WO2010099388A1

WO2010099388A1 - Combinational use of a pde3 inhibitor and other agents

Info

Publication number: WO2010099388A1
Application number: PCT/US2010/025512
Authority: WO
Inventors: Russell H. Ellison; Robert J. Polke; Albert Yehaskel
Original assignee: Indigo Pharmaceuticals
Priority date: 2009-02-27
Filing date: 2010-02-26
Publication date: 2010-09-02

Abstract

The present invention provides the use of a PDE3 inhibitor and one or more additional active agent for the treatment of various diseases.

Description

COMBINATIONAL USE OF A PDE3 INHIBITOR AND OTHER AGENTS

CROSS-REFERENCE TO RELATED APPLICATION

This application claims benefit to U.S. Provisional Patent Application No. 61/156,390, filed on February 27, 2009. This application is also related to International Application No.

PCT/US2009/032,404, filed January 29, 2009 and entitled "A METHOD OF ADMINISTERING A PDE3 INHIBITOR VIA TITRATION FOR THE TREATMENT OF PERIPHERAL ARTERIAL DISEASE", the content of which is hereby 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

The present invention relates to the use of a type III phosphodiesterase (PDE3) inhibitor in combination with at least one additional active agent for the treatment of various diseases, particularly peripheral arterial diseases..

BACKGROUND OF THE INVENTION

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.

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.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides a pharmaceutical composition comprising a type III phosphodiesterase (PDE3) inhibitor; at least one additional active agent; and a pharmaceutically acceptable excipient. In another embodiment, the present invention provides a combination package comprising at least one individual dose of a type III phosphodiesterase (PDE3) inhibitor; and at least one individual dose of one or more active agent.

In one embodiment, the present invention provides a method for treating a TXA₂- mediated disease in a mammal in need thereof comprising co-administering to the mammal a therapeutically effective amount of a PDE3 inhibitor and at least one additional active agent.

In another embodiment, the present invention provides a method of treating a peripheral artery disease ("PAD") in a mammal comprising co-administering to the mammal a therapeutically effective amount of a PDE3 inhibitor and at least one additional active agent. In another embodiment, the present invention provides a method of treating arteriosclerosis obliterans in a mammal comprising co-administering to the mammal a therapeutically effective amount of a PDE3 inhibitor and at least one additional active agent. In another embodiment, the present invention provides a method of treating intermittent claudication in a mammal comprising co-administering to the mammal a therapeutically effective amount of a PDE3 inhibitor and at least one additional active agent.

In another embodiment, the present invention provides a method of distributing a PDE3 inhibitor comprising distributing to a subject a predetermined amount of a first pharmaceutical composition comprising the PDE3 inhibitor, in combination with a predetermined amount of a second pharmaceutical composition comprising one or more active agent.

In another embodiment, the present invention provides a method of distributing a PDE3 inhibitor comprising distributing to a subject a predetermined amount of a first pharmaceutical composition comprising the PDE3 inhibitor, in combination with an instruction of administering the first pharmaceutical composition with a predetermined amount of a second pharmaceutical composition comprising one or more active agent.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides combined use of a type III phosphodiesterase (PDE3) inhibitor and at least one additional active agent for the treatment of a variety of diseases. In one embodiment of the present invention, the PDE3 inhibitor is also a thromboxane A₂ (TXA2) synthase inhibitor. A. The PDE3 Inhibitors In one embodiment of the present invention, the PDE3 inhibitor is a 3(2H)-pyridazinone derivative or its pharmaceutically acceptable salt, solvate, ester, and/or prodrug which is both a PDE3 inhibitor and a TXA₂ synthase inhibitor. 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. 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 known as chronic arteriosclerosis obliterans, and have been demonstrated to improve and extend walking distance, stair climbing, and walking time.

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

wherein R¹ is a hydrogen atom, a straight chained or branched Ci -C₄ alkyl group, a C3-C4 alkenyl group or (CH₂)_n 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);

R² is A¹^-Y¹, wherein A¹ is a straight chained or branched Ci-Ci₂ alkylene group, Y¹ is

CO₂ R⁵ (R⁵ is as defined above), a cyano group, OR⁶ (R⁶ is a hydrogen atom, a straight chained or branched C₁-C₄ alkyl group or a phenyl group), or a thienyl or pyridyl group which may be substituted at any position,

/

CON

\.

R⁷ and R⁸ are respectively and independently a hydrogen atom, a straight chained or branched Cj-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 Cj -C₃ alkyl group or a phenyl group, or form a morpholine ring with a nitrogen atom,

N— SOj;R^s R⁵ is as defined above, R⁹ is a straight chained or branched C₁-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,

R¹⁰ and R¹¹ are respectively and independently a hydrogen atom, a halogen atom, a straight chained or branched C]-C₄ alkyl group, a Ci-C₄ acylamino group, OR⁵ (R⁵ is as defined above), NHSO₂ R⁹ (R⁹ is as defined above) or S(O)_1n -R¹² (m is an integer of from 0 to 2 and R¹² is a straight chained or branched Ci-C₄ alkyl group), provided that R¹⁰ and R¹¹ are not hydrogen atoms at the same time,

0

_N__C__R14

R¹³ is a hydrogen atom, R¹⁴ is a phenyl group, or R¹³ and R¹⁴ together form a C₂-Cs alkylene group which may be substituted with a straight chained C1-C₃ alkyl group,

N-CO₂-R¹⁶ A*

R¹⁵ is a hydrogen atom or a straight chained or branched Ci-C₄ alkyl group, R¹⁶ is a straight chained or branched C₁-C₄ alkyl group, or R¹⁵ and R¹⁶ together form a C₂-Cg alkylene group which may be substituted with a straight chained Ci -C₃ alkyl group,

R¹⁷

/

N

\ RiS

R¹⁷ and R¹⁸ are respectively and independently a straight chained or branched Ci-C₄ alkyl group, or R¹⁷ and R¹⁸ together form a C₂-C₈ alkylene group which may be substituted with a straight chained C₁-C₃ alkyl group,

