MXPA01001994A - Therapies for treating pulmonary diseases - Google Patents

Abstract

This invention relates to treating pulmonary diseases such as chronic obstructive pulmonary disease or asthma by administering a phosphodiesterase 4 inhibitor in combination with beta adrenergic bronchodilator.

Description

THERAPIES TO TREAT PULMONARY DISEASES FIELD OF THE INVENTION This invention relates to compositions and methods for preventing or reducing the onset of symptoms of pulmonary diseases, or treating or reducing the severity of lung diseases. In particular it relates to compositions and methods for treating pulmonary diseases mediated by phosphodiesterase 4 (PDE4) by administering a PDE4 inhibitor with other pharmaceutically active agents that accept pulmonary function.

BACKGROUND OF THE INVENTION The identification of novel therapeutic agents to treat lung diseases is hindered by the fact that multiple mediators are responsible for the development of the disease. Thus, it seems unlikely that eliminating the effects of a single mediator can have a substantial effect on the three components of chronic asthma. An alternative to the "mediating procedure" is to regulate the activity of the cells responsible for the pathophysiology of the disease. One of these ways is to raise cAMP levels (3 ', 5'-cyclic adenosine monophosphate). Cyclic AMP has been shown to be a second messenger in the mediation of lal responses to a wide range of hormones, neurotransmitters and drugs; [Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973]. When the appropriate agonist binds to specific cell surface receptors, adenylate cyclase is activated, which converts Mg + 2-ATP to cAMP at an accelerated rate. Cyclic AMP modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of extrinsic (allergic) asthma. As such, an elevation of the cAMP would produce beneficial effects including: 1) relaxation of smooth muscle of the airways, 2) inhibition of release of mast cell mediator, 3) suppression of degranulation of neutrophils, 4) , - inhibition of degranulation of basophils, and 5) .- inhibition of activation of monocytes and macrophages. Thus, compounds that activate adenylate cyclase or inhibit phosphodiesterase may be effective in suppressing inappropriate activation of airway smooth muscle and a wide variety of inflammatory cells. The main cellular mechanism for the inactivation of cAMPs S is the hydrolysis of 3'-phosphodiester linkage by one or more of a family of isozymes referred to as nucleotide cyclic phosphodiesterases (PDEs). It has been shown that a distinct cyclic nucleotide phosphodiesterase (PDE) isozyme, PDE IV is responsible for the breakdown of cAMP in the smooth muscle of airways and inflammatory cells. Torphy, "Phosphodiesterase isozymes: Potential Targets for Novel Anti-asthmatic Agents" in New Drugs for Asthma, Barnes, ed IBC TechnicalServices Ltd., 1989], Research indicates that inhibition of this enzyme not only results in relaxation of smooth muscle the airways if not also suppress the degranulation of macrocells, basophils and neutrophils in addition to inhibiting the activation of monocytes and neutrophils. In addition, the beneficial effects of PDE IV inhibitors are markedly enhanced when the adenylate cyclase activity of the target cells is increased by suitable hormones or autocoids, as would be the case in vivo. In this way, PDE IV inhibitors could be effective in the lung, where the levels of prostaglandin E2 and prostacyclin (adenylate cyclase activators) are high. These compounds would offer a unique approach to the pharmacotherapy of bronchial asthma and have considerable therapeutic advantages over agents that are currently on the market. Furthermore, it would be useful to combine therapies in light of the fact that the etiology of many pulmonary diseases involves multiple mediators. In this invention there is presented a combination of a PDE4 inhibitor and a long-acting beta agonist inhaled to treat lung diseases, particularly CORD or asthma.

BRIEF DESCRIPTION OF THE INVENTION In a first aspect, this invention relates to a method for treating a lung disease by administering to a patient in need of such treatment, an effective amount of a PDE4 inhibitor and a long-acting beta-adrenergic bronchodilator either in single or combined form , separately, or separately and sequentially in which the sequential administration is made with a short or prolonged time difference. In a second aspect, this invention relates to a composition for treating a lung disease comprising an effective amount of a PDE4 inhibitor, an effective amount of a long-acting beta-adrenergic bronchodilator and a pharmaceutically acceptable excipient. In a third aspect, this invention relates to a method for preparing a composition that is effective to avoid the symptoms of treating a lung disease whose method comprises mixing an effective amount of a PDE4 inhibitor and a long-acting beta-adrenergic bronchodilator. with a pharmaceutically acceptable excipient.

