WO2006040103A1

WO2006040103A1 - Use of cold menthol receptor modulators for the treatment of respiratory disorders

Info

Publication number: WO2006040103A1
Application number: PCT/EP2005/010862
Authority: WO
Inventors: Cristina Alonso-Alija; Peter Sandner; Beatrix Stelte-Ludwig
Original assignee: Bayer Healthcare Ag
Priority date: 2004-10-13
Filing date: 2005-10-08
Publication date: 2006-04-20

Abstract

The present invention relates to methods and pharmaceutical compositions for treatment and/or prophylaxis of respiratory diseases or disorders. More particularly, this invention concerns the use of a cold menthol receptor (CMR-1) modulator for the treatment of asthma, chronic obstructive pulmonary (or airways) disease (COPD) and allergic rhinitis.

Description

USE OF COLD MENTHOL RECEPTOR MODULATORS FOR THE TREATMENT OF RESPIRATORY DISORDERS

TECHNICAL FIELD

The present invention relates to methods and pharmaceutical compositions for treatment and/or prophylaxis of respiratory diseases or disorders. More particularly, this invention concerns the use of a cold menthol receptor (CMR-I) modulator for the treatment of asthma, chronic obstructive pulmonary (or airways) disease (COPD) and allergic rhinitis.

BACKGROUND OF THE INVENTION

A cold- and menthol-sensitive receptor (CMR-I) derived from rat has been cloned recently [McKemy D.D., Neuhausser W.M., and Julius, D.: Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416:52-58, 2002]. This receptor is an excitatory ion channel expressed by small-diameter neurons in trigeminal and dorsal root ganglia. This channel receptor is activated by cold temperature (8-28⁰C) and menthol as a chemical agonist of a thermally responsive receptor, eliciting the same sensation of cool feeling. CMR-I belongs in a member of the transient receptor potential (TRP) channel subfamily, which is similar to other thermoreceptors, VR-I and VRLl, responding with a noxious heat and transfer the sensory information to the spinal cord and brain [Nagy L, Rang H.: Noxious heat activates all capsaicin- sensitive and also a sub-population of capsaicin-insensitive dorsal root ganglion neurons. Neuroscience 88:995-997, 1999] [Cesare P., McNaughton P.: A novel heat-activated current in nociceptive neurons and its sensitization by bradykinin. Proc. Natl. Acad. Sci. U.S.A. 93:15435-

15439, 1996]. US 2003/0206866 describes a therapeutic composition of a substituted 1,2,3,6- tetrahydropyrimidine-2-one cold receptor agonist for the treatment of upper airway breathing disorders.

Since CMR-I has been cloned recently object of the invention was to find new indications for CMR-I modulators. CMR-I is co expressed with other receptors of the transient receptor potential

(TRP) channel family in various tissues and is signaling via modulation of intracellular calcium.

Therefore it should have influence on respiratory function in humans, on mucus secretion, on mucus hypersecretion, on the sneeze reflex, and on local allergy reactions.

The respiratory system in man reacts to foreign substances through a complex mechanism involving cough, sneeze, increased nasal secretion or rhinorrhea and congestion. Cough is a protective reflex that can expel secretions, exudates, transudates or extraneous materials from the respiratory tract. Antitussive medications inhibit or supress cough by acting on either the central or peripheral components of the cough reflex. Many agents, such as codeine and dextromethorphan, suppress the cough reflex by depressing the medullary cough center or associated higher centers. Other antitussives act as mild analgesic or anesthetics on the repiratory mucosa. Demulcents are useful against cough arising above the larynx, acting by forming a protective coating over the irritated pharyngeal mucosa. Local anesthetics such as benzocaine, cyclaine and tetracaine are used to inhibit the cough reflex under special circumstances; e. g., before bronchoscopy or bronchography. Other antitussives such as humidifying aerosols and steam inhalation exert their effects by demulcent action and by decreasing the viscosity of bronchial secretions. Expectorants also produce their antitussive effect by decreasing the viscosity of broncial secretions, often producing increased bronchial secretions through reflex irritation of the bronchial mucosa.

