HK1119068A - Roflumilast for the treatment of pulmonary hypertension - Google Patents

Description

Roflumilast for treating pulmonary hypertension

Technical Field

The present invention relates to the use of Roflumilast (Roflumilast), the pharmaceutically acceptable salts thereof, the nitrogen-oxides and the pharmaceutically acceptable salts of the nitrogen-oxides for the prophylactic or curative treatment of pulmonary hypertension.

Furthermore, the present invention relates to the combination of roflumilast, pharmaceutically acceptable salts, nitric oxide and pharmaceutically acceptable salts of nitric oxide with a PDE5 inhibitor; and the use of pharmaceutical compositions, combination products and kits comprising these combinations for the treatment of pulmonary hypertension.

Background of the invention

In international patent application WO9837894, it is disclosed that combinations of phosphodiesterase inhibitors and either adenyl or guanyl cyclase agonists are particularly useful for the treatment of pulmonary hypertension. In international patent application WO9509636, a method of treating pulmonary hypertension is disclosed comprising intratracheal or intrabronchial administering to a subject an effective amount of an agent selected from the group consisting of cyclic nucleotides, phosphodiesterase inhibitors, nitric oxide precursors, nitric oxide donors and nitric oxide analogs, thereby reducing pulmonary circulatory vascular resistance. In cardiovasc. rev & Rep 2002; 23, pp 274-279, Martin r. wilkins et al reviewed the use of phosphodiesterase inhibitors in the treatment of pulmonary hypertension. In Am J Physiol Lung Cell MolPhysiol 288: L103-L115, 2005, discloses that cAMP phosphodiesterase inhibitors enhance the effect of prostacyclin analogs on hypoxic pulmonary vascular remodeling. In CurrentOption in Investigational Drugs 20056 (3), pp 283-288, Wang D et al describe a novel method for the treatment of hypertension using PDE4 inhibitors. In CurrentOption in Investigational Drugs 20023 (8), Reid P describes the metabolism of roflumilast to roflumilast-N-oxide in vivo, and these two compounds function in a similar manner under most experimental conditions. In international patent application WO03070279 an oral dosage form comprising a PDE4 inhibitor, to name one sole example a composition comprising roflumilast, is disclosed for use in the treatment or prevention of all diseases including COPD which are believed to be treatable or preventable by the use of a PDE4 inhibitor.

Pulmonary Hypertension (PH)Defined as mean Pulmonary Artery Pressure (PAP) > 25mm Hg at rest or > 30mm Hg at exercise. According to the current guidelines for diagnosis and treatment of pulmonary hypertension published in 2004 by the European Society of Cardiology (Eur Heart J25: 2243-. Group (1) includes, for example, idiopathic and familial PAH as well as PAH caused by connective tissue diseases (e.g., scleroderma, CREST), congenital systemic to pulmonary shunts, portal hypertension, HIV, ingestion of drugs and toxins (e.g., anorexigens). The pH occurring in COPD was classified into group (3). Musculature of the small pulmonary arteries (less than 500 μm in diameter) is widely recognized as a general pathological criterion for PAH (group 1), however, it may also occur in other forms of PH, such as PH based on COPD or thrombotic and/or thromboembolic disease. Other pathoanatomical features of PH are intimal thickening based on migration and proliferation of (muscle) fibroblasts or smooth muscle cells, extracellular matrix hyperproliferation, endothelial injury and/or proliferation, and perivascular inflammatory cell infiltration. Remodeling of the peripheral pulmonary arterial vasculature results in increased pulmonary circulatory vascular resistance, continuous right heart failure, and death. While background treatments and more general measures such as oral anticoagulants, diuretics, digoxin and oxygen supply remain listed in current guidelines, it is not expected that these treatments interfere with the causes and mechanisms of pulmonary artery remodeling. Some patients with PAH may also benefit from Ca + + -antagonists, especially those with a vigorous response to vasodilators. Innovative therapeutic approaches developed in the past decade suggest that molecular aberrations, in particular, increase endothelin-1 formation and decrease Prostacyclin (PGI)₂) eNOS activity in PAH vasculature is produced and attenuated. Endothelin-1 acting through ETA-receptors is mitogenic to pulmonary artery smooth muscle cells, promoting acute vasoconstriction. Oral ETA/ETB-antagonist bosentan has recently been approved after demonstrating improvement in clinical endpoints such as mean PAP, PVR or 6 minute walk testFor the treatment of PAH in EU and us. However, bosentan increases liver enzymes, and routine in vivo testing is mandatory. Currently selective ETA antagonists such as sitaxsentan or ambrisentan are under scrutiny.

As PGI₂Another strategy for the management of PAH replacement of prostacyclin deficiency by analogs may employ epoprostenol, treprostinil, oral beraprost or iloprost. Prostacyclin acts as an inhibitor of vascular smooth muscle cell excessive mitosis, increasing cAMP production. Intravenous prostacyclin (epoprostenol) significantly improves the survival rate and motility of idiopathic pulmonary hypertension and has been approved in north america and some european countries in the mid 1990 s. However, because of its short half-life epoprostenol has to be administered by continuous intravenous infusion, which, while feasible, is uncomfortable, complex and expensive. In addition, adverse events frequently occur due to the systemic effects of prostacyclin. An alternative prostacyclin analogue is treprostinil, which has recently been approved in the united states for treatment of PAH by continuous subcutaneous infusion and delivery, beraprost, the first biologically stable and orally active PGI₂An analogue which has been approved in Japan for the treatment of PAH. The treatment profile of patients with idiopathic PAH seems to be more favorable than other forms of pulmonary hypertension, side effects associated with systemic vasodilation after beraprost administration and local pain at the infusion site under treprostinil treatment are frequent. The administration of the prostacyclin analogue iloprost via the aerosol inhalation route has recently been approved in europe. Its beneficial effects on motor capacity and hemodynamic parameters will be balanced to higher dosing frequencies, including 6-12 inhalations per day from a suitable device.

As reported in pulmonary hypertension, the functional consequences of impaired endothelial nitric oxide formation can be overcome by selective phosphodiesterase-5 (PDE5) inhibitors expressed in pulmonary artery smooth muscle cells. Of course, the selective PDE5 inhibitor sildenafil was shown to improve pulmonary hemodynamics and exercise capacity of PAH.

Most of these new therapies are primarily directed at smooth muscle cell function, however, endothelial cells as well as perivascular macrophages and T-lymphocytes are thought to contribute to the development of pulmonary hypertension in addition to pulmonary arterial fibroblasts.

Despite the different treatments mentioned above, the drugs necessary to reduce the disease burden in pulmonary hypertension are expensive. It is therefore an object of the present invention to provide a pharmaceutical composition useful for the prophylactic or curative treatment of pulmonary hypertension which overcomes some or all of the above disadvantages.

Description of the invention

By using compounds of formula 1.1

Or a pharmaceutically acceptable salt thereof and/or a compound of formula 1.2

Or a pharmaceutically acceptable salt thereof, surprisingly treat pulmonary hypertension.

The international non-proprietary name (INN) for the compound of formula 1.1 is roflumilast [ 3-cyclopropyl-methoxy-4-difluoromethoxy-N- (3, 5-dichloropyridin-4-yl) benzamide ].

The compound of formula 1.2 is roflumilast-N-oxide [ 3-cyclopropylmethoxy-4-difluoromethoxy-N- (3, 5-dichloro-1-oxo-pyridin-4-yl) benzamide ].

The preparation of roflumilast, its pharmaceutically acceptable salts and its N-oxides, and the use of these compounds as PDE 4-inhibitors is described in international patent application WO 9501338.