1 is 0, 1, or 2, k is an integer of from 0 to 3, and R¹⁹ is a hydrogen atom or a halogen atom, (it should be understood that when 1 is 0, 1 , or 2, respectively, the carbon atom to which the phenyl ring is attached has 3, 2, or 1 hydrogen atoms attached respectively);

or alternatively, R² is A²- Y² wherein A² is a C₂-Ci₀ alkylene group which may be substituted with a straight chained C₁-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;

R³ and R⁴ are respectively and independently a hydrogen atom or a straight chained or branched Ci-C₃ alkyl group; X is a chlorine atom, a bromine atom, a hydrogen atom or a cyano group; and

Ar is

j is 0 or 1 and R is a hydrogen atom, a halogen atom or OR (R is as defined above),

Z¹ is an oxygen atom or a sulfur atom,

R²¹ is a hydrogen atom or OR⁵ (R⁵ is as defined above), or

Z² and Z³ are respectively and independently a hydrogen atom, a halogen atom, a straight chained or branched C]-C₄ alkyl group, OR²² (R²² is a hydrogen atom or a straight chained or branched C₁-C₈ alkyl group), or 0-A^!-Y³ (A¹ 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, CO₂R⁵), or

R⁷

CON

R⁵, R⁷ and R⁸ are as defined above, or Z² and Z³ together with a benzene ring, form

W forms a C]-C₈ alkylene group which may be substituted with a straight chained C1-C₃ alkyl group; and a pharmaceutically acceptable salt thereof.

R¹, R², R³, R⁴, X and Ar in the above general formula (I) representing the compound of the present invention are explained hereinafter.

Examples of R¹ 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.

Examples of R² include A¹ -Y¹ or A² -Y² wherein A¹ is a straight chained or branched C₁-C₁₂ alkylene group and A² is a C₂-Ci_O alkylene group which may be substituted with a straight chained C₁-C₃ alkyl group, except for the case that a carbon chain connecting an oxygen atom with Y² has one carbon atom.

Examples of Y¹ 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 l-(2,5-dimethyl)pyrrolidinocarbonyl group, a l-(2,6-dimethyl)piperidinocarbonyl group, a l-(3- phenyl)pyrrolidinocarbonyl group, a l-(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- moφholinocarbonyl 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 l-(2-oxo)azetidinyl group, a l-(2-oxo)pyrrolidinyl group, a l-(2- oxo)piperidinyl group, a l-(2-oxo)homopiperidinyl group, a l-(2-oxo-3,3-dimethyl)pyrrolidinyl group, a 1 -(2-0X0-5, 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-butoxycarbonyl amino 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 l-(2,5- dimethyl)pyrrolidino group, a l-(3,4-dimethyl)pyrrolidino group, a l-(4,4-dimethyl)piperidino group, a l-(4-phenylmethyl)piperadino group, l-(4-diphenylmethyl)piperadino group, a l-(4- substituted phenylmethyl)piperadinyl or l-(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. Examples of Y² include a phenyl group.

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. 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.

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 C₁-Cg alkyl group), a dioxyemthylene, 1 ,2-dioxyethylene or 1,3-dioxypropylene group (which comprises adjacent two substituents joined together), or an O--A¹ -Y³ group. A¹ is a linear or branched Ci-C₁₀ 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 Y¹) 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.

In the above description "n", "i", "sec" and "t" respectively stand for "normal", "iso", "secondary" and "tertiary". Preferable compounds of the compounds having the general formula (I) of the present invention are represented by the following general formula (Ia),

wherein R^lc is a hydrogen atom;

R² is A¹ -Y³ , wherein A¹ is a straight Chained or branched C]-Ci₂ alkylene group, Y³ is CO₂ R⁵ wherein R⁵ is a straight chained or branched Q-₄ alkyl group,

R⁷ and R⁸ are respectively and independently a hydrogen atom, a straight chained or branched C₁-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,

R⁵ is a hydrogen atom or a straight chained or branched C₁-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,

R^10' and R¹¹ are respectively and independently a hydrogen atom, a halogen atom, a straight chained or branched Ci-C₄ alkyl group, a Cj-C₄ acylamino group, OR⁵ (R⁵ is as defined above), NHSO₂ R⁹ (R⁹ is a straight chained or branched Ci-C₄ alkyl group) or S(O)_m — R¹² (m is 0 or 2 and R¹² is a straight chained or branched Cj-C₄ alkyl group), provided that R¹⁰ and R¹¹ are not hydrogen atoms at the same time),

O

N~^»C—R¹*^' ^

R¹³ is a hydrogen atom, R¹⁴ is a phenyl group, or R¹³ and R¹⁴ together form a C₂-C₅ alkylene group,

N— COj—R^16'

R¹⁵ is a hydrogen atom or a straight chained or branched Ci-C₄ alkyl group, R¹⁶ is a straight chained or branched Ci-C₄ alkyl group, or R¹⁵ and R¹⁶ together form a C₂-C₆ alkylene group,

R^!T / R¹⁷ and R¹⁸ are respectively and independently a straight chained or branched Ci-C₄ alkyl group, or R¹⁷ and R¹⁸ together form a C₂-C₆ alkylene group,

1 is 0, 1, or 2; k is an integer of 0, 1, 2, or 3; and R¹⁹ is a hydrogen atom or a halogen atom, (it should be understood that when 1 is 0, 1 , or 2, respectively, the carbon atom to which the phenyl ring is attached has 3, 2, or 1 hydrogen atoms attached respectively) or

or R² is A² -Y² wherein A² is a C₂-Cg 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;

Xc' is a chlorine atom, a bromine atom, or a cyano group; and Ar' is a 3-pyridyl group, or

Z¹ is a halogen atom, a straight chained or branched Cj-C₄ alkyl group, OR²² (R²² is a hydrogen atom or a straight chained or branched C_\-% alkyl group) or O— A³— Y³ (A³ is a Ci-C₄ alkylene group, Y³ is a phenyl group, CO₂ R^{5 '}),

R'¹ /

CON

V

R⁵ , R⁷ and R⁸ are as defined above.

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.

