodiment of the present method, the multiple doses of the PDE3 inhibitor are administered for a period of about four weeks or more. In other embodiments of the present method, the multiple doses of the PDE3 inhibitor are administered for a period of over months or years.

[0014] The present method is applicable to any PDE3 inhibitor. In one embodiment of the present method, the PDE inhibitor is also a TXA2 synthase inhibitor. TXA2 is mainly produced and released from platelets, and shows strong platelet aggregating action and vasopressing action. There are many reports with regard to the pathophysiological role thereof. The production of TXA2 has been found to be accelerated in the diseases such as arteriosclerosis, diabetes, ischemic heart diseases, pulmonary diseases, hypertension, shock, Kawasaki disease and alcoholic liver disease, thus indicating a high probability of TXA2 being involved in the onset and aggravation of these diseases. For the improvement of these diseases, TXA2 synthetase inhibitors and TXA2 antagonists such as imidazole derivatives, pyridine derivatives and imidazopyridine derivatives have been developed.

[0015] In another embodiment, the present invention provides a method for treating a TXA2-mediated disease in a mammal in need thereof via the method of administering a PDE3 inhibitor as described above. In a preferred embodiment, the PDE3 inhibitor is also a TXA2 inhibitor.
Examples of the TXA2-mediated disease include, but are not limited to arteriosclerosis obliterans, intermittent claudication associated with arteriosclerosis obliterans, hypertriglyceridemia caused by diabetes, diabetic nephropathy, diabetic neuropathy, and a combination thereof.

[0016] In another embodiment, the present invention provides a method for treating a PAD
disease in a mammal in need thereof via the method of administering a PDE3 inhibitor as described above. In a preferred embodiment, the PDE3 inhibitor is also a TXA2 inhibitor.
Examples of the PAD include, but are not limited to arteriosclerosis obliterans, intermittent claudication, and a combination thereof.

[0017] In another embodiment, the present invention provides a method for treating arteriosclerosis obliterans including the symptoms associated with arteriosclerosis obliterans in a mammal in need thereof via the method of administering a PDE3 inhibitor as described above.
In a preferred embodiment, the PDE3 inhibitor is also a TXA2 inhibitor. As a common type of PAD, arteriosclerosis obliterans has many causes. Generally, people are at higher risk if they have a personal or family history of heart disease (coronary artery disease), high blood pressure (hypertension), kidney disease involving hemodialysis, smoking, stroke (cerebrovascular disease), or a combination thereof. The symptoms can affect one or both limbs and be debilitating. The symptoms that can be treated by the present invention include, but are not limited to walking or gait abnormalities, weak or absent pulse in the limb, change of color of the legs, cold legs or feet, leg pain (also known as intermittent claudication), loss of hair on the legs and/or feet, muscle pain in the thighs, calves, or feet, numbness of the legs or feet at rest, paleness or blueness (cyanosis).

[0018] In another embodiment, the present invention provides a method for treating intermittent claudication in a mammal in need thereof via the method of administering a PDE3 inhibitor as described above. In a preferred embodiment, the PDE3 inhibitor is also a TXA2 inhibitor. In one specific embodiment, the intermittent claudication is associated with arteriosclerosis obliterans.

[0019] Certain 3(2H)-pyridazinone derivatives and their pharmaceutically acceptable salts, solvates, esters, and/or prodrugs are both PDE3 inhibitors and TXA2 synthase inhibitors. Those 3(2H)-pyridazinone derivatives are excellent compounds for anti-thrombotic agents, cardiotonic agents, vasodilators and/or anti-SRS-A (Slow Reacting Substances of Anaphylaxis) agents, and that they can be active ingredients of prophylactic or therapeutic drugs for the above-mentioned various thrombotic diseases, congestive heart failure, hypertension and/or asthma or immediate type allergy diseases. For example, INDI-702, also known as NM-702 or parogrelil hydrochloride, has a chemical name of 4-bromo-6-[3-(4-chlorophenyl)propoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone hydrochloride. INDI-702 is a pyridazinone derivative showing selective inhibition for PDE3 and PDE5. INDI-702 also inhibits TXA2 synthase.
Clinical studies indicate that NM-702 is well tolerated and might improve treadmill performance in claudicants.

[0020] The 3(2H)-pyridazinone derivatives as mentioned above are suitable PDE3 inhibitors for the present invention including the methods of administration and the methods of treatment as described above. In one embodiment, those 3(2H)-pyridazinone derivatives are indicated for the treatment of peripheral arterial obstructive disease with intermittent claudication also know as chronic arteriosclerosis obliterans, and has been demonstrated to improve and extend walking distance, stair climbing, and walking time.

[0021] The above-mentioned 3(2H)-pyridazinone derivatives typically have a structure represented by formula (I):

R1,N X R4 I
N
N Ar (I) [0022] wherein R' is a hydrogen atom, a straight chained or branched C1-C4 alkyl group, a C3-C4 alkenyl group or (CH2),, CO2 R5 (n is an integer of from 1 to 4, R5 is a hydrogen atom or a straight chained or branched C1-C4 alkyl group);

[0023] R2 is A'-Y', wherein A' is a straight chained or branched CI-C,2 alkylene group, Y' is CO2 R5 (R5 is as defined above), a cyano group, OR6 (R6 is a hydrogen atom, a straight chained or branched CI -C4 alkyl group or a phenyl group), or a thienyl or pyridyl group which may be substituted at any position, CON
'N R9 [0024] R7 and R8 are respectively and independently a hydrogen atom, a straight chained or branched CI-C4 alkyl group, a C3-C8 cycloalkyl group, a phenyl group or a thiazolyl or thiadiazolyl group which may be substituted at any position, or R7 and R8 together form a C2-C8 alkylene group which may be substituted with a straight chained or branched C, -C3 alkyl group or a phenyl group, or form a morpholine ring with a nitrogen atom, jZ5 [0025] R5 is as defined above, R9 is a straight chained or branched CI-C4 alkyl group or a phenyl group which may be substituted with a straight chained or branched CI-C4 alkyl group or a halogen atom, RIO
its [0026] R10 and R" are respectively and independently a hydrogen atom, a halogen atom, a straight chained or branched CI-C4 alkyl group, a CI-C4 acylamino group, OR5 (R5 is as defined above), NHSO2 R9 (R9 is as defined above) or S(O)m --R'2 (m is an integer of from 0 to 2 and Rig is a straight chained or branched CI-C4 alkyl group), provided that R10 and RII are not hydrogen atoms at the same time, [0027] R13 is a hydrogen atom, R14 is a phenyl group, or R13 and R14 together form a C2-C8 alkylene group which may be substituted with a straight chained CI-C3 alkyl group, [0028] R15 is a hydrogen atom or a straight chained or branched C, -C4 alkyl group, R16 is a straight chained or branched CI-C4 alkyl group, or R15 and R16 together form a C2-C8 alkylene group which may be substituted with a straight chained CI -C3 alkyl group, N

[0029] R'7 and Rig are respectively and independently a straight chained or branched CI-C4 alkyl group, or R17 and Rig together form a C2-C8 alkylene group which may be substituted with a straight chained CI-C3 alkyl group, N N-(CH2)4-.