Salts included within the scope of "pharmaceutically acceptable salts" of the compounds of formulae 1.1 and 1.2 refer to non-toxic salts of these compounds, which are generally prepared by reacting the free base with a suitable organic or inorganic acid or by reacting an acid with a suitable organic or inorganic base. Particular mention may be made of the pharmaceutically acceptable inorganic and organic acids usually used in pharmacy. Particularly suitable are water-soluble and water-insoluble acid addition salts with acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2- (4-hydroxybenzoyl) -benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, pamoic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 1-hydroxy-2-naphthoic acid. Examples of pharmaceutically acceptable salts with bases may be mentioned lithium, sodium, potassium, calcium, aluminium, magnesium, titanium, ammonium, meglumine or guanidinium salts.

It will be appreciated that the compounds of formulae 1.1 and 1.2 and their pharmaceutically acceptable salts may also exist in the form of their pharmaceutically acceptable solvates, especially their hydrates.

The word "pulmonary hypertension" as used herein encompasses different forms of pulmonary hypertension. Non-limiting examples that may be mentioned herein are idiopathic pulmonary hypertension; familial pulmonary hypertension; pulmonary arterial hypertension associated with collagen vascular disease, congenital systemic pulmonary shunt, portal hypertension, HIV infection, drugs or toxins; pulmonary arterial hypertension associated with thyroid disease, glycogen storage disease, gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathy, myeloproliferative disease, or splenectomy; pulmonary hypertension associated with pulmonary capillary hemangioma; persistent pulmonary hypertension of the newborn; pulmonary arterial hypertension associated with chronic obstructive pulmonary disease, interstitial lung disease, alveolar hypoventilation caused by hypoxia, sleep disordered breathing caused by hypoxia, or long-term exposure to high altitude; pulmonary hypertension associated with dysplasia; and pulmonary hypertension caused by thromboembolic occlusion of the peripheral pulmonary artery.

The term "effective amount" refers to a therapeutically effective amount of a compound of formula 1.1 or formula 1.2 for prophylactic or curative treatment of pulmonary hypertension. In the case of a combination therapy, the term "effective amount" refers to the total amount of the components of the combination, which is therapeutically effective for the prophylactic or curative treatment of pulmonary hypertension.

"patient" includes humans and other mammals.

It has been found that roflumilast reduces Pulmonary Arterial Pressure (PAP), right ventricular hypertrophy and peripheral muscle organization in rats caused by hypoxia or monocrotaline, while systemic arterial pressure and heart rate remain unchanged.

Thus, one aspect of the invention is the use of a compound selected from the group consisting of roflumilast, a pharmaceutically acceptable salt of roflumilast, roflumilast-N-oxide and a pharmaceutically acceptable salt of roflumilast-N-oxide for the preparation of a pharmaceutical composition for the prophylactic or curative treatment of pulmonary hypertension.

A second aspect of the invention relates to a method for the prophylactic or curative treatment of pulmonary hypertension in a patient, comprising administering to said patient in need thereof an effective amount of a compound selected from the group consisting of roflumilast, a pharmaceutically acceptable salt of roflumilast, roflumilast-N-oxide and a pharmaceutically acceptable salt of roflumilast-N-oxide.

As noted above, the word "pulmonary hypertension" as used herein includes different forms of pulmonary hypertension. Thus a further aspect of the invention is the use of a compound selected from roflumilast, a pharmaceutically acceptable salt of roflumilast, roflumilast-N-oxide and a pharmaceutically acceptable salt of roflumilast-N-oxide for the preparation of a medicament for the prophylactic or curative treatment of a disorder selected from idiopathic pulmonary hypertension; familial pulmonary hypertension; pulmonary arterial hypertension associated with collagen vascular disease, congenital systemic pulmonary shunt, portal hypertension, HIV infection, drugs or toxins; pulmonary arterial hypertension associated with thyroid disease, glycogen storage disease, gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathy, myeloproliferative disease, or splenectomy; pulmonary hypertension associated with pulmonary capillary hemangioma; persistent pulmonary hypertension of the newborn; pulmonary arterial hypertension associated with chronic obstructive pulmonary disease, interstitial lung disease, alveolar hypoventilation caused by hypoxia, sleep disordered breathing caused by hypoxia, or long-term exposure to high altitude; pulmonary hypertension associated with dysplasia; and pulmonary arterial hypertension caused by peripheral pulmonary thromboembolic occlusion.

Another aspect of the invention relates to a method for the prophylactic or curative treatment of a form of pulmonary hypertension in a patient, comprising administering to a patient in need thereof an effective amount of a compound selected from the group consisting of roflumilast, a pharmaceutically acceptable salt of roflumilast, roflumilast-N-oxide and a pharmaceutically acceptable salt of roflumilast-N-oxide, wherein the manifestation of pulmonary hypertension is selected from idiopathic pulmonary hypertension; familial pulmonary hypertension; pulmonary arterial hypertension associated with collagen vascular disease, congenital systemic pulmonary shunt, portal hypertension, HIV infection, drugs or toxins; pulmonary arterial hypertension associated with thyroid disease, glycogen storage disease, gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathy, myeloproliferative disease, or splenectomy; pulmonary hypertension associated with pulmonary capillary hemangioma; persistent pulmonary hypertension of the newborn; pulmonary arterial hypertension associated with chronic obstructive pulmonary disease, interstitial lung disease, alveolar hypoventilation caused by hypoxia, sleep disordered breathing caused by hypoxia, or long-term exposure to high altitude; pulmonary hypertension associated with dysplasia; and pulmonary hypertension caused by thromboembolic occlusion of the peripheral pulmonary artery.

Roflumilast, roflumilast-N-oxide, or a pharmaceutically acceptable salt of either can be administered to a patient in need of treatment in any of the generally acceptable modes of administration available in the art. Illustrative examples of suitable modes of administration include oral, intravenous, nasal, parenteral, transdermal and rectal delivery and administration by inhalation. The most preferred mode of administration of roflumilast, roflumilast-N-oxide or a pharmaceutically acceptable salt of either is oral. In another preferred embodiment, roflumilast-N-oxide or a pharmaceutically acceptable salt of either is administered by intravenous infusion or injection. In another preferred embodiment, roflumilast-N-oxide or a pharmaceutically acceptable salt of either is administered.

Typically, roflumilast-N-oxide or a pharmaceutically acceptable salt of either will be administered in the form of a pharmaceutical composition comprising roflumilast, roflumilast-N-oxide or a pharmaceutically acceptable salt of either and at least one pharmaceutically acceptable adjuvant.

The pharmaceutical compositions are prepared by methods known or familiar to those skilled in the art. As pharmaceutical compositions roflumilast, roflumilast-N-oxide or a pharmaceutically acceptable salt of either is used as such or, preferably, in combination with at least one pharmaceutically acceptable auxiliary, for example in the form of tablets, coated tablets, capsules, caplets, suppositories, emulsions, suspensions, gels or solutions, advantageously in an amount of 0.1 to 99.9% by weight, preferably 5 to 95% by weight, more preferably 20 to 80% by weight, where, by appropriate selection of the auxiliary, a pharmaceutical administration form (e.g. sustained-release form or enteric form) can be obtained which is completely suitable for the active compound and/or for the desired effect to occur.

The person skilled in the art is familiar with auxiliaries which are suitable for the desired pharmaceutical preparations on the basis of his expert knowledge. As pharmaceutically acceptable adjuvants, any known adjuvants suitable for the preparation of pharmaceutical compositions may be used. Examples thereof include, but are not limited to, solvents, excipients, dispersants, emulsifiers, solubilizers, gel formers, ointment bases, antioxidants, preservatives, stabilizers, carriers, fillers, binders, thickeners, complexing agents, disintegrants, buffers, penetration enhancers, polymers, lubricants, coatings, propellants, tonicity adjusting agents, surfactants, colorants, flavors, sweeteners, and dyes. In particular, excipients suitable for the desired formulation and the desired mode of administration are used.