In one embodiment of the present invention, the pyridazinone compound of formula (I) has a structure of formula (Ib):

wherein R¹, R^2a and R³ are each independently a hydrogen atom or a lower alkyl, X is a halogen atom, a cyano or a hydrogen atom, Y^a 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.

The symbols used in the present specification are explained in the following. The lower alkyl for R¹, R^2a 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. Preferable R¹ and R³ are each hydrogen atom, and preferable R^2a is hydrogen atom or C₁-

C₄ alkyl.

The Ci -C₄ alkyl for R^2a is exemplified by methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl.

The halogen atom for X and Y^a 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 Y^a.

The Cj-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.

In the formula (Ib), 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.

Y^a may be substituted at any position on the benzene ring, with preference given to the 4- position. In particular, a pyridazinone compound wherein, in the formula (Ib), R¹ and R³ are hydrogen atoms, R^2a is a hydrogen atom or a C₁-C₄ alkyl, X is a halogen atom, Y^a is a halogen atom or hydrogen atom and A is a Ci-C₅ alkylene optionally substituted by hydroxyl is preferable.

Examples of more preferable pyridazinone compound of formula (Ib) 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.

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

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).

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

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.

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, exhibit low toxicity 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. B, The Additional Active Agents

The additional active agent of the present invention can be any compound, agent, molecule, composition, or medication that has biological activity or therapeutic effect. The additional active agent may or may not be a PDE3 inhibitor. Ih one embodiment, the additional active agent is not a PDE3 inhibitor.

Examples of the additional active agent include, but are not limited to, Angiotensin- Converting Enzyme (ACE) inhibitors; Angiotensin II Receptor Blockers (ARBs); Diuretics; Statins; Ezetimibe; Omega-3 fatty acids; Biguanides; Adenosine Diphosphate (ADP) receptor inhibitors; Aspirin; Calcium Channel Blockers; Beta Blockers; and combinations thereof. For example, the at least one active agent can be selected from the group consisting of

Captopril, Zofenopril, Enalapril, Ramipril, Quinapril, Perindopril, Lisinopril, Benazepril, Fosinopril, Valsartan, Telmisartan, Losartan, Irbesartan, Olmesartan Medoxomil, Olmesartan Medoxomil - HCT, Furosemide, Ethacrynic acid, Torsemide, Bumetanide, Hydrochlorothiazide, Spironolactone, Amiloride, Triamterene, Potassium canreonate, Thiazides, Acetazolamide, Indapamide, Atorvastatin, Cerivastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, Ezetimibe, α-Linolenic acid, Stearidonic acid, Eicosatrienoic acid, Eicosatetraenoic acid, Eicosapentaenoic acid, Docosapentaenoic acid, Clupanodonic acid, Docosahexaenoic acid, Tetracosapentaenoic acid, Tetracosahexaenoic acid, Metformin, Prasugrel, Clopidogrel, Ticlopidine, Aspirin, Amlodipine, Aranidipine, Azelnidipine, Barnidipine, Benidipine, Cilnidipine, Clevidipine, Efonidipine, Felodipine, Lacidipine, Lercanidipine, Manidipine, Nicardipine, Nifedipine, Nilvadipine, Nimodipine, Nisoldipine,

Nitrendipine, Pranidipine, Verapamil, Gallopamil, Diltiazem, Acebutolol, Bisoprolol, Esmolol, Propranolol, Atenolol, Labetalol, Carvedilol, Metoprolol, Nebivolol, Alprenolol, Carteolol, Levobunolol, Mepindolol, Metipranolol, Nadolol, Oxprenolol, Penbutolol, Pindolol, Sotalol, Timolol, Betaxolol, Bisoprolol, Esmolol, Metoprolol, Nebivolol, Amosulalol, Landiolol, Tilisolol, Arotinolol, Celiprolol, Labetalol, Butaxamine, and a combination thereof. C. Pharmaceutical Compositions or Packages

The PDE3 inhibitor and the at least one additional active agent can be formulated into a single pharmaceutical composition, or can be used in forms of two individual pharmaceutical compositions. In one embodiment, the present invention provides a pharmaceutical composition comprising a PDE3 inhibitor; at least one additional active agent; and a pharmaceutically acceptable excipient.

In another embodiment, the present invention provides a combination package comprising at least one individual dose of a type III phosphodiesterase (PDE3) inhibitor; and at least one individual dose of one or more active agent.

The dosage form of the pharmaceutical composition or each individual doses are 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. The PDE3 inhibitor and the at least one additional active agent can be formulated into preparations by a method conventionally used for manufacturing pharmaceuticals. 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).

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.

The PDE3 inhibitor and the additional active agent, in combination or solely, is in a therapeutically effective amount. The term "therapeutically effective amount", as used herein, denotes an amount that can produce one or more intended biological effects in a patient, such as ameliorating, relieving, improving, or remedying the conditions, symptoms, and/or effects of the target disease. It is understood to one skilled in the art that the therapeutically effective amount may vary for each patient depending on the patient's condition and/or the therapeutic effect to be achieved.

In one embodiment, the pyridazinone compound of formula (I) or a pharmacologically acceptable salt thereof is appropriately determined according to age, body weight, severity of symptom and the like of patients, and they are generally administered in about 0.001 to about 500 mg/day, preferably about 0.005 to about 100 mg/day in a single to several times divided doses to a human adult. In one embodiment, the pyridazinone compound of formula (I) is administered in about 0.5 to about 15 mg/day, preferably about 1 to about 10 mg/day. In another embodiment, the additional active agent is appropriately determined according to age, body weight, severity of symptom and the like of patients, and they are generally administered in about 0.001 to about 500 mg/day, preferably about 0.005 to about 100 mg/day in a single to several times divided doses to a human adult.

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 about 0.05 to about 20 parts by weight per part by weight of the pyridazinone compound.

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.

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.

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 μm. Micronization by a known method can make the average particle size about 7 to about 10 μm. The micronization of the pyridazinone compound contributes to improvement in dissolution and absorption.

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.

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.

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.