Rhinorrhea and congestion are also present in a number of respiratory diseases or disorders. Bronchial asthma can occur secondarily to a variety of stimuli. Persons manifestings this disorder often have hyperreactive bronchi, sometimes with associated bronchoconstriction. Asthmatic attacks are characterized by narrowing of large and small airways due to spasm of bronchial smooth muscle, edema and inflammation of the bronchial mucosa and production of tenacious mucus. Asthma precipitated by allergens is often termed "extrinsic asthma" and accounts for about 10 to 20% of adult asthmatics. 30 to 50% of asthmatic episodes appear to be triggered by non- allergenic factors (e.g., infection, irritants). These asthmatics are said to have nonallergic or "intrinsic asthma". In many persons, both allergenic and non-allergenic factors are significant. Persistent asthma and chronic asthmatic bronchitis sufferers also display chronic, productive cough.

Acute bronchitis may develop after nasopharyngeal, throat or tracheobronchial tree infections, with exposure to external elements and other agents as contributory factors. Sore throat followed by onset of cough usually signals onset of bronchitis, with initially dry nonproductive cough becoming mucoid or mucopurulent (productive) with the passage of a few hours or days. Chronic bronchitis is a condition associated with prolonged exposure to nonspecific bronchial irritants and accompanied by mucus hypersecretion and certain structural changes in the bronchi. Chronic bronchitis is also characterized clinically by chronic productive cough.

Pain or itch is often associated with irritation of respiratory mucosa. Anesthetics may reduce such pain, but often results in loss of mechanical sensation (numbing) of the nasal and upper respiratory tract mucosa. DETAILED DESCRIPTION OF INVENTION

The present invention relates to the use of a CMR-I modulator for treatment and/or prophylaxis of respiratory diseases or disorders in a mammal. Object of the invention is to provide long-lasting relief from the symptoms associated with respiratory diseases or disorders. By applying a CMR-I modulator suffering from respiratory symptoms associated with respiratory diseases or disorders, such symptoms as cough, sneeze, throat pain and itch, rhinorrhea (mucus hypersecretion) and congestion are eliminated.

The present invention further provides a pharmaceutical composition which includes a CMR-I modulator or a pharmaceutically acceptable salt thereof for treatment and/or prophylaxis of respiratory diseases or disorder.

The present invention also provides a use of a CMR-I modulator or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treatment and/or prophylaxis of respiratory diseases or disorders and the attendant discomfort often associated with respiratory diseases or disorders.

Further this invention is to provide a method for treatment and/or prophylaxis of respiratory diseases or disorders in a mammal, preferably in a human, which method comprises administering to said mammal a therapeutically effective amount of a CMR-I modulator or a pharmaceutically acceptable salt thereof.

This invention particularly relates to methods of treatment and/or prophylaxis whereby pharmaceutical compositions containing said CMR-I modulator are locally or regionally applied to the respiratory tract to treat the respiratory symptoms associated with respiratory diseases or disorders.

As CMR-I modulator a CMR-I antagonist is preferred.

It is a further object of the present invention to provide methods for topically treating such respiratory diseases or disorders.

It is a still further object of the present invention to provide methods of treatment which resolve clinical symptoms of respiratory diseases or disorders without causing loss of mechanical sensation (i. e., "numbing") in the respiratory tract or loss of olfactory competence.

It is a still further object of the present invention to provide methods of treatment which resolve clinical symptoms of respiratory diseases or disorders while also decreasing the pain or itch associated with irritation of respiratory mucosa. Respiratory diseases or disorders that can be treated by the methods of the present invention include such diseases or disorders as the common cold; extrinsic or intrinsic asthma; chronic obstructive pulmonary disease (COPD) including chronic bronchitis and bronchiolitis; diseases of the extrathoracic (upper) airways caused by viral infection; allergic rhinitis; vasomotor rhinitis; disorders associated with exogenous irritants such as tobacco smoke, smog, high levels of atmospheric SO₂ and noxious gases in the workplace; airways hyperreactivity; milk product intolerance; Loffler's pneumonia; emphysema; cystic fibrosis; bronchiectasis; pulmonary fibrosis; pneumoconiosis; collagen vascular disease; granulomatous disease; laryngitis; acute bronchitis; pharyngitis; pneumonia; pleuritis; persistent asthma and chronic asthmatic bronchitis.