DETAILED DESCRIPTION OF THE INVENTION The combination therapy contemplated by this invention comprises administering a PDE4 inhibitor with a long-acting beta-adrenergic bronchodilator to prevent the onset of a lung disease or to treat an existing condition. The compounds can be administered together in a single dose form. Or they can be administered in the form of different doses. They can be administered at the same time. Or they can be administered with a short or prolonged time difference, such as administering a drug in the morning and the second drug in the afternoon. The combination can be used prophylactically or after the onset of symptoms. In some cases the combination can be used to prevent the progression of a lung disease or to stop the decline of a function such as lung function. The PDE4 inhibitor useful in this invention may be any compound that is known to inhibit the PDE4 enzyme or that is found to act as an inhibitor of PDE4, and which are only PDE4 inhibitors, not compounds that inhibit other members of the PDE family as well as PDE4. It is generally preferred to use a PDE4 antagonist having an IC5o ratio of about 0.1 or greater relative to IC50 for the catalytic form of PDE IV that binds rolipram with a high affinity divided by IC50 for the form that binds rolipram with a low affinity. PDE inhibitors used to treat inflammation and as bronchodilators, drugs such as theophylline and pentoxifylline, inhibit PDE isozymes indiscriminately in all tissues. These compounds show side effects, apparently because they do not selectively inhibit all isozyme classes of PDE in all tissues. The pathological condition in question can be effectively treated with said compounds, but unwanted side effects may be shown which, if they could be avoided or minimized, would increase the overall therapeutic effect of this procedure to treat certain disease states. For example, clinical studies with the selective PDE4 inhibitor rolipram, which was being developed as an antidepressant, indicate that it has psychotropic activity and produces gastrointestinal effects, for example heartburn, nausea and emesis. It turns out that there are at least two forms of binding in human monocyte recombinant PDE 4 (hPDE 4) to which the inhibitors bind. One explanation for these observations is that hPDE 4 exists in two different forms. One binds to the similar ones of rolipram and denbufilin with a high affinity while the other binds to these compounds with a low affinity. Preferred PDE4 inhibitors to be used in this invention will be those compounds that have a healthy therapeutic relationship, i.e., compounds that preferably inhibit the catalytic activity of cAMP where the enzyme is in the form that binds to rolipram with a low affinity, thereby reducing the side effects that are apparently linked to the inhibition of the form that binds to rolipram with a high affinity. Another way to state this is that preferred compounds have an IC 50 ratio of about 0.1 or greater with respect to IC 50 for the catalytic form of PDE 4 that binds rolipram with a high affinity divided by IC 50 for the form that binds to rolipram with a low affinity. Some examples of such compounds are: Papaverine 1 - [(3,4-dimethoxy-phenyl) methyl] -6,4-dimethoxyisoquinoline; Trequinsine 2,3,6,7-tetrahydro-2- (mesitylimino) -9,10-dimethoxy-3-methyl-4H-pyrimido [6,1-a] ¡s-quinolin-4-one; Dipyrimadol - the generic name for 2,2 ', 2", 2'" - [(4,8-d, piperidinopyrimido [5,4-] pyrimid-na-2-diyl) dina Trilo] tetraethanol; (R) - (+) - 1- (4-bromobenzyl) -4 - [(3-cyclopentyloxy) -4-methoxyphenyl] -2-pyrrolidone; (R) - (+) - 1- (4-bromobenzyl) -4 - [(3-cyclopentyloxy) -4-methoxyphenyl] -2-pyrrolidone, 3- (cyclopentyloxy-4-methoxyphenyl) -1- (4 -N '- [N2-cyano-S-methyl-isothioureido] benzyl) -2-pyrrolidone, cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -cyclohexan-1-carboxylate]; cis- [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol]; [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidine-2-ylidene] acetate (R) - (+) - ethyl; [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidine-2-ylidene] acetate of (S) - (-) - ethyl; Very preferred are those PDE4 inhibitors that have an IC50 ratio greater than 0.5 and particularly those compounds that have a ratio greater than 1.0. The preferred compounds are trequinsin, dipyridamole, and papaverine. Compounds such as cis- [cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylate], 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl) -cyclohexan-1- ona, and cis- [4-cyano- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexane-1-ol] are examples of structures that are preferably attached to the low affinity binding site and have an IC50 ratio of 0.1 or higher. Reference is made to the co-pending patent application E.U.A. 08 / 456,274 issued May 