Suitable oral dosage forms of roflumilast and roflumilast-N-oxide are described in international patent application WO 03070279.

Roflumilast or roflumilast-N-oxide can also be administered in the form of an aerosol; the aerosol particles of the solid, liquid or mixed composition are preferably 0.5 to 10 μm in diameter, advantageously 2 to 6 μm. Aerosol generation can be carried out, for example, by pressure-driven jet nebulizers or ultrasonic nebulizers, by propellant-driven metered aerosols or propellant-free administration of micronized active compounds from inhalation capsules.

Depending on the inhalation system used, the administration forms additionally contain, in addition to the active compound, the necessary excipients, for example propellants (e.g. Freon in metered-dose aerosols), surfactants, emulsifiers, stabilizers, preservatives, flavorings, fillers (e.g. lactose in dry powder inhalers) or, if appropriate, further active compounds.

For inhalation purposes, a large number of devices are available with which aerosols of optimum particle size can be generated and administered, with inhalation techniques that are as correct as possible for the patient. Except for the use of adapters (spacers, expanders) and pear-shaped containers (e.g. Nebulilator)^®、Volumatic^®) And an automatic device for emitting a blowing spray (Autohaler)^®) In addition, a number of technical solutions are available for metered aerosols, especially in the case of dry powder inhalation devices (e.g. Diskhaler)^®、Rotadisk^®、Turbohaler^®Or the inhaler described in european patent application EP 0505321), with which optimal administration of the active compound can be obtained.

It is known to the person skilled in the art that the optimal dosage of the active compound can vary depending on the weight, age and general condition of the patient and the patient's response behavior to the active compound.

For oral administration of 3-cyclopropylmethoxy-4-difluoromethoxy-N- (3, 5-dichloropyridin-4-yl) benzamide (roflumilast), the daily dose (for adult patients) is in the range from 50 to 1000. mu.g, preferably in the range from 50 to 500. mu.g, more preferably in the range from 250 to 500. mu.g, preferably once daily.

For intravenous administration of 3-cyclopropylmethoxy-4-difluoromethoxy-N- (3, 5-dichloropyridin-4-yl) benzamide (roflumilast), the daily dose (for adult patients) is in the range from 50 to 500. mu.g, preferably in the range from 150. mu.g to 300. mu.g.

For the treatment of pulmonary hypertension, roflumilast, a pharmaceutically acceptable salt of roflumilast, roflumilast-N-oxide or a pharmaceutically acceptable salt of roflumilast-N-oxide can be administered in combination with a PDE5 inhibitor or a pharmaceutically acceptable salt thereof.

Non-limiting examples of PDE5 inhibitors that may be used in combination with roflumilast, a pharmaceutically acceptable salt of roflumilast, roflumilast-N-oxide or a pharmaceutically acceptable salt of roflumilast-N-oxide according to the invention are listed in Table 1 below.

Table 1:

thus, a further aspect of the invention is:

a composition comprising an amount of a compound selected from the group consisting of roflumilast, a pharmaceutically acceptable salt of roflumilast, roflumilast-N-oxide and a pharmaceutically acceptable salt of roflumilast-N-oxide, and an amount of a PDE5 inhibitor or a pharmaceutically acceptable salt thereof, wherein the first amount and the second amount together constitute an effective amount for the prophylactic or curative treatment of pulmonary hypertension.

In another aspect of the present invention there is provided the use of a composition as described above in the prophylactic or curative treatment of pulmonary hypertension.

In a further aspect of the invention there is provided the use of a compound selected from roflumilast, a pharmaceutically acceptable salt of roflumilast, roflumilast-N-oxide and a pharmaceutically acceptable salt of roflumilast-N-oxide in combination with a PDE5 inhibitor or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition, combination product or kit for the prophylactic or curative treatment of pulmonary hypertension.

The roflumilast, pharmaceutically acceptable salts of roflumilast, roflumilast-N-oxide or pharmaceutically acceptable salts of roflumilast-N-oxide and the PDE5 inhibitor or pharmaceutically acceptable salts thereof may be administered simultaneously, sequentially or separately. To this effect, the combination of active compounds can be formulated in a single preparation (pharmaceutical composition) or in separate preparations (combination product or kit).

Thus, according to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a pharmaceutical formulation including an amount of a compound selected from roflumilast, a pharmaceutically acceptable salt of roflumilast, roflumilast-N-oxide and a pharmaceutically acceptable salt of roflumilast-N-oxide, an amount of a PDE5 inhibitor or a pharmaceutically acceptable salt thereof, wherein the first amount and the second amount together constitute an effective amount for the prophylactic or curative treatment of pulmonary hypertension, and at least one pharmaceutically acceptable auxiliary.

The above pharmaceutical compositions are provided for administration of roflumilast, a pharmaceutically acceptable salt of roflumilast, roflumilast-N-oxide or a pharmaceutically acceptable salt of roflumilast-N-oxide in admixture with a PDE5 inhibitor or a pharmaceutically acceptable salt thereof and thus are present in a single formulation.

Alternatively, roflumilast, a pharmaceutically acceptable salt of roflumilast, roflumilast-N-oxide or a pharmaceutically acceptable salt of roflumilast-N-oxide and the PDE5 inhibitor or a pharmaceutically acceptable salt thereof may be present in separate formulations, wherein at least one of those formulations comprises roflumilast, a pharmaceutically acceptable salt of roflumilast, roflumilast-N-oxide or a pharmaceutically acceptable salt of roflumilast-N-oxide, and at least one comprises a PDE5 inhibitor or a pharmaceutically acceptable salt thereof.

Thus, there is further provided:

a combination comprising the following components: (A) an amount of a compound selected from the group consisting of roflumilast, a pharmaceutically acceptable salt of roflumilast, roflumilast-N-oxide and a pharmaceutically acceptable salt of roflumilast-N-oxide; (B) an amount of a PDE5 inhibitor, or a pharmaceutically acceptable salt thereof; wherein the first amount and the second amount together constitute an effective amount for treating pulmonary hypertension, and wherein each of components (a) and (B) is in admixture with at least one pharmaceutically acceptable adjuvant.

The medicine box comprises the following components: (A) pharmaceutical formulations comprising an amount of a compound selected from roflumilast, pharmaceutically acceptable salts of roflumilast, roflumilast-N-oxide and pharmaceutically acceptable salts of roflumilast-N-oxide in admixture with at least one pharmaceutically acceptable auxiliary; (B) a pharmaceutical formulation comprising an amount of a PDE5 inhibitor or a pharmaceutically acceptable salt thereof in admixture with at least one pharmaceutically acceptable adjuvant; wherein the first amount and the second amount together constitute an effective amount for treating pulmonary hypertension.

The simultaneous administration of roflumilast, a pharmaceutically acceptable salt of roflumilast, roflumilast-N-oxide or a pharmaceutically acceptable salt of roflumilast-N-oxide and a PDE5 inhibitor or a pharmaceutically acceptable salt thereof can be accomplished by administering a pharmaceutical composition of the invention in one dosage form, e.g. a single capsule, tablet or injection, to a patient in need of treatment for pulmonary hypertension.

The components (A) and (B) of the combination product and kit may be administered continuously or separately during the treatment of pulmonary hypertension.

The sequential or separate administration of roflumilast, a pharmaceutically acceptable salt of roflumilast, roflumilast-N-oxide or a pharmaceutically acceptable salt of roflumilast-N-oxide and a PDE5 inhibitor or a pharmaceutically acceptable salt thereof can be carried out by administering the components (a) and (B) of the combination product or kit of the invention in divided dose form(s), for example separate capsules, tablets or injections, to a patient in need of treatment of pulmonary hypertension.