[0030] 1 is 1 or 2, x is an integer of from 0 to 3, and R19 is a hydrogen atom or a halogen atom, OCNHI -----]

[0031] or alternatively, R2 is A2-Y2 wherein A2 is a C2-CIO alkylene group which may be substituted with a straight chained CI-C3 alkyl group, except for the case that a carbon chain connecting an oxygen atom with Y2 has one carbon, and Y2 is a phenyl group;

[0032] R3 and R4 are respectively and independently a hydrogen atom or a straight chained or branched CI-C3 alkyl group;

[0033] X is a chlorine atom, a bromine atom, a hydrogen atom or a cyano group;
and [0034] Ar is N
(O)j [0035] j is 0 or 1 and R20 is a hydrogen atom, a halogen atom or OR12 (R12 is as defined above), -~CIN

[0036] Zi is an oxygen atom or a sulfur atom, [0037] R21 is a hydrogen atom or OR5 (R5 is as defined above), or z2 [0038] Z2 and Z3 are respectively and independently a hydrogen atom, a halogen atom, a straight chained or branched CI-C4 alkyl group, OR22 (R22 is a hydrogen atom or a straight chained or branched CI-C8 alkyl group), or O-A'-Y3 (A' is as defined above and Y3 is a phenyl group which may be substituted with a straight chained or branched Ci-C4 alkyl group or a halogen atom, C02R5), or CON

[0039] R5, R7 and R8 are as defined above, or Z2 and Z3 together with a benzene ring, form [0040] W forms a CI-C8 alkylene group which may be substituted with a straight chained CI-C3 alkyl group; and a pharmaceutically acceptable salt thereof.

[0041] R', R2, R3, R4, X and Ar in the above general formula (I) representing the compound of the present invention are explained hereinafter.

[0042] Examples of R' 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, 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-carboxylbutyl group, a methoxycarbonylmethyl group, a 2-methoxycarbonylethyl group, a 3-methoxycarbonylpropyl group, a 4-methoxycarbonyl butyl 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, a 2-i-propoxycarbonylethyl group, a 3-n-propoxycarbonylpropyl group, a 3-i-propoxycarbonylpropyl group, a 4-n-propoxycarbonylbutyl group, a 4-i-propoxycarbonylbutyl group, an n-butoxycarbonylmethyl group, an -i-butoxycarbonylmethyl group, a sec-butoxycarbonylmethyl group, a t-butoxycarbonylmethyl group, a 2-n-butoxycarbonylethyl 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-sec-butoxycarbonylpropyl group, a 3-t-butoxycarbonylpropyl group, a 4-n-butoxycarbonylbutyl group, a 4-i-butoxycarbonylbutyl group, a 4-sec-butoxycarbonylbutyl group, a 4-t-butoxycarbonylbutyl group and the like, preferably a hydrogen atom, an ethyl group and an i-propyl group, and more preferably a hydrogen atom.

[0043] Examples of R2 include A' -Y' or A2 -Y2 wherein A' is a straight chained or branched CI -C12 alkylene group and A2 is a C2-Cio alkylene group which may be substituted with a straight chained CI-C3 alkyl group, except for the case that a carbon chain connecting an oxygen atom with Y2 has one carbon atom.

[0044] Examples of Y' 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 t-butoxycarbonyl group, 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-, an i-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-ethylaminocarbonyl group, an N-n-propylaminocarbonyl group, an N-i-propylaminocarbonyl group, an N-n-butylaminocarbonyl group, an N-i-butylaminocarbonyl group, an N-sec-butylaminocarbonyl group, an N-t-butylaminocarbonyl group, an N-cyclopropylaminocarbonyl group, an N-cyclobutylaminocarbonyl group, an N-cyclopentylaminocarbonyl group, an N-cyclohexylaminocarbonyl group, an N-cycloheptylaminocarbonyl group, an N-cyclooctylaminocarbonyl group, an N-phenylaminocarbonyl group, an N-2-thiazolylaminocarbonyl group, an N-4-thiazolylaminocarbonyl group, an N-5-thiazolylaminocarbonyl group, an N-2-thiadiazolylaminocarbonyl group, an N-5-thiadiazolylaminocarbonyl group, a 1-aziridinocarbonyl group, a 1-azetidinocarbonyl group, a 1-pyrrolidinocarbonyl group, a 1-piperidinocarbonyl group, a 1-homopiperidinocarbonyl group, a 1-(2,5-dimethyl)pyrrolidinocarbonyl group, a 1-(2,6-dimethyl)piperidinocarbonyl group, a 1-(3-phenyl)pyrrolidinocarbonyl group, a 1-(4-phenyl)piperidinocarbonyl group, an N-methylsulfonylamino group, an N-ethylsulfonylamino group, an N-n-propylsulfonyl group, an N-i-propylsulfonylamino group, an N-n-butylsulfonylamino group, an N-i-butylsulfonylamino group, an N-sec-butylsulfonylamino group, an N-t-butylsulfonylamino group, a 1-morpholinocarbonyl group, an N-phenylsulfonylamino group, an N-substituted phenylsulfonylamino group (which is substituted with 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 bromine atom or an iodine atom on the ortho-, meta- or para-position of the benzene ring), a substituted phenyl group (which is substituted with 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 bromine atom, an iodine atom, a formylamino group, an acetylamino group, a propionylamino group, a butyrylamino group, a methylsulfonylamino group, an ethylsulfonylamino group, an N-n-propylsulfonylamino group, an N-i-propylsulfonylamino group, an N-n-butylsulfonylamino group, an N-i-butylsulfonylamino group, an N-sec-butylsulfonylamino group, an N-t-butylsulfonylamino group, an N-phenylsulfonylamino group, a hydroxyl group, a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, a t-butoxy group, an N-substituted phenylsulfonylamino group (which is substituted with 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 bromine atom or an iodine atom on the ortho-, meta- or para-position of the benzene ring), 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 group, a t-butylthio group, a methylsulfoxy group, an ethylsulfoxy group, an n-propylsulfoxy group, an i-propylsulfoxy group, an n-butylsulfoxy group, an i-butylsulfoxy group, a sec-butylsulfoxy group, a t-butylsulfoxy group, a methylsulfonyl group, an ethylsulfonyl group, an n-propylsulfonyl group, an i-propylsulfonyl group, an n-butylsulfonyl group, an i-butylsulfonyl group, a sec-butylsulfonyl group, or a t-butylsulfonyl group on the ortho-, meta- or para-position of the benzene ring), an N-phenylcarbonylamino 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 1-(2-oxo-3,3-dimethyl)pyrrolidinyl group, a 1-(2-oxo-5,5-dimethyl)pyrrolidinyl group, an N-methoxycarbonylamino group, an N-ethoxycarbonylamino group, an N-n-propoxycarbonylamino group, an N-i-propoxycarbonylamino group, an N-n-butoxycarbonylamino group, an N-i-butoxycarbonylamino group, an N-sec-butoxycarbonylamno group, an N-t-butoxycarbonylamino 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-oxo-5,5-diethyl)oxazolidinyl group, an N,N-di-substituted amino group (having an optional combination of 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-butyl group), 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-(4,4-dimethyl)piperidino group, a 1-(4-phenylmethyl)piperadino group, 1-(4-diphenylmethyl)piperadino group, a 1-(4-substituted phenylmethyl)piperadinyl or 1-(4-di-substituted phenylmethyl)piperadinyl group (which is substituted with a fluorine atom, a chlorine atom, a bromine atom or an iodine atom on the ortho-, meta- or para-position of the benzene ring), a phenylaminocarboxyl group, an N,N-di-substituted aminocarbonyl group (having an optional combination of a linear or cyclic alkyl group, a phenyl group, a thiazolyl group or a thiadiazolyl group on the above described N-substituted aminocarbonyl groups), N-alkyl-N-phenylsulfonylamino, N,N-dialkylsulfonylamino or N-alkyl-N-alkoxycarbonylamino groups (having a linear or branched Ci -C4 alkyl substituent on the nitrogen atom of the above described N-phenylsulfonylamino, N-alkylsulfonylamino or N-alkoxycarbonylamino groups), di-substituted phenyl groups (which are substituted on the ortho-, meta- or para-position of the benzene ring with an optional combination of a halogen atom, a linear alkyl group, an acylamino group, a hydroxyl group, an alkoxy group, an N-phenylsulfonylamino group, an N-alkylsulfonylamino group, a linear alkylthio group and a linear alkylsulfonyl group on the above described substituted phenyl groups), and the like.