31, 1995 and its predecessor a PCT patent application published on January 5, 1995 as WO95 / 00139 for methods and techniques that can be used to identify a compound having a high / low IC50 ratio of 0.1 or greater as referred to in the following paragraph. This copending application, USSN 08 / 456,274 is hereby included by way of reference in its entirety. The various specific compounds ioned above that do not have a generic or commercial name can be made by the process described in the co-pending patent applications of E.U.A. USSN 862,083 filed October 30, 1992; US $ 862,111 granted October 30, 1992; USSN 862,030 filed October 30, 1992; and USSN 862,114 filed October 30, 1992 or its predecessors or US patents. who claim priority of one or more of these requests. Each of these related applications or patents is hereby incorporated by reference in its entirety herein. The beta-adrenergic bronchodilator, in fact β2-adrenergic agonists, used in this invention will be a long-lasting compound. Any compound of this type can be used in this combination therapy procedure. For long duration it is understood that the drug will have an effect on the bronchi that lasts about 6 hours or more, up to 12 hours in some cases. By way of illustration, certain resorcinols such as metaproterenol, terbutaline, and fenoterol can be combined with a PDE4 inhibitor in the practice of this invention. Other examples of useful beta-adrenergic bronchodilators are the similar ones of two structurally related compounds, albuterol. { (racemic oc1 - [(f-butylamino) methyl] -4-hydroxy- / t? -xylene-o, oc'-diol)} and formoterol. { (R *, R *) - (±) -N- [2-hydroxy-5- [1-hydroxy-2 - [[2- (4-methoxyphenyl) -1-methylethyl] ethyl] phenyl] formamide} . Metaproterenol is the subject of the patent of E.U.A. 3,341,594 and is commercially available under the trade name of Alotec, Alupent, Metaprel or Novasmasol. Terbutaline is described in the patent of E.U.A. 3,938,838 and is commercially available as Brethine from Novartis. The preparation of fenoterol is described in the patent of E.U.A. 4,341,593. It is sold under various trade names, including Airum, Berotec, Dosberotec and Partusisten. Albuterol is sold under the registered trademark Proventil® by Schering Corporation. Formoterol is described in the US patent. 3, 994,974 and is commercially available under the names of Atock and Foradil. A preferred combination therapy is that of formoterol and cis- [cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylate]. These drugs, the beta agonists, are generally administered as an oral or nasal spray, or as an inhalation powder. Generally these drugs are not administered systemically or by injection. PDE4 inhibitors can be administered orally or by inhalation (orally or internally). This invention contemplates co-administering both drugs in a form of delivery as an inhaler, ie, putting both drugs in the same inhaler. Alternatively, you can put the PDE4 inhibitor in pill and pack it with an inhaler that contains the beta agonist. The formulations are within the field of the art. It is contemplated that both active agents can be administered at the same time, or with a very short time difference. Alternatively, a drug can be taken in the morning and another later in the day. In another perspective, a drug can be taken twice a day and the other once a day, either at the same time as one of the two daily doses, or separately. Preferably both drugs can be taken together at the same time. The following statements and examples are intended to illustrate the invention, but not to limit it. The claims are referred to as reserved for the inventors below.

Claims (4)

NOVELTY OF THE INVENTION CLAIMS

1. - The use of a) a first compound, said compound being a PDE4 inhibitor and b) a second compound, said second compound being a long-lasting beta-adrenergic bronchodilator for the manufacture of a medicament for treating a lung disease in a patient, wherein the first medicament and the second medicament are administered either in a combined form, separately, or separately and sequentially, wherein the sequential administration has a short or prolonged time difference.

2. The use according to claim 1, wherein the PDE4 inhibitor is cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylate] and the beta agonist is formoterol.

3. A composition for treating a lung disease comprising an effective amount of a PDE4 inhibitor, an effective amount of a long-acting beta-adrenergic bronchodilator and a pharmaceutically acceptable excipient.

4. A method for preparing a composition that is effective in preventing the symptoms of, or treating, a lung disease which method comprises mixing an effective amount of a PDE4 inhibitor and a long-acting beta-adrenergic bronchodilator with a pharmaceutically acceptable excipient.