In the alternative, one of components (a) and (B) may be formulated as a tablet or capsule and the other component may be formulated for administration, for example by injection or inhalation.

Continuous administration includes a short gap during administration of components (a) and (B) of the combination product or kit of the invention (e.g. the time required to swallow one tablet after the other).

Separate administration includes both relatively short and long gaps during the administration of components (A) and (B) of the combination product or kit of the invention. However, for the purposes of the present invention, at least one component is administered while the other component is still effective in the patient being treated. In a preferred embodiment of the invention, the effect on the treated patient is a synergistic effect.

The combined administration of roflumilast, the pharmaceutically acceptable salt of roflumilast, roflumilast-N-oxide or the pharmaceutically acceptable salt of roflumilast-N-oxide and a PDE5 inhibitor or a pharmaceutically acceptable salt thereof in the form of a pharmaceutical composition, combination product or kit according to the invention leads to an effective treatment of pulmonary hypertension, which is superior to the use of one of them alone in a preferred embodiment. Moreover, in a particularly preferred embodiment, the combined administration of roflumilast, a pharmaceutically acceptable salt of roflumilast, roflumilast-N-oxide or a pharmaceutically acceptable salt of roflumilast-N-oxide and a PDE5 inhibitor or a pharmaceutically acceptable salt thereof shows synergistic efficacy for the treatment of pulmonary hypertension.

The term "synergistic" as used herein refers to the efficacy of roflumilast, a pharmaceutically acceptable salt of roflumilast, roflumilast-N-oxide or a pharmaceutically acceptable salt of roflumilast-N-oxide in combination with a PDE5 inhibitor or a pharmaceutically acceptable salt thereof in the form of a pharmaceutical composition, combination product or kit according to the invention for the treatment of pulmonary hypertension which is greater than the sum of their individual effects. The synergistic effects of embodiments of the present invention include other unexpected advantages for treating pulmonary hypertension. These additional advantages may include, but are not limited to, lowering the required dosage of the combined active compound or compounds, reducing the side effects of the combined active compound or compounds, or making the active compound or compounds more tolerable to patients in need of treatment for pulmonary hypertension.

The combined administration of roflumilast, a pharmaceutically acceptable salt of roflumilast, roflumilast-N-oxide or a pharmaceutically acceptable salt of roflumilast-N-oxide and a PDE5 inhibitor or a pharmaceutically acceptable salt thereof can also be used to reduce the required number of separate doses, thereby possibly increasing the compliance of patients in need of treatment for pulmonary hypertension.

A further aspect of the invention is the use of a pharmaceutical composition, a pharmaceutical combination or a kit according to the invention for the preparation of a medicament for the prophylactic or curative treatment of pulmonary hypertension.

A further aspect of the invention is a method for the prophylactic or curative treatment of pulmonary hypertension, comprising administering to a patient in need thereof a pharmaceutical composition comprising a pharmaceutical formulation including an amount of a compound selected from roflumilast, a pharmaceutically acceptable salt of roflumilast, roflumilast-N-oxide and a pharmaceutically acceptable salt of roflumilast-N-oxide, an amount of a PDE5 inhibitor or a pharmaceutically acceptable salt thereof, wherein the first amount and the second amount together constitute an effective amount for the prophylactic or curative treatment of pulmonary hypertension, and at least one pharmaceutically acceptable adjuvant.

Another aspect of the invention is a method for the prophylactic and curative treatment of pulmonary hypertension, comprising administering to a patient in need thereof a combination product comprising:

(A) an amount of a compound selected from the group consisting of roflumilast, a pharmaceutically acceptable salt of roflumilast, roflumilast-N-oxide and a pharmaceutically acceptable salt of roflumilast-N-oxide;

(B) an amount of a PDE5 inhibitor, or a pharmaceutically acceptable salt thereof;

wherein the first amount and the second amount together constitute an effective amount for the prophylactic or curative treatment of pulmonary hypertension;

wherein each of components (A) and (B) is formulated in admixture with at least one pharmaceutically acceptable adjuvant;

and wherein components (a) and (B) are applied sequentially or separately.

As already mentioned above, non-limiting examples of PDE5 inhibitors which may be used in the pharmaceutical compositions, combination products and kits of the present invention are listed in Table 1.

In one embodiment of the invention the PDE5 inhibitor for use in the pharmaceutical composition, combination product or kit according to the invention is selected from sildenafil (CAS-No.139755-83-2), TADALALFIL (CAS-No.171596-29-5), vardenafil (CAS-No.224785-90-4), UK-343664(CAS-No.215297-27-1), UK-357903(CAS-No.247580-98-9), UK-371800(CAS-No.247582-13-4), AVANAFIL (CAS-No.330784-47-9), BEMINAFIIL (CAS-No.566906-50-1), DASANTAFIL (CAS-No.405214-79-1), UDENAFIL (CAS-No.268203-93-6), BMS-341400(Cas-No.296250-53-8), and pharmaceutically acceptable salts of these compounds.

In one embodiment of the invention, the PDE5 inhibitor for use in the pharmaceutical composition, combination product or kit of the present invention is sildenafil or a pharmaceutically acceptable salt thereof.

In another embodiment of the invention, the pharmaceutically acceptable salt of sildenafil is the hemi-citrate, citrate or mesylate salt of sildenafil.

In another embodiment of the invention the PDE5 inhibitor for use in the pharmaceutical composition, combination product or kit of the present invention is TADALAFIL or a pharmaceutically acceptable salt thereof.

In another embodiment of the invention the PDE5 inhibitor for use in the pharmaceutical composition, combination product or kit of the present invention is vardenafil or a pharmaceutically acceptable salt thereof.

In another embodiment of the invention, the pharmaceutically acceptable salt of vardenafil is the monohydrochloride or dihydrochloride of vardenafil.

In another embodiment of the invention the PDE5 inhibitor for use in the pharmaceutical composition, combination product or kit of the invention is UK-343664 or a pharmaceutically acceptable salt thereof.

In another embodiment of the invention the PDE5 inhibitor for use in the pharmaceutical composition, combination product or kit of the invention is UK-357903 or a pharmaceutically acceptable salt thereof.

In another embodiment of the invention the PDE5 inhibitor for use in the pharmaceutical composition, combination product or kit of the invention is UK-371800 or a pharmaceutically acceptable salt thereof.

In another embodiment of the invention, the PDE5 inhibitor for use in the pharmaceutical composition, combination product or kit of the present invention is AVANAFIL or a pharmaceutically acceptable salt thereof.

In another embodiment of the invention, the pharmaceutically acceptable salt of AVANAFIL is a benzenesulfonate salt of AVANAFIL.

In another embodiment of the invention, the PDE5 inhibitor for use in the pharmaceutical composition, combination product or kit of the invention is bemifacil or a pharmaceutically acceptable salt thereof.

In another embodiment of the invention, the pharmaceutically acceptable salt of bemifnafil is the sodium or ethanolamine salt of bemifnafil.

In another embodiment of the invention, the PDE5 inhibitor for use in the pharmaceutical composition, combination product or kit of the present invention is DASANTAFIL or a pharmaceutically acceptable salt thereof.

In another embodiment of the invention the PDE5 inhibitor for use in the pharmaceutical composition, combination product or kit of the present invention is UDENAFIL or a pharmaceutically acceptable salt thereof.

In another embodiment of the invention, the PDE5 inhibitor for use in the pharmaceutical composition, combination product or kit of the invention is BMS-341400 or a pharmaceutically acceptable salt thereof.

For additional information on the formulation, suitable dosage forms and dosage ranges for the PDE5 inhibitors listed in table 1 can be found in the following patents/patent applications: EP0463756, WO2004072079, EP1097711, EP0967214, EP1049695, WO03011262, EP0740668, WO9849166, EP1073658, WO9954333, EP1219609, WO9955708, WO0224698, WO0027848 and EP 1165521.