[0045] Examples of Y2 include a phenyl group.

[0046] Examples of R3 and R4 include a hydrogen atom, a methyl group, an ethyl group, an n-propyl group and an i-propyl group, preferably a hydrogen atom.

[0047] Examples of X include a hydrogen atom, a chlorine atom, a bromine atom and a cyano group, preferably each substituent other than a hydrogen atom.

[0048] Examples of Ar include a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a substituted 2-pyridyl group, 3-pyridyl or 4-pyridyl (which is substituted with a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group or a t-butoxy group on the 2-, 3-, 4-, 5- or 6-position of the pyridine ring), an N-oxidopyrizyl group corresponding to the above described pyridyl or substituted pyridyl group, a 2-furyl group, a 3-furyl group, a 2-thienyl group, a 3-thienyl group, a 1-naphthyl group, a 2-naphthyl group, a 1-naphthyl or 2-naphthyl group (which is substituted with a hydroxy group, a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group or a t-butoxy group on an optional position of the naphthalene ring) or substituted phenyl groups having the following one or two substituents in optional combination at an optional position. Examples of the substituents 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, an n-butyl group, an i-butyl group, a sec-butyl group, a t-butyl group, a hydroxy group, an alkoxy group (having a linear or branched CJ-C8 alkyl group), a dioxyemthylene, 1,2-dioxyethylene or 1,3-dioxypropylene group (which comprises adjacent two substituents joined together), or an O--A' --Y3 group. A' is a linear or branched Ci-Cio alkylene group, Y3 is a phenyl group, a substituted phenyl group (which is substituted with 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 bromine atom or an iodine atom on the ortho-, meta- or para-position of the benzene ring), or the above-mentioned (with regard to Y') carboxyl, alkoxycarbonyl, 1-cycloaminocarbonyl, 1-morpholinocarbonyl, or carbamoyl, N-substituted or N,N-disubstituted aminocarbonyl group (having on a nitrogen atom an optional combination of two substituents of a hydrogen atom, a linear, branched or cyclic alkyl group, a phenyl group, a thiazolyl group and a thiadiazolyl group).
Preferable examples include a 3-pyridyl group or 3-substituted-4-methoxyphenyl type group, but the present invention should not be limited to these examples.

[0049] In the above description "n", "i", "sec" and "t" respectively stand for "normal", "iso", "secondary" and "tertiary".

[0050] Preferable compounds of the compounds having the general formula (I) of the present invention are represented by the following general formula (Ia), 0i3 YY

O ` (la) [0051] wherein Ric is a hydrogen atom;

[0052] R" is A'-Y", wherein A' is a straight Chained or branched CI-C,2 alkylene group, Y3 is CO2 Rs wherein Rs is a straight chained or branched C1-4 alkyl group, CON

[0053] R7' and R8 are respectively and independently a hydrogen atom, a straight chained or branched CI-C4 alkyl group, a C3-C8 cycloalkyl group or a phenyl group, R7' and R8 together form a C2-C8 alkylene group which may be substituted with a straight chained Ci-C3 alkyl group or a phenyl group, or form a morpholine ring with a nitrogen atom, s [0054] R5 is a hydrogen atom or a straight chained or branched C,-C4 alkyl group, R9, is a phenyl group which may be substituted with a straight chained or branched CI-C4 alkyl group or a halogen atom, [0055] R10' and R"' are respectively and independently a hydrogen atom, a halogen atom, a straight chained or branched CI-C4 alkyl group, a CI-C4 acylamino group, OR5 (R5 is as defined above), NHSO2 R9õ (R9õ is a straight chained or branched CI-C4 alkyl group) or S(O)m --R'2 (m is 0 or 2 and Rig is a straight chained or branched CI-C4 alkyl group), provided that R10' and R"' are not hydrogen atoms at the same time), O