D. Methods of Co-administration

The PDE3 inhibitor and the additional active agent can be co-administered to a patient in need thereof for the treatment of various diseases. The term "co-administration" or "coadministration" refers to administration of the PDE3 inhibitor and the additional active agent together in a coordinated fashion. For example, the co-administration can be simultaneous administration, sequential administration, overlapping administration, interval administration, continuous administration, or a combination thereof.

By "simultaneous administration" or "administered simultaneously", it is meant that the PDE3 inhibitor and the additional active agent are administered on the same day. For the simultaneous administration, the PDE3 inhibitor and the additional active agent can be administered at the same time or one at a time on the same day.

By "sequential administration", it is meant that during a period of two or more days of continuous co-administration without any void day, only one of the PDE3 inhibitor and the additional active agent is administered on any given day. By "overlapping administration", it is meant that during a period of two or more days of continuous co-administration without any void day, there is at least one day of simultaneous administration and at least one day when only one of the PDE3 inhibitor and the additional active agent is administered. The term "administered sequentially" includes both sequential administration and overlapping administration as described above.

By "interval administration" or "administered separately", it is meant a period of co- administration with at least one void day. By "continuous administration", it is meant a period of co-administration without any void day. The continuous administration may be simultaneous, sequential, or overlapping, as described above. By "void day", it is meant a day when neither the PDE3 inhibitor nor the additional active ingredient is administered. In other words, none of the PDE3 inhibitor and the additional active ingredient is administered on a void day. In one embodiment, the present invention provides a method for treating a TXA₂- mediated disease in a mammal in need thereof comprising co-administering to the mammal a therapeutically effective amount of a PDE3 inhibitor and at least one additional active agent. 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.

In another embodiment, the present invention provides a method of treating a peripheral artery disease ("PAD") in a mammal comprising co-administering to the mammal a therapeutically effective amount of a PDE3 inhibitor and at least one additional active agent. Examples of the PAD include, but are not limited to, arteriosclerosis obliterans, intermittent claudication, or a combination thereof.

In another embodiment, the present invention provides a method of treating arteriosclerosis obliterans in a mammal comprising co-administering to the mammal a therapeutically effective amount of a PDE3 inhibitor and at least one additional active agent. In another embodiment, the present invention provides a method of treating intermittent claudication in a mammal comprising co-administering to the mammal a therapeutically effective amount of a PDE3 inhibitor and at least one additional active agent. In one embodiment, the intermittent claudication is associated with arteriosclerosis obliterans.

In another embodiment, the present invention provides a method of distributing a PDE3 inhibitor comprising distributing to a subject a predetermined amount of a first pharmaceutical composition comprising the PDE3 inhibitor, in combination with a predetermined amount of a second pharmaceutical composition comprising one or more active agent. In another embodiment, the present invention provides a method of distributing a PDE3 inhibitor comprising distributing to a subject a predetermined amount of a first pharmaceutical composition comprising one or more active agent, in combination with a predetermined amount of a second pharmaceutical composition comprising the PDE3 inhibitor.

In another embodiment, the present invention provides a method of distributing a PDE3 inhibitor comprising distributing to a subject a predetermined amount of a first pharmaceutical composition comprising the PDE3 inhibitor, in combination with an instruction of administering the first pharmaceutical composition with a predetermined amount of a second pharmaceutical composition comprising one or more active agent. In another embodiment, the present invention provides a method of distributing one or more active agent comprising distributing to a subject a predetermined amount of a first pharmaceutical composition comprising the one or more active agent, in combination with an instruction of administering the first pharmaceutical composition with a predetermined amount of a second pharmaceutical composition comprising a PDE3 inhibitor.

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.

AU 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.

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

We claim:

1. A pharmaceutical composition comprising a type III phosphodiesterase (PDE3) inhibitor; at least one additional active agent; and a pharmaceutically acceptable excipient.

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

3. The pharmaceutical composition of claim 1 or 2, wherein the PDE3 inhibitor is a compound of formula (I):

wherein:

R¹ is a hydrogen atom, a straight chain or branched C1-C4 alkyl group, a C3 -C4 alkenyl group or (CH₂)_nCO₂R⁵ 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 Al-Yl where Al is a straight chain or branched Cl -C 12 alkyl ene group, Yl 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 alkyl ene group which is unsubstituted or substituted with a straight chain or branched Cl- 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 Cl -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 R¹ ' 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)_1n-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-C10 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

^ ^J where j is O or 1 and R20 is a hydrogen atom, a halogen atom or OR¹² where R¹² is

as defined above, ^z' where Z¹ is an oxygen atom or sulfur atom; or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.

4. The pharmaceutical composition of any of claims 1 to 3, wherein the PDE3 inhibitor is a compound of formula (Ia):

or a pharmaceutically acceptable salt, solvate, ester, and/or prodrug thereof, wherein:

R¹, R^2a 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;

Y^a is a halogen atom, a trifluoromethyl group or a hydrogen atom; and

A is a C1-C8 alkylene group optionally substituted by a hydroxyl group.

5. The pharmaceutical composition of any of claims 1 to 4, wherein the PDE3 inhibitor 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.

6. The pharmaceutical composition of any of claims 1 to 5, wherein the at least one additional active agent is not a PDE3 inhibitor.

7. The pharmaceutical composition of any of claims 1 to 5, wherein the at least one additional active agent is selected from the group consisting of Angiotensin-Converting Enzyme (ACE) inhibitors; Angiotensin II Receptor Blockers (ARBs); Diuretics; Statins; Ezetimibe; Omega-3 fatty acids; Biguanides; Adenosine Diphosphate (ADP) receptor inhibitors; Aspirin; Calcium Channel Blockers; Beta Blockers; and combinations thereof.