The "pharmaceutically acceptable salts" of the PDE5 inhibitor are not limited to the examples given above. The term refers to non-toxic salts of these compounds. These pharmaceutically acceptable salts are typically prepared by reacting the free base with a suitable organic or inorganic acid, or by reacting the acid with a suitable organic or inorganic base. Particular mention may be made of the pharmaceutically acceptable inorganic and organic acids usually used in pharmacy. Those which are suitable are, in particular, water-soluble and water-insoluble acid addition salts with acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2- (4-hydroxybenzoyl) -benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, pamoic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 1-hydroxy-2-naphthoic acid. Examples of pharmaceutically acceptable salts with bases may be mentioned lithium, sodium, potassium, calcium, aluminium, magnesium, titanium, ammonium, meglumine or guanidinium salts.

It will be appreciated that the PDE5 inhibitors and their pharmaceutically acceptable salts may also be present in the form of their pharmaceutically acceptable solvates, especially their hydrates.

Mode of administration, dosage form and combined dose:

the combination of the invention may be administered to a patient in need of treatment in any of the generally acceptable modes of administration available in the art. Illustrative examples of suitable modes of administration include oral, intravenous, nasal, parenteral, transdermal and rectal delivery and administration by inhalation.

Tablets, coated tablets (troches), pills, cachets, capsules (caplets), granules, solutions, emulsions and suspensions are, for example, suitable for oral administration. In particular, the formulations may be modified to represent, for example, enteric forms, immediate release forms, sustained release forms, repeated dose release forms, extended release forms, or sustained release forms. The dosage forms can be obtained, for example, by coating the tablets, dividing the tablets into several compartments separated by several layers which disintegrate under different conditions (e.g. pH conditions), or by coupling the active compound with a biodegradable polymer.

Administration by inhalation is preferably carried out by means of an aerosol; the aerosol particles of the solid, liquid or mixed composition are preferably 0.5 to 10 μm in diameter, advantageously 2 to 6 μm. Aerosol generation can be carried out, for example, by pressure-driven jet nebulizers or ultrasonic nebulizers, by propellant-driven metered aerosols or propellant-free administration of micronized active compounds from inhalation capsules.

Depending on the inhalation system used, the administration forms additionally contain, in addition to the active compound, the necessary excipients, for example propellants (e.g. Freon in metered-dose aerosols), surfactants, emulsifiers, stabilizers, preservatives, flavorings, fillers (e.g. lactose in dry powder inhalers) or, if appropriate, further active compounds.

For inhalation purposes, a large number of devices are available with which aerosols of optimum particle size can be generated and administered, with inhalation techniques that are as correct as possible for the patient. Except for the use of adapters (spacers, expanders) and pear-shaped containers (e.g. Nebulilator)^®、Volumatic^®) And an automatic device for emitting a blowing spray (Autohaler)^®) In addition, a number of technical solutions are available for metered aerosols, especially in the case of dry powder inhalation devices (e.g. Diskhaler)^®、Rotadisk^®、Turbohaler^®Or the inhaler described in european patent application EP 0505321), with which optimal administration of the active compound can be obtained.

Pharmaceutical compositions (formulations) containing roflumilast, roflumilast-N-oxide or a pharmaceutically acceptable salt of either and/or a PDE5 inhibitor or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable auxiliary material can be prepared in a manner known to the person skilled in the art, for example by dissolving, mixing, granulating, dragee-making, levigating, emulsifying, encapsulating or lyophilizing operations.

As pharmaceutically acceptable adjuvants, any adjuvant known to be suitable for the preparation of pharmaceutical compositions (preparations) can be used. Examples thereof include, but are not limited to, solvents, excipients, dispersants, emulsifiers, solubilizers, gel-forming agents, ointment bases, antioxidants, preservatives, stabilizers, carriers, fillers, binders, thickeners, complexing agents, disintegrants, buffers, permeation enhancers, polymers, lubricants, coating agents, propellants, osmotic pressure, surfactants, colorants, flavors, sweeteners, and dyes. In particular, the type of adjuvant suitable for the desired dosage form and the desired mode of administration is used.

For intravenous administration, solutions (e.g., sterile solutions, isotonic solutions) are preferably used.

The preferred mode of administration of the combination of the invention depends on the particular combination partner.

As described above, roflumilast-N-oxide or a pharmaceutically acceptable salt of either can be administered in various forms. These forms include, for example, liquid, semi-solid, and solid dosage forms, such as liquid solution (e.g., injectable solutions and infusion solutions) dispersions or suspensions, tablets, pills, powders, liposomes, or suppositories. The preferred form depends on the intended mode of administration and the combination of ingredients.

The most preferred mode of administration of roflumilast, roflumilast-N-oxide or a pharmaceutically acceptable salt of either is oral. In another preferred embodiment, roflumilast-N-oxide or a pharmaceutically acceptable salt of either is administered by intravenous infusion or injection. In a further preferred embodiment, roflumilast-N-oxide or a pharmaceutically acceptable salt of either is administered by inhalation.

The PDE5 inhibitor or a pharmaceutically acceptable salt thereof used in the compositions of the present invention may also be administered in any acceptable mode of administration available in the art. A preferred mode of administration of the PDE5 inhibitor or a pharmaceutically acceptable salt thereof is oral.

The citrate salt of sildenafil is the preferred salt for oral administration of sildenafil, however other pharmaceutically acceptable salts may also be used. Sildenafil can also be administered by inhalation. Preferred dosage forms of sildenafil for administration by inhalation include aqueous formulations of sildenafil mesylate for use in aerosol nebulizers or nebulizers.

As part of the combination therapy of the invention, roflumilast-N-oxide or a pharmaceutically acceptable salt of either and the PDE5 inhibitor or a pharmaceutically acceptable salt thereof are quantified to an order of magnitude customary for monotherapy, which is more likely to be reasonable, and the effects positively influence and potentiate each other on the basis of the individual's effects to reduce the respective dose when roflumilast, roflumilast-N-oxide or a pharmaceutically acceptable salt of either and the PDE5 inhibitor or a pharmaceutically acceptable salt thereof are normally administered in combination.

As described above, for the oral administration of 3-cyclopropylmethoxy-4-difluoromethoxy-N- (3, 5-dichloropyridin-4-yl) benzamide (roflumilast), the daily dose (for adult patients) is in the range of 50-1000. mu.g, preferably in the range of 50-500. mu.g, more preferably in the range of 250-500. mu.g, preferably once daily. For intravenous administration of 3-cyclopropyl-methoxy-4-difluoromethoxy-N- (3, 5-dichloropyridin-4-yl) benzamide (roflumilast), the daily dose (for adult patients) is in the range of 50-500 μ g per day, preferably in the range of 150 μ g per day and 300 μ g per day.

For oral and parenteral administration to human patients, the daily dosage level of the PDE5 inhibitor or a pharmaceutically acceptable salt thereof (for adult patients) will generally be in the range of 1-500mg, preferably in the range of 1-200mg, more preferably in the range of 1-100mg (in single or divided doses).

For the PDE5 inhibitors TADALAFIL, vardenafil and sildenafil the daily dosage level (for adult patients) will preferably be up to 100mg, more preferably up to 50mg, more preferably up to 20mg (in single or divided doses).

For sildenafil, the currently approved dose for treating pulmonary hypertension is 20mg of sildenafil (in the form of an oral tablet containing sildenafil citrate) three times a day.