[0056] R13' is a hydrogen atom, R14' is a phenyl group, or R13' and R14' together form a C2-C5 alkylene group, [0057] R'5 is a hydrogen atom or a straight chained or branched C, -C4 alkyl group, R16' is a straight chained or branched CI-C4 alkyl group, or R'5 and R16' together form a C2-C6 alkylene group, N
181, [0058] R'7 and Rig' are respectively and independently a straight chained or branched CI-C4 alkyl group, or R17' and Rig together form a C2-C6 alkylene group, Res [0059] 1 is 1 or 2, and R19 is a hydrogen atom or a halogen atom, or [0060] or R2 is A2-Y2 wherein A2 is a C2-C8 alkylene group which may be substituted with a straight chained CI-C3 alkyl group, except for the case that a carbon chain connecting an oxygen atom with Y2 has one carbon, and Y2 is a phenyl group;

[0061] Xc' is a chlorine atom, a bromine atom, or a cyano group; and [0062] Ar' is a 3-pyridyl group, or [0063] Z' is a halogen atom, a straight chained or branched CI-C4 alkyl group, OR22 (R22 is a hydrogen atom or a straight chained or branched CJ-8 alkyl group) or O--A3--Y3 (A3 is a C1-C4 alkylene group, Y3 is a phenyl group, CO2 R"), PT
CON

[0064] R", R7' and R8' are as defined above.

[0065] The compounds of the general formula (I) of the present invention include optical isomers and stereoisomers based on from 1 to 6 asymmetric carbon atoms.

[0066] In one embodiment of the present invention, the pyridazinone compound of formula (I) has a structure of formula (lb):

Rl,, N X

p R3 N
R2a i Ya (lb) [0067] wherein R', R2a and R3 are each independently a hydrogen atom or a lower alkyl, X is a halogen atom, a cyano or a hydrogen atom, Ya is a halogen atom, a trifluoromethyl or a hydrogen atom and A is a Ci-C8 alkylene optionally substituted by hydroxyl, or a pharmacologically acceptable salt thereof.

[0068] The symbols used in the present specification are explained in the following.

[0069] The lower alkyl for R', R2a and R3 may be linear or branched and has 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl and hexyl.

[0070] Preferable R' and R3 are each hydrogen atom, and preferable R 2a is hydrogen atom or Ci-C4 alkyl.

[0071] The C1-C4 alkyl for R 2a is exemplified by methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl.

[0072] The halogen atom for X and Ya is, for example, fluoro atom, chloro atom, bromo atom or iodo atom, with preference given to halogen atom for X, and halogen atom or hydrogen atom for Ya [0073] The C1-C8 alkylene for A, which is optionally substituted by hydroxyl, may be linear or branched and is exemplified by methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, 2,2-dimethylethylene, 2,2-diethylethylene, 2,2-di-n-propylethylene, hydroxymethylene, 1-hydroxyethylene, 2-hydroxyethylene and 3-hydroxypropylene.
Preferred is Ci -C5 alkylene optionally substituted by hydroxyl.

[0074] In the formula (lb), the bonding site of methylene and pyridine ring is not particularly limited. Preferable site is the 3-position relative to the nitrogen atom on the pyridine ring.

[0075] ya may be substituted at any position on the benzene ring, with preference given to the 4-position.

[0076] In particular, a pyridazinone compound wherein, in the formula (Ib), R1 and R3 are hydrogen atoms, R2a is a hydrogen atom or a C1-C4 alkyl, X is a halogen atom, ya is a halogen atom or hydrogen atom and A is a C1-C5 alkylene optionally substituted by hydroxyl is preferable.

[0077] Examples of more preferable pyridazinone compound of formula (lb) include 4-bromo-6-(3-phenylpropoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-chloro-6-(3-phenylpropoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-chloro-6-[3-(4-chlorophenyl)propoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-bromo-6-[3-(4-chlorophenyl)propoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-bromo-6-(2,2-dimethyl-3-phenylpropoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-chloro-6-(2,2-dimethyl-3-phenylpropoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-bromo-6-[3-(4-chlorophenyl)-2,2-dimethylpropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-chloro-6-[3-(4-chlorophenyl)-2,2-dimethylpropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-bromo-6-[3-(4-chlorophenyl)-3-hydroxypropoxy] -5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-chloro-6-[3-(4-chlorophenyl)-3-hydroxypropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-bromo-6-[3-(4-chlorophenyl)-2-hydroxypropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone and 4-chloro-6-[3-(4-chlorophenyl)-2-hydroxypropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone. It should be understood by one skilled in the art that the above-listed chemical names may have other variations. For example, the above-mentioned 4-bromo-6-[3-(4-chlorophenyl)propoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone may also be referred to as 4-bromo-6-[3-(4-chlorophenyl)propoxy] -5 -[(pyridine-3-yl-methyl)amino] pyridazin-3(2H)-one.

[0078] The most preferable pyridazinone compound of formula (lb) or its pharmaceutically acceptable salt, solvate, ester or prodrug contains a structure shown below:

Br HN
N~ N N
O H

CI

[0079] The pharmacologically acceptable salts of the pyridazinone compound of formula (I) are, for example, salts with inorganic acid (e.g. hydrochloride, hydrobromide, phosphate and sulfate) and salts with organic acid (acetate, succinate, maleate, fumarate, malate and tartrate).

[0080] The pyridazinone compound of formula (I) can be converted to the aforementioned salts by a known method.

[0081] The method for confirming the action of the compound of formula (I) used in the present invention is subject to no particular limitation and the action can be confirmed by a known method.

[0082] The pyridazinone compound of formula (I) including any subgenus and specific compounds encompassed thereby or pharmacologically acceptable salts, solvates, esters, and/or prodrugs thereof, which are the active ingredients in the present invention, are extremely low toxic and have prophylactic and therapeutic activities against PAD as well as TXA2-mediated diseases, particularly a TXA2 synthetase inhibitory action, in mammals such as human, dog, cow, horse, rabbit, mouse and rat. That is, they have prophylactic and therapeutic effects against PAD
and TXA2-mediated diseases. Examples of the diseases that can be prevented, ameliorated, or treated include, but are not limited to cerebral infarction, cerebral thrombosis, bronchial asthma, cerebral stroke, myocardial infarction, acute heart failure, angina pectoris, hypertension, arteriosclerosis obliterans, intermittent claudication including intermittent claudication associated with arteriosclerosis obliterans, thromboangitis obliterans, diabetic nephropathy, diabetic neuropathy and hypertriglyceridemia caused by diabetes.