8. The pharmaceutical composition of any of claims 1 to 5, wherein the at least one additional active agent is selected from the group consisting of Captopril, Zofenopril, Enalapril, Ramipril, Quinapril, Perindopril, Lisinopril, Benazepril, Fosinopril, Valsartan, Telmisartan, Losartan, Irbesartan, Olmesartan Medoxomil, Olmesartan Medoxomil - HCT, Furosemide, Ethacrynic acid, Torsemide, Bumetanide, Hydrochlorothiazide, Spironolactone, Amiloride, Triamterene, Potassium canreonate, Thiazides, Acetazolamide, Indapamide, Atorvastatin, Cerivastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, Ezetimibe, α-Linolenic acid, Stearidonic acid, Eicosatrienoic acid, Eicosatetraenoic acid, Eicosapentaenoic acid, Docosapentaenoic acid, Clupanodonic acid, Docosahexaenoic acid, Tetracosapentaenoic acid, Tetracosahexaenoic acid, Metformin, Prasugrel, clopidogrel, ticlopidine, Aspirin, Amlodipine, Aranidipine, Azelnidipine, Barnidipine, Benidipine, Cilnidipine, Clevidipine, Efonidipine, Felodipine, Lacidipine, Lercanidipine, Manidipine, Nicardipine, Nifedipine, Nilvadipine, Nimodipine, Nisoldipine, Nitrendipine, Pranidipine, Verapamil, Gallopamil, Diltiazem, Acebutolol, Bisoprolol, Esmolol, Propranolol, Atenolol, Labetalol, Carvedilol, Metoprolol, Nebivolol, Alprenolol, Carteolol, Levobunolol, Mepindolol, Metipranolol, Nadolol, Oxprenolol, Penbutolol, Pindolol, Sotalol, Timolol, Betaxolol, Bisoprolol, Esmolol, Metoprolol, Nebivolol, Amosulalol, Landiolol, Tilisolol, Arotinolol, Celiprolol, Labetalol, Butaxamine, and a combination thereof.

9. A combination package comprising at least one individual dose of a type III phosphodiesterase (PDE3) inhibitor; and at least one individual dose of one or more active agent.

10. The combination package of claim 9, wherein the PDE3 inhibitor is also a thromboxane A₂ (TXA2) synthase inhibitor.

11. The combination package of claim 9 or 10, wherein the PDE3 inhibitor is a compound of formula (I) as defined in claim 3 or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.

12. The combination package of any of claims 9 to 11, wherein the PDE3 inhibitor is a compound of formula (Ia) as defined in claim 4 or a pharmacologically acceptable salt, solvate, ester, or prodrug thereof.

13. The combination package of any of claims 9 to 12, wherein the PDE3 inhibitor 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-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-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

14. The combination package of any of claims 9 to 13, wherein the one or more active agent is not a PDE3 inhibitor.

15. The combination package of any of claims 9 to 13, wherein the one or more active agent is selected from the group consisting of ACE inhibitors; ARBs; Diuretics; Statins; Ezetimibe; Omega-3 fatty acids; Biguanides; ADP receptor inhibitors; Aspirin; Calcium Channel Blockers; Beta Blockers; and combinations thereof.

16. The combination package of any of claims 9 to 13, wherein the one or more active agent is selected from the group consisting of Captopril, Zofenopril, Enalapril, Ramipril, Quinapril, Perindopril, Lisinopril, Benazepril, Fosinopril, Valsartan, Telmisartan, Losartan, Irbesartan, Olmesartan Medoxomil, Olmesartan Medoxomil - HCT, Furosemide, Ethacrynic acid, Torsemide, Bumetanide, Hydrochlorothiazide, Spironolactone, Amiloride, Triamterene, Potassium canreonate, Thiazides, Acetazolamide, Indapamide, Atorvastatin, Cerivastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, Ezetimibe, α-Linolenic acid, Stearidonic acid, Eicosatrienoic acid, Eicosatetraenoic acid, Eicosapentaenoic acid, Docosapentaenoic acid, Clupanodonic acid, Docosahexaenoic acid, Tetracosapentaenoic acid, Tetracosahexaenoic acid, Metformin, Prasugrel, clopidogrel, ticlopidine, Aspirin, Amlodipine, Aranidipine, Azelnidipine, Barnidipine, Benidipine, Cilnidipine, Clevidipine, Efonidipine, Felodipine, Lacidipine, Lercanidipine, Manidipine, Nicardipine, Nifedipine, Nilvadipine, Nimodipine, Nisoldipine, Nitrendipine, Pranidipine, Verapamil, Gallopamil, Diltiazem, Acebutolol, Bisoprolol, Esmolol, Propranolol, Atenolol, Labetalol, Carvedilol, Metoprolol, Nebivolol, Alprenolol, Carteolol, Levobunolol, Mepindolol, Metipranolol, Nadolol, Oxprenolol, Penbutolol, Pindolol, Sotalol, Timolol, Betaxolol, Bisoprolol, Esmolol, Metoprolol, Nebivolol, Amosulalol, Landiolol, Tilisolol, Arotinolol, Celiprolol, Labetalol, Butaxamine, and a combination thereof.

17. A method for treating a TXA₂-mediated disease in a mammal in need thereof comprising co-administering to the mammal a therapeutically effective amount of a PDE3 inhibitor and at least one additional active agent.

18. The method of claim 17, wherein the PDE3 inhibitor is also a TXA₂ inhibitor.

19. The method of claim 17 or 18, wherein the PDE3 inhibitor is a compound of formula (I) as defined in claim 3 or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.

20. The method of any one of claims 17 to 19, wherein the PDE3 inhibitor is a compound of formula (Ia) as defined in claim 4 or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.

21. The method of any one of claims 17 to 20, wherein the PDE3 inhibitor 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-(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)-3-hydroxypropoxy]-5-(3-pyridylmethylamino)-3(2H)- pyridazinone,

22. The method of any of claims 17 to 21 , wherein the at least one additional active agent is not a PDE3 inhibitor.

23. The method of any of claims 17 to 22, wherein the at least one additional active agent is selected from the group consisting of ACE inhibitors; ARBs; Diuretics; Statins; Ezetimibe; Omega-3 fatty acids; Biguanides; ADP receptor inhibitors; Aspirin; Calcium Channel Blockers; Beta Blockers; and combinations thereof.