Table 2: preferred combinations

Example numbering	Combination of
			1	Roflumilast	Sildenafil
2	roflumilast-N-oxide	Sildenafil
			3	Roflumilast	Sildenafil citrate
4	roflumilast-N-oxide	Sildenafil citrate
			5	Roflumilast	Sildenafil hemicitrate
6	roflumilast-N-oxide	Sildenafil hemicitrate
			7	Roflumilast	Sildenafil mesylate
8	roflumilast-N-oxide	Sildenafil mesylate
			9	Roflumilast	Vardenafil
10	roflumilast-N-oxide	Vardenafil
			11	Roflumilast	Vardenafil hydrochloride
12	roflumilast-N-oxide	Vardenafil hydrochloride
			13	Roflumilast	Vardenafil dihydrochloride
14	roflumilast-N-oxide	Vardenafil dihydrochloride
			15	Roflumilast	TADALAFIL
16	roflumilast-N-oxide	TADALAFIL
			17	Roflumilast	UK-343664
18	roflumilast-N-oxide	UK-343664
			19	Roflumilast	UK-357903
20	roflumilast-N-oxide	UK-357903
			21	Roflumilast	UK-371800
22	roflumilast-N-oxide	UK-371800
			23	Roflumilast	AVANAFIL
24	roflumilast-N-oxide	AVANAFIL
			25	Roflumilast	Avanafil Benzenesulfonic acid
26	roflumilast-N-oxide	Avanafil Benzenesulfonic acid

27	Roflumilast	BEMINAFIL
			28	roflumilast-N-oxide	BEMINAFIL
29	Roflumilast	BEMINAFIL sodium salt
			30	roflumilast-N-oxide	BEMINAFIL sodium salt
31	Roflumilast	BEMINAFIL Ethanolamine
			32	roflumilast-N-oxide	BEMINAFIL Ethanolamine
33	Roflumilast	DASANTAFIL
			34	roflumilast-N-oxide	DASANTAFIL
35	Roflumilast	UDENAFIL
			36	roflumilast-N-oxide	UDENAFIL
37	Roflumilast	BMS-341400
			38	roflumilast-N-oxide	BMS-341400

Pharmacology of

The selective PDE4 inhibitor roflumilast reduces Pulmonary Arterial Pressure (PAP), right ventricular hypertrophy and peripheral muscle organization in rat hypoxia or monocrotaline-induced chronic pulmonary hypertension.

Purpose(s) to

The aim of the pharmacological study was to present 0.5mg kg^-1d^-1And 1.5mg kg^-1d^-1Effect of orally administered roflumilast on the increase of mean PAP and RV/LV + S ratio in rats and peripheral arteriolar musculature triggered by chronic hypoxia or Monocrotaline (MCT). Hypoxia or MCT-induced pulmonary hypertension in rats represents a widely recognized animal model to investigate the possibility of investigated drugs to reverse chronic pulmonary hypertension based on pulmonary vascular remodeling. In MCT settings, roflumilast is administered in both prophylactic and therapeutic instances.

Animal(s) production

The experiments were performed with adult male Wistar rats (200-.

Chronic hypoxic pulmonary hypertension

Rats were subjected to chronic hypoxia (10% O) in a fume hood (500 liter volume, Flufrance, Cachan, France)₂). To establish an oxygen deficient environment, a mixture of room air and nitrogen is injected into the fume hood and the gases are recirculated. The environment within the fume hood was monitored with an oxygen analyzer (Oxiquant M, EnviTeC-Wismar, Germany). Carbon dioxide is removed with automatically indicated soda lime particles. Prevention by cooling recirculation loopExcess moisture. The fume hood temperature was maintained at 22-24 ℃. The hood was opened every other day for 1 hour to clean the cages and supplement food and water supplies. Normoxic control rats were placed in the same room with the same light-dark cycle. Rats suffering from chronic hypoxia were randomly divided into 3 groups (8-10 animals per group): group 1 received 0.5mg kg^-1d^-1Roflumilast, group 2 received 1.5mg kg^-1d^-1Roflumilast, group 3, received vehicle (methocel). The group not suffering from hypoxia was used as a control group. Roflumilast or vehicle was administered once daily by gavage within 15 days of suffering from hypoxia.

Monocrotaline (MCT) induced pulmonary hypertension

Rats were randomly divided into 3 groups (8-10 animals per group): the two groups respectively receive 0.5mg kg^-1d^-1And 1.5mg kg^-1d^-1Roflumilast, one group received vehicle. In prophylactic treatment, MCT (60mg kg) was injected subcutaneously in a single injection^-1) The administration of example roflumilast or vehicle was started immediately thereafter once a day for 21 days by gavage. The group that did not receive MCT served as the control group. In one treatment method, rats were not treated 21 days after MCT (60mg/kg subcutaneously) administration and then were randomized into two groups, one group receiving roflumilast (1.5mg/kg/d) p.o. and the other group receiving vehicle from day 21 to day 42.

Identification of pulmonary hypertension

At the end of the treatment period, the rats were sacrificed with sodium pentobarbital (60mg/kg i.p.). A polyethylene catheter was inserted into the right jugular vein and advanced into the pulmonary artery through the right ventricle. Another polyethylene catheter was inserted into the right carotid artery. After measurement of Pulmonary Arterial Pressure (PAP) and Systemic Arterial Pressure (SAP), the thorax was opened, the lungs were rapidly removed and frozen in liquid nitrogen. The heart was dissected and weighed and the right ventricular hypertrophy index (ratio of right ventricular free wall weight to sum of septum plus left ventricular free wall weight; RV/LV + S) was calculated. The right lung was fixed in an expanded state with formalin buffer. After routine processing and paraffin embedding, multiple sections from each slice were stained with hematoxylin and eosin. In each rat, 60 intraacinar arteries were analyzed and classified as muscular (whole or partial) or non-muscular to assess the degree of musculature. In addition, fully musculature arteries within the acinus were evaluated to measure the medial wall thickness, which was calculated and expressed as follows: index (%) - (outer diameter-inner diameter)/outer diameter × 100%.

Statistical analysis

Data are expressed as mean ± SEM. The nonparametric Mann-Whitney test was used to compare the two groups. Comparison of data at various time points post MCT injection or for different treatment groups was performed using the nonparametric Kruskal-Wallis test followed by Dunn's test if significant. To compare the degree of pulmonary vascular musculature between groups, we used the nonparametric Mann-Whitney test or the Kruskal-Wallis test after the vessel order classification as non-muscular, partially muscular or fully muscular.

Results

Effect of roflumilast on chronic hypoxic pulmonary hypertension

Rats were exposed for 15 days to develop chronic hypoxic progressive pulmonary hypertension, which is accompanied by right ventricular hypertrophy as reflected by increased pulmonary mean pressure (mean PAP) and RV/LV + S ratio. Roflumilast, a selective PDE4 inhibitor, was administered at 0.5mg kg in a dose-dependent manner^-1d^-1And 1.5mg kg^-1d^-1Both at doses (p < 0.05 vs vehicle) reduced mean PAP increased by chronic hypoxia (table 3). Systemic arterial pressure and heart rate were unaffected by the treatment regimen. At the same time, with 0.5mg kg^-1d^-11.5mg kg of roflumilast^-1d^-1Roflumilast (p < 0.01 relative to vehicle) partially reversed the increase in RV/LV + S ratio after persistent hypoxia to a greater extent (table 3).

Increased muscle organization of peripheral pulmonary arterioles can cause increased PAP and right ventricular hypertrophy. Significant roflumilastDi (p < 0.001) reduced peripheral muscle organization increased by 15 days of chronic hypoxia, with 0.5mg kg^-1d^-1In contrast, 1.5mg kg^-1d^-1With higher efficacy (table 3).