[0083] The dosage form of the pyridazinone compound of formula (I) and pharmacologically acceptable salts thereof is exemplified by non-oral administration of, for example, injection (subcutaneous, intravenous, intramuscular, intraperitoneal injections), ointment, suppository or aerosol, and oral administration of, for example, tablet, capsule, granule, pill, syrup, liquid, emulsion or suspension.

[0084] The pyridazinone compound of formula (I) and the pharmacologically acceptable salts, solvates, esters, or prodrugs thereof are formulated into preparations by a method conventionally used for manufacturing pharmaceuticals.

[0085] The tablet, capsule, granule and pill for oral administration are prepared by using, for example, excipient (e.g. sucrose, lactose, glucose, starch and mannitol), binder (e.g. syrup, gum arabic, gelatin, sorbit, tragacanth, methylcellulose and polyvinylpyrrolidone), disintegrator (e.g.
starch, carboxymethylcellulose or calcium salt thereof, microcrystalline cellulose and polyethylene glycol) and lubricant (e.g. talc, magnesium stearate, calcium stearate, silica, sodium laurate and glycerol).

[0086] The injection, aerosole, syrup, liquid, emulsion and suspension are prepared using solvents for the active ingredient (e.g. water, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycol and polyethylene glycol), surfactant (e.g. sorbitan fatty acid ester, polyoxyethylenesorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene ether of hydrogenated castor oil and lecithin), suspending agent (e.g. cellulose derivative such as methylcellulose and sodium salt of carboxymethylcellulose, and natural rubber such as tragacanth and gum arabic), preservative (e.g. p-hydroxybenzoate, benzalkonium chloride and sorbic acid salt) and the like. Suppositories are prepared using, for example, polyethylene glycol, lanolin and coconut oil.

[0087] The dose of the pyridazinone compound of formula (I) and pharmacologically acceptable salts thereof is appropriately determined according to age, body weight, severity of symptom and the like of patients, and they are generally administered in 0.001-500 mg/day, preferably 0.005-100 mg/day in a single to several times divided doses to a human adult.

[0088] The pyridazinone compound of formula (I) can also be formulated with an organic acid.
The organic acid to be used in the present invention includes, for example, citric acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid and the like, with particular preference given to citric acid. The organic acid is preferably added in a proportion of 0.05-20 parts by weight per part by weight of the pyridazinone compound.

[0089] When to add an organic acid is not particularly limited and an organic acid may be added before granulation or after granulation but before compression. Considering the absorption of the pyridazinone compound, an organic acid is preferably added before granulation.

[0090] By adding an organic acid to a pyridazinone compound, the dissolution and absorption of the pyridazinone compound can be improved, and a composition for oral administration which is stable to heat, light, moisture and the like can be provided.

[0091] When formulating the composition for oral administration of the present invention, the pyridazinone compound is preferably micronized. The pyridazinone compound as a bulk powder has an average particle size of about 20 m. Micronization by a known method can make the average particle size about 7-10 m. The micronization of the pyridazinone compound contributes to improvement in dissolution and absorption.

[0092] The composition for oral administration of the present invention can be formulated into a dosage form of tablet, capsule, powder, granule, pill and the like by a conventional method using excipients, binders, disintegrators, lubricants and the like. The excipients and the like to be used are not particularly limited. Examples of excipient include lactose, corn starch, sucrose, glucose, mannitol, sorbit, crystalline cellulose, silicon dioxide and the like.
Examples of binder include polyvinyl alcohol, polyvinyl ether, ethylcellulose, methylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropyl starch, polyvinylpyrrolidone and the like. Examples of disintegrator include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogencarbonate, calcium citrate, dextrin, pectin, carboxymethylcellulose calcium, low substitution hydroxypropylcellulose, croscarmellose sodium, partly pregelatinized starch and the like. Examples of lubricant include magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil and the like.
The use of lactose as an excipient or the use of hydroxypropylcellulose as a binder may unexpectedly lead to undesirable coloring of the preparation. Thus, the use of other excipients and other binders is preferable. Preferable excipient may be crystalline cellulose, corn starch, mannitol and the like. Preferable binder may be hydroxypropylmethylcellulose and the like.

[0093] The excipient, binder, disintegrator and lubricant are contained in a proportion of preferably 10-150 parts by weight, 0.5-10 parts by weight, 1-20 parts by weight and 0.1-1.5 parts by weight, respectively, per part by weight of the pyridazinone compound.

[0094] While the dosage form of the inventive pharmaceutical composition is not limited, it is preferably tablet. When tablets are prepared, for example, water is added to an admixture of ingredients in a proportion of about 5-70% (w/w), and the resulting mixture is granulated by a stirring-granulation method using a high speed mixer and the like, followed by compression (wet granulation compression method), or the respective ingredients are mixed homogeneously, followed by compression molding (direct compression method), or they are prepared by other method. To the tablets is preferably applied a coating base material such as a commercially available "Opadry AMB" manufactured by Colorcon Inc. and the like to increase resistance to moisture.

[0095] The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The term "or" or "and/or" is used as a function word to indicate that two words or expressions are to be taken together or individually. The terms "comprising", "having", "including", and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to"). The endpoints of all ranges directed to the same component or property are inclusive and independently combinable.

[0096] All publications and patent applications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0097] While the present invention has been particularly shown and described with respect to preferred embodiments thereof, it will be understood by those skilled in the art that the foregoing and other changes in forms and details may be made without departing from the spirit and scope of the invention. It is therefore intended that the present invention not be limited to the exact forms and details described and illustrated but fall within the scope of the appended claims.

Claims (64)

1. A method of administering a type III phosphodiesterase (PDE3) inhibitor, comprising administering to a mammal multiple doses of the PDE3 inhibitor, wherein one or more doses are administered in an initial dosage amount and one or more doses are subsequently administered in an end dosage amount, and the initial dosage amount is less in amount than the end dosage amount.

2. The method of claim 1, wherein the PDE3 inhibitor is also a thromboxane A2 (TXA2) synthase inhibitor.

3. The method of claim 1 or 2, wherein the initial dosage amount is about 75%
of the end dosage amount or less.

4. The method of claim 3, wherein the initial dosage amount is about 50% of the end dosage amount or less.

5. The method of claim 4, wherein the initial dosage amount is about 25% of the end dosage amount or less.

6. The method of any of claims 1 to 5, wherein at least one of the multiple doses of the PDE3 inhibitor is administered in an intermediate dosage amount which is more in amount than the initial dosage amount and less in amount than the end dosage amount.