24. The method of any of claims 17 to 22, wherein the at least one additional active agent is selected from the group consisting of Captopril, Zofenopril, Enalapril, Ramipril, Quinapril, Perindopril, Lisinopril, Benazepril, Fosinopril, Valsartan, Telmisartan, Losartan, Irbesartan, Olmesartan Medoxomil, Olmesartan Medoxomil - HCT, Furosemide, Ethacrynic acid, Torsemide, Bumetanide, Hydrochlorothiazide, Spironolactone, Amiloride, Triamterene, Potassium canreonate, Thiazides, Acetazolamide, Indapamide, Atorvastatin, Cerivastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, Ezetimibe, α-Linolenic acid, Stearidonic acid, Eicosatrienoic acid, Eicosatetraenoic acid, Eicosapentaenoic acid, Docosapentaenoic acid, Clupanodonic acid, Docosahexaenoic acid, Tetracosapentaenoic acid, Tetracosahexaenoic acid, Metformin, Prasugrel, clopidogrel, ticlopidine, Aspirin, Amlodipine, Aranidipine, Azelnidipine, Barnidipine, Benidipine, Cilnidipine, Clevidipine, Efonidipine, Felodipine, Lacidipine, Lercanidipine, Manidipine, Nicardipine, Nifedipine, Nilvadipine, Nimodipine, Nisoldipine, Nitrendipine, Pranidipine, Verapamil, Gallopamil, Diltiazem, Acebutolol, Bisoprolol, Esmolol, Propranolol, Atenolol, Labetalol, Carvedilol, Metoprolol, Nebivolol, Alprenolol, Carteolol, Levobunolol, Mepindolol, Metipranolol, Nadolol, Oxprenolol, Penbutolol, Pindolol, Sotalol, Timolol, Betaxolol, Bisoprolol, Esmolol, Metoprolol, Nebivolol, Amosulalol, Landiolol, Tilisolol, Arotinolol, Celiprolol, Labetalol, Butaxamine, and a combination thereof.

25. The method of any of claims 17 to 24, wherein the PDE3 inhibitor and the at least one additional active agent is administered simultaneously, sequentially, or separately.

26. The method of any of claims 17 to 25, 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.

27. A method of treating a peripheral artery disease ("PAD") in a mammal comprising coadministering to the mammal a therapeutically effective amount of a PDE3 inhibitor and at least one additional active agent.

28. The method of claim 27, wherein the PDE3 inhibitor is also a TXA₂ inhibitor.

29. The method of claim 27 or 28, wherein the PDE3 inhibitor is a compound of formula (I) as defined in claim 3 or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.

30. The method of any of claims 27 to 29, wherein the PDE3 inhibitor is a compound of formula (Ia) as defined in claim 4 or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.

31. The method of any of claims 27 to 30, wherein the PDE3 inhibitor 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-bromo-6- [3 -(4-chlorophenyl)-2,2-dimethylpropoxy] -5-(3 -pyridylmethylamino)-3 (2H)- pyrdazinone,

32. The method of any of claims 27 to 31 , wherein the at least one additional active agent is not a PDE3 inhibitor.

33. The method of any of claims 27 to 32, wherein the at least one additional active agent is selected from the group consisting of ACE inhibitors; ARBs; Diuretics; Statins; Ezetimibe; Omega-3 fatty acids; Biguanides; ADP receptor inhibitors; Aspirin; Calcium Channel Blockers; Beta Blockers; and combinations thereof.

34. The method of any of claims 27 to 33, wherein the at least one additional active agent is selected from the group consisting of Captopril, Zofenopril, Enalapril, Ramipril, Quinapril, Perindopril, Lisinopril, Benazepril, Fosinopril, Valsartan, Telmisartan, Losartan, Irbesartan, Olmesartan Medoxomil, Olmesartan Medoxomil - HCT, Furosemide, Ethacrynic acid, Torsemide, Bumetanide, Hydrochlorothiazide, Spironolactone, Amiloride, Triamterene, Potassium canreonate, Thiazides, Acetazolamide, Indapamide, Atorvastatin, Cerivastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, Ezetimibe, α-Linolenic acid, Stearidonic acid, Eicosatrienoic acid, Eicosatetraenoic acid, Eicosapentaenoic acid, Docosapentaenoic acid, Clupanodonic acid, Docosahexaenoic acid, Tetracosapentaenoic acid, Tetracosahexaenoic acid, Metformin, Prasugrel, clopidogrel, ticlopidine, Aspirin, Amlodipine, Aranidipine, Azelnidipine, Barnidipine, Benidipine, Cilnidipine, Clevidipine, Efonidipine, Felodipine, Lacidipine, Lercanidipine, Manidipine, Nicardipine, Nifedipine, Nilvadipine, Nimodipine, Nisoldipine, Nitrendipine, Pranidipine, Verapamil, Gallopamil, Diltiazem, Acebutolol, Bisoprolol, Esmolol, Propranolol, Atenolol, Labetalol, Carvedilol, Metoprolol, Nebivolol, Alprenolol, Carteolol, Levobunolol, Mepindolol, Metipranolol, Nadolol, Oxprenolol, Penbutolol, Pindolol, Sotalol, Timolol, Betaxolol, Bisoprolol, Esmolol, Metoprolol, Nebivolol, Amosulalol, Landiolol, Tilisolol, Arotinolol, Celiprolol, Labetalol, Butaxamine, and a combination thereof.

35. The method of any of claims 27 to 34, wherein the PDE3 inhibitor and the at least one additional active agent is administered simultaneously, sequentially, or separately.

36. The method of any of claims 27 to 35, wherein the PAD is arteriosclerosis obliterans, intermittent claudication, or a combination thereof.

37. A method of treating arteriosclerosis obliterans in a mammal comprising coadministering to the mammal a therapeutically effective amount of a PDE3 inhibitor and at least one additional active agent.

38. The method of claim 37, wherein the PDE3 inhibitor is also a TXA₂ inhibitor.

39. The method of claim 37 or 38, wherein the PDE3 inhibitor is a compound of formula (I) as defined in claim 3 or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.

40. The method of any of claims 37 to 39, wherein the PDE3 inhibitor is a compound of formula (Ia) as defined in claim 4 or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.