Table 3: in chronic hypoxia induced pulmonary hypertension in rats

Effect of roflumilast on pulmonary artery hemodynamics and peripheral pulmonary artery musculature

	PAP[mm Hg]	PV/LV+S[％]	Musculature [% ]]
				Control	17±1	26±1.1	9±3
Lack of oxygen	30.8±2.4	42.6±1.6	57±3
				Hypoxia +0.5mg/kg roflumilast	28±1.8	37.8±2.3	31.8±2
Hypoxia +1.5mg/kg roflumilast	25.5±1.8	30.5±0.8	18.5±2

Effect of roflumilast on the development of MCT-induced pulmonary hypertension

Monocrotaline produced severe pulmonary hypertension in rats characterized by a significant increase in mean PAP, RV/LV + S, and peripheral pulmonary musculature after 21 days. And 0.5mgkg^-1d^-1Comparison (p < 0.05 relative to vehicle), 1.5mg kg^-1d^-1Roflumilast (p < 0.01 relative to vehicle) reduced mean PAP and right ventricular hypertrophy with higher efficacy. The improvement of these hemodynamic parameters of pulmonary circulation was supplemented by a dose-dependent (p < 0.001) reduction in peripheral pulmonary artery musculature caused by a selective PDE4 inhibitor (table 4).

Table 4: effect of roflumilast on pulmonary hemodynamics and peripheral pulmonary musculature in Monocrotaline (MCT) -induced pulmonary hypertension in rats

	PAP[mm Hg]	PV/LV+S[％]	Musculature [% ]]
				Control	14.8±4	25±1.4	9±3
MCT	37.6±1.5	44.3±1.7	77.9±4.8
				MCT +0.5mg/kg roflumilast	29.3±1.3	38.9±1.6	62.7±5.4
MCT +1.5mg/kg roflumilast	21.4±2.0	31.3±1.8	30.3±8.2

In the treatment method, roflumilast (1.5mg/kg/d) p.o. or vehicle was administered starting 21 days after MCT, i.e. when pulmonary vascular remodeling and subsequent increased PAP and right ventricular hypertrophy were evident. After a further 3 weeks (i.e., day 42), PAP was measured and rats were sacrificed to assess RV/LV + S ratio and muscle organization of peripheral pulmonary arteries.

Table 5: in rat Monocrotaline (MCT) -induced pulmonary hypertension (treatment method), starting on day 21, the effect of roflumilast (1.5mg/kg/d) p.o. on pulmonary hemodynamics and musculature of peripheral pulmonary arteries.

	PAP[mm Hg]	PV/LV+S[％]	Musculature [% ]]
				Day 0	15.1±1.1	25.9±1.4	9±3
Day 21	32.1±0.9	46.2±0.9	68.2±1.6
				Excipient on day 42	37.9±2.8	49.2±2.0	67.3±2.4
Roflumilast on day 42	23.6±0.7	33.8±0.9	36.4±2.4

As expected, the Pulmonary Arterial Pressure (PAP) and right ventricular hypertrophy (RV/LV + S) ratio further increased from day 21 to day 42 in the vehicle group. However, treatment with roflumilast reduced the PAP and RV/LV + S ratios from day 21, even exceeding the values at day 21 at day 42. These hemodynamic findings may be due to the significant reduction in peripheral pulmonary artery musculature brought about by roflumilast. More specifically, on days 21 and 42 of the vehicle group, — 70% of these arterioles were completely musculature. Roflumilast significantly reduced fully musculature arterioles by > 50% at day 42, starting on day 21. The sidewall thickness index of fully musculature pulmonary arterioles calculated as (outer-inner diameter)/outer diameter x 100% increased to 51 ± 3% on day 21 post MCT, maintained at 52 ± 4% on day 42, and significantly decreased to 18 ± 2% by roflumilast (starting from day 21) on day 42 in the vehicle group. Importantly, the rate of fully occluded arterioles at day 42 was significantly reduced (30 ± 5%) in rats that received roflumilast from day 21 compared to vehicle groups at day 21 (50 ± 1%) and day 42 (66 ± 3%). After MCT, a Proliferating Cell Nuclear Antigen (PCNA) marker of smooth muscle cells in the peripheral pulmonary artery wall was present, but absent in the roflumilast (1.5mg/kg/d) group, indicating that PDE4 inhibitor effectively inhibited pulmonary artery smooth muscle proliferation in vivo. Roflumilast (1.5mg/kg/d) significantly improved survival in therapeutic methods. Whereas 21 (54%) of the 39 rats in the vehicle group survived to day 42, 17 (71%) of the 24 rats in the roflumilast group were alive at day 42. Taking the examples of rat MCT-induced pulmonary arterial revascularization and subsequent pulmonary arterial hypertension together, administration of roflumilast (1.5mg/kg/d) after the treatment regimen caused a partial regression of the preexisting pulmonary arterial revascularization and therefore pulmonary arterial hypertension.

Conclusion

Roflumilast dose-dependently ameliorated chronic pulmonary hypertension in rats triggered by hypoxia or monocrotaline, while systemic arterial pressure and heart rate remained unaffected.

Claims (41)

1. Use of a compound selected from roflumilast, pharmaceutically acceptable salts of roflumilast, roflumilast-N-oxide and pharmaceutically acceptable salts of roflumilast-N-oxide for the preparation of a pharmaceutical composition for the prophylactic or curative treatment of pulmonary hypertension.

2. The use of claim 1, wherein the pharmaceutical composition is for the prophylactic treatment of pulmonary hypertension.

3. The use according to claim 1, wherein the pharmaceutical composition is for the curative treatment of pulmonary hypertension.

4. Use according to any one of claims 1, 2 or 3, wherein the compound is selected from roflumilast and pharmaceutically acceptable salts of roflumilast.

5. Use according to any one of claims 1, 2 or 3, wherein the compound is selected from roflumilast-N-oxide and pharmaceutically acceptable salts of roflumilast-N-oxide.

6. Use according to any one of claims 1, 2 or 3, wherein the compound is roflumilast.

7. Use according to any one of claims 1, 2 or 3, wherein the compound is roflumilast-N-oxide.

8. A method of prophylactically or curatively treating pulmonary hypertension in a patient, the method comprising administering to the patient in need thereof an effective amount of a compound selected from the group consisting of roflumilast, a pharmaceutically acceptable salt of roflumilast, roflumilast-N-oxide and a pharmaceutically acceptable salt of roflumilast-N-oxide.

9. The method of claim 8, wherein the treatment of pulmonary hypertension is prophylactic treatment.

10. The method of claim 8, wherein the treatment of pulmonary hypertension is a curative treatment.

11. The method according to any one of claims 8, 9 or 10, wherein the compound is selected from roflumilast and pharmaceutically acceptable salts of roflumilast.

12. The method according to any one of claims 8, 9 or 10, wherein the compound is selected from roflumilast-N-oxide and pharmaceutically acceptable salts of roflumilast-N-oxide.

13. A process according to any one of claims 8, 9 or 10 wherein the compound is roflumilast.

14. A process according to any one of claims 8, 9 or 10, wherein the compound is roflumilast-N-oxide.

15. Use of a compound selected from the group consisting of roflumilast, pharmaceutically acceptable salts of roflumilast, roflumilast-N-oxide and pharmaceutically acceptable salts of roflumilast-N-oxide in combination with a PDE5 inhibitor or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition, combination product or kit for the prophylactic or curative treatment of pulmonary hypertension.

16. A pharmaceutical composition comprising a pharmaceutical preparation comprising an amount of a compound selected from the group consisting of roflumilast, a pharmaceutically acceptable salt of roflumilast, roflumilast-N-oxide and a pharmaceutically acceptable salt of roflumilast-N-oxide, an amount of a PDE5 inhibitor or a pharmaceutically acceptable salt thereof, wherein the first amount and the second amount together constitute an effective amount for the prophylactic or curative treatment of pulmonary hypertension, and at least one pharmaceutically acceptable auxiliary.