7. The method of any of claims 1 to 5, wherein some of the multiple doses of the PDE3 inhibitor are administered with multiple intermediate dosage amounts which are more in amount than the initial dosage amount and less in amount than the end dosage amount, wherein the multiple intermediate dosage amounts are applied in a manner of subsequently increasing amounts.

8. The method of any of claims 1 to 7, wherein the initial dosage amount is from about 0.005 mg/kg to about 0.035 mg/kg.

9. The method of claim 8, wherein the initial dosage amount is from about 0.01 mg/kg to about 0.03 mg/kg.

10. The method of claim 9, wherein the initial dosage amount is from about 0.015 ng/kg to about 0.025 mg/kg.

11. The method of any of claims 1 to 10, wherein the initial dosage amount is from about 1 mg to about 7 mg.

12. The method of claim 11, wherein the initial dosage amount is from about 1.5 mg to about 6.5 mg.

13. The method of claim 12, wherein the initial dosage amount is from about 2 mg to about 6 mg.

14. The method of any of claims 1 to 13, wherein the multiple doses of the PDE3 inhibitor are administered at a time interval of about 8 hours or more per dose.

15. The method of claim 14, wherein the time interval are about 12 hours or more per dose.

16. The method of claim 15, wherein the time interval are about 24 hours or more per dose.

17. The method of any of claims 1 to 16, wherein the multiple doses of the PDE3 inhibitor are administered for a period of about one week or more.

18. The method of claim 17, wherein the multiple doses of the PDE3 inhibitor are administered for a period of about two weeks or more.

19. The method of claim 18, wherein the multiple doses of the PDE3 inhibitor are administered for a period of about four weeks or more.

20. The method any of claim 1 to 19, wherein the PDE3 inhibitor is a compound of formula (I):

or a pharmaceutically acceptable salt, solvate, ester, and/or prodrug thereof, wherein:
R1 is a hydrogen atom, a straight chain or branched C1-C4 alkyl group, a C3 -C4 alkenyl group or (CH2)n CO2R5 where n is an integer from 1 to 4, R5 is a hydrogen atom or a straight chain or branched C1-C4 alkyl group;
R2 is A1 -Y1 where A1 is a straight chain or branched C1-C12 alkylene group, Y1 is C(O)2R5, a cyano group, OR6 where R6 is a hydrogen atom, a straight chain or branched C1-C4 alkyl group or a phenyl group, a thienyl or pyridyl group, C(O)N7N8, where R7 and R8 are independently a hydrogen atom, a straight chain or branched C1-C4 alkyl group, a C3-C8 cycloalkyl group, a phenyl group, a thiazolyl or thiadiazolyl group, or R7 and R8 together form a C2-C8 alkylene group which is unsubstituted or substituted with a straight chain or branched C1-C3 alkyl group or a phenyl group, or form a morpholine ring with a nitrogen atom, N(R5)-S(O)2R9, where R5 is as defined above and R9 is a straight chain or branched C1-C4 alkyl group or a phenyl group which is unsubstituted or substituted with a straight chain or branched C1-C4 alkyl group or a halogen atom, where R10 and R11 are independently a hydrogen atom, a halogen atom, a straight chain or branched C1-C4 alkyl group, a C1-C4 acylamino group, OR5, NHSO2R9 or S(O)m-R12 where m is an integer from 0 to 2 and R12 is a straight chain or branched C1-C4 alkyl group, provided that R10 and R11 are not hydrogen atoms at the same time, N(R13)-C(O)R14, where R13 is a hydrogen atom and R14 is a phenyl group, or R13 and R14 together form a C2-C8 alkylene group which is unsubstituted or substituted with a straight chain C1-C3 alkyl group, N(R15)-C(O)2R16, where R15 is a hydrogen atom or a straight chain or branched C1-C4 alkyl group, R16 is a straight chain or branched C1-C4 alkyl group, or R15 and R16 together form a C2-C8 alkylene group which is unsubstituted or substituted with a straight chain C1-C3 alkyl group, NR17R18, where R17 and R18 are independently a straight chain or branched C1-C4 alkyl group, or R17 and R18 together form a C2-C8 alkylene group which is unsubstituted or substituted with a straight chain C1-C3 alkyl group, where 1 is 1 or 2, k is an integer from 0 to 3, and R19 is a hydrogen atom or a halogen atom, or OC(O)-NHPh; or alternatively, R2 is A2-Y2 where A2 is a C2-C 10 alkylene group which is unsubstituted or substituted with a straight chain C1-C3 alkyl group, except where a carbon chain connecting an oxygen atom with Y2 has one carbon, and Y2 is a phenyl group;
R3 and R4 are independently a hydrogen atom or a straight chain or branched C1-C3 alkyl group; X is a chlorine atom, a bromine atom, a hydrogen atom or a cyano group;
and Ar is where j is 0 or 1 and R20 is a hydrogen atom, a halogen atom or OR12 where R12 is as defined above, where Z1 is an oxygen atom or sulfur atom;
or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.

21. The method of claim 20, wherein the PDE3 inhibitor is a compound of formula (Ia):
or a pharmaceutically acceptable salt, solvate, ester, and/or prodrug thereof, wherein:
R1, R2a and R3 are each independently a hydrogen atom or a lower alkyl group, X is a halogen atom, a cyano group or a hydrogen atom, Ya is a halogen atom, a trifluoromethyl group or a hydrogen atom and A is a C1-alkylene group optionally substituted by a hydroxyl group, or a pharmacologically acceptable salt, solvate, ester, or prodrug thereof.

22. The method of claim 21, wherein the compound of the formula (Ia) is selected from the group consisting of:
4-bromo-6-(3-phenylpropoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-chloro-6-(3-phenylpropoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-chloro-6-[3-(4-chlorophenyl)propoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-bromo-6-[3-(4-chlorophenyl)propoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-bromo-6-(2,2-dimethyl-3-phenylpropoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-chloro-6-(2,2-dimethyl-3-phenylpropoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-bromo-6-[3-(4-chlorophenyl)-2,2-dimethylpropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyrdazinone, 4-chloro-6-[3-(4-chlorophenyl)-2,2-dimethylpropoxy]-5-(3 -pyridylmethylamino)-3(2H)-pyridazinone, 4-bromo-6-[3-(4-chlorophenyl)-3-hydroxypropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-chloro-6-[3-(4-chlorophenyl)-3-hydroxypropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-bromo-6-[3-(4-chlorophenyl)-2-hydroxypropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, and 4-chloro-6-[3-(4-chloro phenyl)-2-hydroxypropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone;
or a pharmaceutically acceptable salt, solvate, ester, and/or prodrug thereof.