41. The method of any of claims 37 to 40, wherein the PDE3 inhibitor 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,

42. The method of any of claims 37 to 41 , wherein the at least one additional active agent is not a PDE3 inhibitor.

43. The method of any of claims 37 to 42, wherein the at least one additional active agent is selected from the group consisting of ACE inhibitors; ARBs; Diuretics; Statins; Ezetimibe; Omega-3 fatty acids; Biguanides; ADP receptor inhibitors; Aspirin; Calcium Channel Blockers; Beta Blockers; and combinations thereof.

44. The method of any of claims 37 to 43, wherein the at least one additional active agent is selected from the group consisting of Captopril, Zofenopril, Enalapril, Ramipril, Quinapril, Perindopril, Lisinopril, Benazepril, Fosinopril, Valsartan, Telmisartan, Losartan, Irbesartan, Olmesartan Medoxomil, Olmesartan Medoxomil - HCT, Furosemide, Ethacrynic acid, Torsemide, Bumetanide, Hydrochlorothiazide, Spironolactone, Amiloride, Triamterene, Potassium canreonate, Thiazides, Acetazolamide, Indapamide, Atorvastatin, Cerivastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, Ezetimibe, α-Linolenic acid, Stearidonic acid, Eicosatrienoic acid, Eicosatetraenoic acid, Eicosapentaenoic acid, Docosapentaenoic acid, Clupanodonic acid, Docosahexaenoic acid, Tetracosapentaenoic acid, Tetracosahexaenoic acid, Metformin, Prasugrel, clopidogrel, ticlopidine, Aspirin, Amlodipine, Aranidipine, Azelnidipine, Barnidipine, Benidipine, Cilnidipine, Clevidipine, Efonidipine, Felodipine, Lacidipine, Lercanidipine, Manidipine, Nicardipine, Nifedipine, Nilvadipine, Nimodipine, Nisoldipine, Nitrendipine, Pranidipine, Verapamil, Gallopamil, Diltiazem, Acebutolol, Bisoprolol, Esmolol, Propranolol, Atenolol, Labetalol, Carvedilol, Metoprolol, Nebivolol, Alprenolol, Carteolol, Levobunolol, Mepindolol, Metipranolol, Nadolol, Oxprenolol, Penbutolol, Pindolol, Sotalol, Timolol, Betaxolol, Bisoprolol, Esmolol, Metoprolol, Nebivolol, Amosulalol, Landiolol, Tilisolol, Arotinolol, Celiprolol, Labetalol, Butaxamine, and a combination thereof.

45. The method of any of claims 37 to 44, wherein the PDE3 inhibitor and the at least one additional active agent is administered simultaneously, sequentially, or separately.

46. A method of treating intermittent claudication in a mammal comprising co-administering to the mammal a therapeutically effective amount of a PDE3 inhibitor and at least one additional active agent.

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 PDE3 inhibitor is a compound of formula (I) as defined in claim 3 or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.

49. The method of any of claims 46 to 48, wherein the PDE3 inhibitor is a compound of formula (Ia) as defined in claim 4 or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.

50. The method of any of claims 46 to 49, wherein the PDE3 inhibitor 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,

51. The method of any of claims 46 to 50, wherein the at least one additional active agent is not a PDE3 inhibitor.

52. The method of any of claims 46 to 51 , wherein the at least one additional active agent is selected from the group consisting of ACE inhibitors; ARBs; Diuretics; Statins; Ezetimibe; Omega-3 fatty acids; Biguanides; ADP receptor inhibitors; Aspirin; Calcium Channel Blockers; Beta Blockers; and combinations thereof.

53. The method of any of claims 46 to 52, wherein the at least one additional active agent is selected from the group consisting of Captopril, Zofenopril, Enalapril, Ramipril, Quinapril, Perindopril, Lisinopril, Benazepril, Fosinopril, Valsartan, Telmisartan, Losartan, Irbesartan, Olmesartan Medoxomil, Olmesartan Medoxomil - HCT, Furosemide, Ethacrynic acid, Torsemide, Bumetanide, Hydrochlorothiazide, Spironolactone, Amiloride, Triamterene, Potassium canreonate, Thiazides, Acetazolamide, Indapamide, Atorvastatin, Cerivastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, Ezetimibe, α-Linolenic acid, Stearidonic acid, Eicosatrienoic acid, Eicosatetraenoic acid, Eicosapentaenoic acid, Docosapentaenoic acid, Clupanodonic acid, Docosahexaenoic acid, Tetracosapentaenoic acid, Tetracosahexaenoic acid, Metformin, Prasugrel, clopidogrel, ticlopidine, Aspirin, Amlodipine, Aranidipine, Azelnidipine, Barnidipine, Benidipine, Cilnidipine, Clevidipine, Efonidipine, Felodipine, Lacidipine, Lercanidipine, Manidipine, Nicardipine, Nifedipine, Nilvadipine, Nimodipine, Nisoldipine, Nitrendipine, Pranidipine, Verapamil, Gallopamil, Diltiazem, Acebutolol, Bisoprolol, Esmolol, Propranolol, Atenolol, Labetalol, Carvedilol, Metoprolol, Nebivolol, Alprenolol, Carteolol, Levobunolol, Mepindolol, Metipranolol, Nadolol, Oxprenolol, Penbutolol, Pindolol, Sotalol, Timolol, Betaxolol, Bisoprolol, Esmolol, Metoprolol, Nebivolol, Amosulalol, Landiolol, Tilisolol, Arotinolol, Celiprolol, Labetalol, Butaxamine, and a combination thereof.

54. The method of any of claims 46 to 53, wherein the PDE3 inhibitor and the at least one additional active agent is administered simultaneously, sequentially, or separately.

55. The method of any of claims 46 to 54, wherein the intermittent claudication is associated with arteriosclerosis obliterans.

56. A method of distributing a PDE3 inhibitor comprising distributing to a subject a predetermined amount of a first pharmaceutical composition comprising the PDE3 inhibitor, in combination with a predetermined amount of a second pharmaceutical composition comprising one or more active agent.