17. A combination comprising the following components: (A) an amount of a compound selected from the group consisting of roflumilast, pharmaceutically acceptable salts of roflumilast, roflumilast-N-oxide and pharmaceutically acceptable salts of roflumilast-N-oxide, and (B) an amount of a PDE5 inhibitor or a pharmaceutically acceptable salt thereof, wherein the first amount and the second amount together form an effective amount for the prophylactic or curative treatment of pulmonary hypertension, and wherein the individual components (a) and (B) are formulated in admixture with at least one pharmaceutically acceptable auxiliary.

18. A kit comprising the following components: (A) a pharmaceutical formulation comprising an amount of a compound selected from the group consisting of roflumilast, a pharmaceutically acceptable salt of roflumilast, roflumilast-N-oxide and a pharmaceutically acceptable salt of roflumilast-N-oxide in admixture with at least one pharmaceutically acceptable adjuvant, and (B) a pharmaceutical formulation comprising an amount of a PDE5 inhibitor or a pharmaceutically acceptable salt thereof in admixture with at least one pharmaceutically acceptable adjuvant, wherein the first amount and the second amount together constitute an effective amount for the prophylactic or curative treatment of pulmonary hypertension.

19. A pharmaceutical composition, combination product or kit according to any one of claims 16 to 18 wherein the treatment of pulmonary hypertension is a prophylactic treatment.

20. Pharmaceutical composition, combination product or kit according to any of claims 16 to 18, wherein the treatment of pulmonary hypertension is a curative treatment.

21. The pharmaceutical composition, combination product or kit according to any one of claims 16 to 20, wherein the compound is selected from roflumilast and pharmaceutically acceptable salts of roflumilast.

22. The pharmaceutical composition, combination product or kit according to any one of claims 16 to 20, wherein the compound is selected from roflumilast-N-oxide and the pharmaceutically acceptable salts of roflumilast-N-oxide.

23. Pharmaceutical composition, combination product or kit according to any of claims 16 to 20, wherein the compound is roflumilast.

24. The pharmaceutical composition, combination product or kit according to any one of claims 16 to 20, wherein the compound is roflumilast-N-oxide.

25. A pharmaceutical composition, combination product or kit according to any one of claims 16 to 24 wherein the PDE5 inhibitor is selected from sildenafil, TADALAFIL, vardenafil, UK-343664, UK-357903, UK-371800, AVANAFIL, bemifnafil, DASANTAFIL, UDENAFIL, BMS-341400 and pharmaceutically acceptable salts of these compounds.

26. A method of prophylactic or curative treatment of pulmonary hypertension, the method comprising administering to a patient in need thereof a pharmaceutical composition comprising a pharmaceutical preparation comprising an amount of a compound selected from roflumilast, a pharmaceutically acceptable salt of roflumilast, roflumilast-N-oxide and a pharmaceutically acceptable salt of roflumilast-N-oxide, an amount of a PDE5 inhibitor or a pharmaceutically acceptable salt thereof, wherein the first amount and the second amount together constitute an effective amount for prophylactic or curative treatment of pulmonary hypertension, and at least one pharmaceutically acceptable adjuvant.

27. A method for the prophylactic and curative treatment of pulmonary hypertension, said method comprising administering to a patient in need thereof a combination product comprising:

(A) an amount of a compound selected from the group consisting of roflumilast, a pharmaceutically acceptable salt of roflumilast, roflumilast-N-oxide and a pharmaceutically acceptable salt of roflumilast-N-oxide; and

(B) an amount of a PDE5 inhibitor, or a pharmaceutically acceptable salt thereof;

wherein the first amount and the second amount together constitute an effective amount for the prophylactic or curative treatment of pulmonary hypertension;

wherein each component (A) and (B) is mixed with at least one pharmaceutically acceptable auxiliary material for preparation;

and wherein components (a) and (B) are administered sequentially or separately.

28. The method or use according to any of claims 15, 26 or 27, wherein the treatment of pulmonary hypertension is a prophylactic treatment.

29. A method or use according to any of claims 15, 26 or 27 wherein the treatment of pulmonary hypertension is a curative treatment.

30. A method or use according to any one of claims 15, 26, 27, 28 or 29 wherein the compound is selected from roflumilast and pharmaceutically acceptable salts of roflumilast.

31. The method or use according to any one of claims 15, 26, 27, 28 or 29 wherein the compound is selected from roflumilast-N-oxide and pharmaceutically acceptable salts of roflumilast-N-oxide.

32. A method or use according to any one of claims 15, 26, 27, 28 or 29 wherein the compound is roflumilast.

33. A method or use according to any one of claims 15, 26, 27, 28 or 29 wherein the compound is roflumilast-N-oxide.

34. The method or use according to any one of claims 15 and 26-33, wherein the PDE5 inhibitor is selected from sildenafil, TADALAFIL, VARDENAFIL, UK-343664, UK-357903, UK-371800, AVANAFIL, bemifalin, DASANTAFIL, udeafil, BMS-341400 and pharmaceutically acceptable salts of these compounds.

35. The method or use according to any of claims 1-15 or 26-34, wherein pulmonary arterial hypertension represents a form of pulmonary arterial hypertension selected from the group consisting of: idiopathic pulmonary hypertension; familial pulmonary hypertension; pulmonary arterial hypertension associated with collagen vascular disease, congenital systemic pulmonary shunt, portal hypertension, HIV infection, drugs or toxins; pulmonary arterial hypertension associated with thyroid disease, glycogen storage disease, gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathy, myeloproliferative disease, or splenectomy; pulmonary hypertension associated with pulmonary capillary hemangiomas; persistent pulmonary hypertension of the newborn; pulmonary arterial hypertension associated with chronic obstructive pulmonary disease, interstitial lung disease, alveolar hypoventilation caused by hypoxia, sleep disordered breathing caused by hypoxia, or long-term exposure to high altitude; pulmonary hypertension associated with dysplasia; and pulmonary hypertension caused by thromboembolic occlusion of the peripheral pulmonary artery.

36. The method or use according to any of claims 1-15 or 26-34, wherein pulmonary arterial hypertension represents a form of pulmonary arterial hypertension selected from the group consisting of: idiopathic pulmonary hypertension; familial pulmonary hypertension; pulmonary arterial hypertension associated with collagen vascular disease, congenital systemic pulmonary shunt, portal hypertension, HIV infection, drugs or toxins; pulmonary arterial hypertension associated with thyroid disease, glycogen storage disease, gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathy, myeloproliferative disease, or splenectomy; pulmonary hypertension associated with pulmonary capillary hemangiomas; persistent pulmonary hypertension of the newborn; pulmonary hypertension associated with interstitial lung disease, alveolar hypoventilation due to hypoxia, sleep disordered breathing due to hypoxia, or long-term exposure to high altitude; pulmonary hypertension associated with dysplasia; and pulmonary hypertension caused by thromboembolic occlusion of the peripheral pulmonary artery.

37. The method or use according to any one of claims 35 or 36, wherein the pulmonary arterial hypertension represents idiopathic pulmonary arterial hypertension.

38. The method or use according to any of claims 35 or 36, wherein pulmonary hypertension represents familial pulmonary hypertension.

39. The method or use according to claim 35, wherein pulmonary arterial hypertension represents pulmonary arterial hypertension associated with chronic obstructive pulmonary disease.

40. The method or use according to any of claims 35 or 36, wherein pulmonary arterial hypertension represents pulmonary arterial hypertension associated with collagen vascular disease, congenital systemic pulmonary bypass, portal hypertension, HIV infection, drugs or toxins.

41. The method or use according to any of claims 35 or 36, wherein pulmonary arterial hypertension represents pulmonary arterial hypertension associated with thyroid disease, glycogen accumulating disease, gaucher disease, hereditary hemorrhagic telangiectasia, haemoglobinopathy, myeloproliferative disorders or splenectomy.