23. A method for treating a TXA2-mediated disease in a mammal in need thereof comprising administering a PDE3 inhibitor to the mammal multiple doses of the PDE3 inhibitor, wherein one or more doses are administered in an initial dosage amount and one or more doses are subsequently administered in an end dosage amount, and the initial dosage amount is less in amount than the end dosage amount.

24. The method of claim 23, wherein the PDE3 inhibitor is also a TXA2 inhibitor.

25. The method of claim 23 or 24, wherein the TXA2-mediated disease is selected from the group consisting of arteriosclerosis obliterans, intermittent claudication associated with arteriosclerosis obliterans, hypertriglyceridemia caused by diabetes, diabetic nephropathy, diabetic neuropathy, and a combination thereof.

26. The method of any of claims 23 to 25, wherein the PDE3 inhibitor is a compound of formula (I) as described in claim 20 or a pharmaceutically acceptable salt, solvate, ester, and/or prodrug thereof.

27. The method of claim 26, wherein the PDE3 inhibitor is a compound of formula (Ib) as described in claim 21 or a pharmaceutically acceptable salt, solvate, ester, and/or prodrug thereof.

28. The method of claim 27, wherein the compound of the formula (Ib) as described in claim 21 is selected from the group consisting of:
4-bromo-6-(3-phenylpropoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-chloro-6-(3-phenylpropoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-chloro-6-[3-(4-chlorophenyl)propoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-bromo-6-[3-(4-chlorophenyl)propoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-bromo-6-(2,2-dimethyl-3-phenylpropoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-chloro-6-(2,2-dimethyl-3-phenylpropoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-bromo-6-[3-(4-chlorophenyl)-2,2-dimethylpropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyrdazinone, 4-chloro-6-[3-(4-chlorophenyl)-2,2-dimethylpropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-bromo-6-[3-(4-chlorophenyl)-3-hydroxypropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-chloro-6-[3-(4-chlorophenyl)-3-hydroxypropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-bromo-6-[3-(4-chlorophenyl)-2-hydroxypropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, and 4-chloro-6-[3-(4-chloro phenyl)-2-hydroxypropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone;
or a pharmaceutically acceptable salt, solvate, ester, and/or prodrug thereof.

29. The method any of claims 23 to 28, wherein at least one of the multiple doses of the PDE3 inhibitor is administered in an intermediate dosage amount which is more in amount than the initial dosage amount and less in amount than the end dosage amount.

30. The method of claim 29, wherein some of the multiple doses of the PDE3 inhibitor are administered with multiple intermediate dosage amounts which are more in amount than the initial dosage amount and less in amount than the end dosage amount, wherein the multiple intermediate dosage amounts are applied in a manner of subsequently increasing amounts.

31. A method of treating a peripheral artery disease comprising administering to a mammal multiple doses of a PDE3 inhibitor, wherein one or more doses are administered in an initial dosage amount and one or more doses are subsequently administered in an end dosage amount, and the initial dosage amount is less in amount than the end dosage amount.

32. The method of claim 31, wherein the PDE3 inhibitor is also a TXA2 inhibitor.

33. The method of claim 31 or 32, wherein the peripheral artery disease comprises arteriosclerosis obliterans, intermittent claudication, or a combination thereof.

34. The method of any of claims 31 to 33, wherein the PDE3 inhibitor is a compound of formula (I) as described in claim 20 or a pharmaceutically acceptable salt, solvate, ester, and/or prodrug thereof.

35. The method of claim 34, wherein the PDE3 inhibitor is a compound of formula (Ib) as described in claim 21 or a pharmaceutically acceptable salt, solvate, ester, and/or prodrug thereof.

36. The method of claim 35, wherein the compound of the formula (Ib) as described in claim 21 is selected from the group consisting of:
4-bromo-6-(3-phenylpropoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-chloro-6-(3-phenylpropoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-chloro-6-[3-(4-chlorophenyl)propoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-bromo-6-[3-(4-chlorophenyl)propoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-bromo-6-(2,2-dimethyl-3-phenylpropoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-chloro-6-(2,2-dimethyl-3-phenylpropoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-bromo-6-[3-(4-chlorophenyl)-2,2-dimethylpropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyrdazinone, 4-chloro-6-[3-(4-chlorophenyl)-2,2-dimethylpropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-bromo-6-[3-(4-chlorophenyl)-3-hydroxypropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-chloro-6-[3-(4-chlorophenyl)-3-hydroxypropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-bromo-6-[3-(4-chlorophenyl)-2-hydroxypropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, and 4-chloro-6-[3-(4-chloro phenyl)-2-hydroxypropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone;
or a pharmaceutically acceptable salt, solvate, ester, and/or prodrug thereof.

37. The method of any of claims 31 to 36, wherein at least one of the multiple doses of the PDE3 inhibitor is administered in an intermediate dosage amount which is more in amount than the initial dosage amount and less in amount than the end dosage amount.

38. The method of claim 37, wherein some of the multiple doses of the PDE3 inhibitor are administered with multiple intermediate dosage amounts which are more in amount than the initial dosage amount and less in amount than the end dosage amount, wherein the multiple intermediate dosage amounts are applied in a manner of subsequently increasing amounts.

39. A method of treating arteriosclerosis obliterans comprising administering to a mammal multiple doses of a PDE3 inhibitor, wherein one or more doses are administered in an initial dosage amount and one or more doses are subsequently administered in an end dosage amount, and the initial dosage amount is less in amount than the end dosage amount.

40. The method of claim 39, wherein the PDE3 inhibitor is also a TXA2 inhibitor.

41. The method of claim 39 or 40, wherein the PDE3 inhibitor is a compound of formula (I) as described in claim 20 or a pharmaceutically acceptable salt, solvate, ester, and/or prodrug thereof.

42. The method of claim 41, wherein the PDE3 inhibitor is a compound of formula (Ib) as described in claim 21 or a pharmaceutically acceptable salt, solvate, ester, and/or prodrug thereof.