57. The method of claim 56, wherein the PDE3 inhibitor is also a TXA₂ inhibitor.

58. The method of claim 56 or 57, wherein the PDE3 inhibitor is a compound of formula (I) as defined in claim 3 or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.

59. The method of any of claims 56 to 58, wherein the PDE3 inhibitor is a compound of formula (Ia) as defined in claim 4 or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.

60. The method of any of claims 56 to 59, wherein the PDE3 inhibitor 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-chloro-6- [3 -(4-chlorophenyl) -2,2-dimethylpropoxy] -5 -(3 -pyridylmethylamino)-3 (2H)- pyridazinone,

61. The method of any of claims 56 to 60, wherein the at least one active agent is not a PDE3 inhibitor.

62. The method of any of claims 56 to 61, wherein the one or more active agent is selected from the group consisting of ACE inhibitors; ARBs; Diuretics; Statins; Ezetimibe; Omega-3 fatty acids; Biguanides; ADP receptor inhibitors; Aspirin; Calcium Channel Blockers; Beta Blockers; and combinations thereof.

63. The method of any of claims 56 to 62, wherein the one or more active agent is selected from the group consisting of Captopril, Zofenopril, Enalapril, Ramipril, Quinapril, Perindopril, Lisinopril, Benazepril, Fosinopril, Valsartan, Telmisartan, Losartan, Irbesartan, Olmesartan Medoxomil, Olmesartan Medoxomil - HCT, Furosemide, Ethacrynic acid, Torsemide, Bumetanide, Hydrochlorothiazide, Spironolactone, Amiloride, Triamterene, Potassium canreonate, Thiazides, Acetazolamide, Indapamide, Atorvastatin, Cerivastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, Ezetimibe, α- Linolenic acid, Stearidonic acid, Eicosatrienoic acid, Eicosatetraenoic acid, Eicosapentaenoic acid, Docosapentaenoic acid, Clupanodonic acid, Docosahexaenoic acid, Tetracosapentaenoic acid, Tetracosahexaenoic acid, Metformin, Prasugrel, clopidogrel, ticlopidine, Aspirin, Amlodipine, Aranidipine, Azelnidipine, Barnidipine, Benidipine, Cilnidipine, Clevidipine, Efonidipine, Felodipine, Lacidipine, Lercanidipine, Manidipine, Nicardipine, Nifedipine, Nilvadipine, Nimodipine, Nisoldipine, Nitrendipine, Pranidipine, Verapamil, Gallopamil, Diltiazem, Acebutolol, Bisoprolol, Esmolol, Propranolol, Atenolol, Labetalol, Carvedilol, Metoprolol, Nebivolol, Alprenolol, Carteolol, Levobunolol, Mepindolol, Metipranolol, Nadolol, Oxprenolol, Penbutolol, Pindolol, Sotalol, Timolol, Betaxolol, Bisoprolol, Esmolol, Metoprolol, Nebivolol, Amosulalol, Landiolol, Tilisolol, Arotinolol, Celiprolol, Labetalol, Butaxamine, and a combination thereof.

64. A method of distributing a PDE3 inhibitor comprising distributing to a subject a predetermined amount of a first pharmaceutical composition comprising the PDE3 inhibitor, in combination with an instruction of administering the first pharmaceutical composition with a predetermined amount of a second pharmaceutical composition comprising one or more active agent.

65. The method of claim 64, wherein the PDE3 inhibitor is also a TXA₂ inhibitor.

66. The method of claim 64 or 65, wherein the PDE3 inhibitor is a compound of formula (I) as defined in claim 3 or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.

67. The method of any of claims 64 to 66, wherein the PDE3 inhibitor is a compound of formula (Ia) as defined in claim 4 or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.

68. The method of any of claims 64 to 67, wherein the PDE3 inhibitor 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,

69. The method of any of claims 64 to 68, wherein the one or more active agent is not a PDE3 inhibitor.

70. The method of any of claims 64 to 69, wherein the one or more active agent is selected from the group consisting of ACE inhibitors; ARBs; Diuretics; Statins; Ezetimibe; Omega-3 fatty acids; Biguanides; ADP receptor inhibitors; Aspirin; Calcium Channel Blockers; Beta Blockers; and combinations thereof.

71. The method of any of claims 64 to 70, wherein the one or more active agent is selected from the group consisting of Captopril, Zofenopril, Enalapril, Ramipril, Quinapril, Perindopril, Lisinopril, Benazepril, Fosinopril, Valsartan, Telmisartan, Losartan, Irbesartan, Olmesartan Medoxomil, Olmesartan Medoxomil - HCT, Furosemide, Ethacrynic acid, Torsemide, Bumetanide, Hydrochlorothiazide, Spironolactone, Amiloride, Triamterene, Potassium canreonate, Thiazides, Acetazolamide, Indapamide, Atorvastatin, Cerivastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, Ezetimibe, α- Linolenic acid, Stearidonic acid, Eicosatrienoic acid, Eicosatetraenoic acid, Eicosapentaenoic acid, Docosapentaenoic acid, Clupanodonic acid, Docosahexaenoic acid, Tetracosapentaenoic acid, Tetracosahexaenoic acid, Metformin, Prasugrel, clopidogrel, ticlopidine, Aspirin, Amlodipine, Aranidipine, Azelnidipine, Barnidipine, Benidipine, Cilnidipine, Clevidipine, Efonidipine, Felodipine, Lacidipine, Lercanidipine, Manidipine, Nicardipine, Nifedipine, Nilvadipine, Nimodipine, Nisoldipine, Nitrendipine, Pranidipine, Verapamil, Gallopamil, Diltiazem, Acebutolol, Bisoprolol, Esmolol, Propranolol, Atenolol, Labetalol, Carvedilol, Metoprolol, Nebivolol, Alprenolol, Carteolol, Levobunolol, Mepindolol, Metipranolol, Nadolol, Oxprenolol, Penbutolol, Pindolol, Sotalol, Timolol, Betaxolol, Bisoprolol, Esmolol, Metoprolol, Nebivolol, Amosulalol, Landiolol, Tilisolol, Arotinolol, Celiprolol, Labetalol, Butaxamine, and a combination thereof.