43. The method of claim 42, wherein the compound of the formula (Ib) as described in claim 21 is selected from the group consisting of:
4-bromo-6-(3-phenylpropoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-chloro-6-(3-phenylpropoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-chloro-6-[3-(4-chlorophenyl)propoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-bromo-6-[3-(4-chlorophenyl)propoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-bromo-6-(2,2-dimethyl-3-phenylpropoxy)-5-(3-pyridylmethylamino)-2H)-pyridazinone, 4-chloro-6-(2,2-dimethyl-3-phenylpropoxy)-5-(3-pyridylmethylamino)-2H)-pyridazinone, 4-bromo-6-[3-(4-chlorophenyl)-2,2-dimethylpropoxy]-5-(3-pyridylmethylamino)-2H)-pyrdazinone, 4-chloro-6-[3-(4-chlorophenyl)-2,2-dimethylpropoxy]-5-(3-pyridylmethylamino)-2H)-pyridazinone, 4-bromo-6-[3-(4-chlorophenyl)-3-hydroxypropoxy]-5-(3-pyridylmethylamino)-2H)-pyridazinone, 4-chloro-6-[3-(4-chlorophenyl)-3-hydroxypropoxy]-5-(3-pyridylmethylamino)-2H)-pyridazinone, 4-bromo-6-[3-(4-chlorophenyl)-2-hydroxypropoxy]-5-(3-pyridylmethylamino)-2H)-pyridazinone, and 4-chloro-6-[3-(4-chloro phenyl)-2-hydroxypropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone;
or a pharmaceutically acceptable salt, solvate, ester, and/or prodrug thereof.

44. The method of any of claims 39 to 43, wherein at least one of the multiple doses of the PDE3 inhibitor is administered in an intermediate dosage amount which is more in amount than the initial dosage amount and less in amount than the end dosage amount.

45. The method of claim 44, wherein some of the multiple doses of the PDE3 inhibitor are administered with multiple intermediate dosage amounts which are more in amount than the initial dosage amount and less in amount than the end dosage amount, wherein the multiple intermediate dosage amounts are applied in a manner of subsequently increasing amounts.

46. A method of treating intermittent claudication comprising administering to a mammal multiple doses of a PDE3 inhibitor, wherein one or more doses are administered in an initial dosage amount and one or more doses are subsequently administered in an end dosage amount, and the initial dosage amount is less in amount than the end dosage amount.

47. The method of claim 46, wherein the PDE3 inhibitor is also a TXA2 inhibitor.

48. The method of claim 46 or 47, wherein the intermittent claudication is associated with arteriosclerosis obliterans.

49. The method of any of claims 46 to 48, wherein the PDE3 inhibitor is a compound of formula (I) as described in claim 20 or a pharmaceutically acceptable salt, solvate, ester, and/or prodrug thereof.

50. The method of claim 49, wherein the PDE3 inhibitor is a compound of formula (lb) as described in claim 21 or a pharmaceutically acceptable salt, solvate, ester, and/or prodrug thereof.

51. The method of claim 50, wherein the compound of the formula (Ib) as described in claim 21 is selected from the group consisting of:
4-bromo-6-(3-phenylpropoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-chloro-6-(3-phenylpropoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-chloro-6-[3-(4-chlorophenyl)propoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-bromo-6-[3-(4-chlorophenyl)propoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-bromo-6-(2,2-dimethyl-3-phenylpropoxy)-5-(3-pyridylmethyl amino)-3(2H)-pyridazinone, 4-chloro-6-(2,2-dimethyl-3-phenylpropoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-bromo-6-[3-(4-chlorophenyl)-2,2-dimethylpropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyrdazinone, 4-chloro-6-[3-(4-chlorophenyl)-2,2-dimethylpropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-bromo-6- [3-(4-chlorophenyl)-3-hydroxypropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-chloro-6-[3-(4-chlorophenyl)-3-hydroxypropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone, 4-bromo-6-[3-(4-chlorophenyl)-2-hydroxypropoxy] -5-(3 -pyridylmethyl amino)-3(2H)-pyridazinone, and 4-chloro-6-[3-(4-chloro phenyl)-2-hydroxypropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone;
or a pharmaceutically acceptable salt, solvate, ester, and/or prodrug thereof.

52. The method of any of claims 46 to 52, wherein at least one of the multiple doses of the PDE3 inhibitor is administered in an intermediate dosage amount which is more in amount than the initial dosage amount and less in amount than the end dosage amount.

53. The method of claim 52, wherein some of the multiple doses of the PDE3 inhibitor are administered with multiple intermediate dosage amounts which are more in amount than the initial dosage amount and less in amount than the end dosage amount, wherein the multiple intermediate dosage amounts are applied in a manner of subsequently increasing amounts.

54. Use of a type III phosphodiesterase (PDE3) inhibitor in the manufacture of a medicament for the treatment of peripheral artery disease in a mammal, comprising administering to the mammal multiple doses of the PDE3 inhibitor, wherein one or more doses are administered in an initial dosage amount and one or more doses are subsequently administered in an end dosage amount, and the initial dosage amount is less in amount than the end dosage amount.

55. The use of claim 54, wherein the PDE3 inhibitor is also a thromboxane A2 (TXA2) synthase inhibitor.

56. The use of claim 54 or 55, wherein the PDE3 inhibitor is a compound of formula (I) as described in claim 20, or a pharmaceutically acceptable salt, solvate, ester, and/or prodrug thereof.

57. The use of any of claims 54 to 56, wherein the peripheral artery disease comprises arteriosclerosis obliterans, intermittent claudication, or a combination thereof.

58. Use of a type III phosphodiesterase (PDE3) inhibitor in the manufacture of a medicament for the treatment of arteriosclerosis obliterans in a mammal, comprising administering to the mammal multiple doses of the PDE3 inhibitor, wherein one or more doses are administered in an initial dosage amount and one or more doses are subsequently administered in an end dosage amount, and the initial dosage amount is less in amount than the end dosage amount.

59. The use of claim 58, wherein the PDE3 inhibitor is also a thromboxane A2 (TXA2) synthase inhibitor.

60. The use of claim 58 or 59, wherein the PDE3 inhibitor is a compound of formula (I) as described in claim 20, or a pharmaceutically acceptable salt, solvate, ester, and/or prodrug thereof.

61. Use of a type III phosphodiesterase (PDE3) inhibitor in the manufacture of a medicament for the treatment of intermittent claudication in a mammal, comprising administering to the mammal multiple doses of the PDE3 inhibitor, wherein one or more doses are administered in an initial dosage amount and one or more doses are subsequently administered in an end dosage amount, and the initial dosage amount is less in amount than the end dosage amount.

62. The use of claim 61, wherein the PDE3 inhibitor is also a thromboxane A2 (TXA2) synthase inhibitor.

63. The use of claim 61 or 62, wherein the PDE3 inhibitor is a compound of formula (I) as described in claim 20, or a pharmaceutically acceptable salt, solvate, ester, and/or prodrug thereof.

64. The use of any of claims 61 to 63, wherein the intermittent claudication is associated with arteriosclerosis obliterans.