More particularly, respiratory diseases or disorders that can be treated by the methods of the present invention include the common cold, extrinsic or intrinsic asthma; chronic bronchitis; diseases of the extrathoracic (upper) airways caused by viral infection; allergic rhinitis and vasomotor rhinitis; airways hyperreactivity; milk product intolerance; Loffler's pneumonia; emphysema; cystic fibrosis; bronchiectasis; pulmonary fibrosis; pneumoconiosis; collagen vascular disease; granulomatous disease; laryngitis and pharyngitis.

Even more particularly, respiratory diseases or disorders that can be treated by the methods of the present invention include the common cold, intrinsic asthma, chronic bronchitis, diseases of the extrathoracic (upper) airways caused by viral infection, allergic rhinitis, vasomotor rhinitis, laryngitis and pharyngitis.

Most particularly, respiratory diseases or disorders that can be treated by the methods of the present invention include intrinsic asthma; allergic rhinitis or vasomotor rhinitis; or laryngitis and pharyngitis.

CMR-I modulators include species that will bind CMR-I and species that will interfere with the binding of CMR-I to its ligands. CMR-I modulators include, without limitation, certain groups of organic small molecules. Especially antagonists that bind CMR-I include, without limitation, certain groups of organic small molecules. CMR-I modulators can be produced by methods well known to those skilled in the art.

CMR-I used in the present invention can be any form of CMR-I, so long as that form of CMR-I is capable of binding its ligands.

Typical salts of an organic small molecule include salts prepared by reaction of the compounds with a mineral or organic acid, or an organic or inorganic base. Such salts are known as acid addition and base addition salts, respectively. Acids to form acid addition salts include inorganic acids such as, without limitation, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid and the like, and organic acids, such as, without limitation, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p- bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.

Base addition salts include those derived from inorganic bases, such as, without limitation, ammonium hydroxide, alkaline metal hydroxide, alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, and organic bases, such as, without limitation, ethanolamine, triethylamine, tris(hydroxymethyl)aminomethane, and the like. Examples of inorganic bases include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.

The pharmaceutical composition of the present invention may be administered in oral forms, such as, without limitation normal and enteric coated tablets, capsules, pills, powders, granules, elixirs, tinctures, solution, suspensions, syrups, solid and liquid aerosols and emulsions. They may also be administered in parenteral forms, such as, without limitation, intravenous, intraperitoneal, subcutaneous, intramuscular, and the like forms, well-known to those of ordinary skill in the pharmaceutical arts. The pharmaceutical composition of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or by inhalation or insufflation, or via transdermal routes, using transdermal delivery systems well-known to those of ordinary skilled in the art.

The preferred methods of the present invention involve topical administration of the CMR-I compounds. These methods include, but are not limited to, administration by insufflator, pressurized insufflator, nebulizer, spray, drop, rinse, jelly, nasal aerosol, ointment formulation, cream, lotion, cotton pled- get, gauge packtail, metered-dose nasal spray, metered-pump sprayer, metered dose aerosolized spray, fixed-volume aerosol spray, nasal spray emulsion, inhalation aerosol, and nebulizer aerosol.

The dosage regimen with the use of the pharmaceutical compositions of the present invention is selected by one of ordinary skill in the arts, in view of a variety of factors, including, without limitation, age, weight, sex, and medical condition of the recipient, the severity of the condition to be treated, the route of administration, the level of metabolic and excretory function of the recipient, the dosage form employed.

The pharmaceutical compositions of the present invention are preferably formulated prior to administration and include one or more pharmaceutically acceptable excipients. Excipients are inert substances such as, without limitation carriers, diluents, flavoring agents, sweeteners, lubricants, solubilizers, suspending agents, binders, tablet disintegrating agents and encapsulating material.

Yet in another embodiment, the pharmaceutical formulation of the present invention comprises one or more pharmaceutically-acceptable excipients that are compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. In making the compositions of the present invention, the active ingredient may be mixed with a diluent, or enclosed within a carrier, which may be in the form of a capsule, sachet, paper, or other container. The carrier may serve as a diluent, which may be solid, semi-solid, or liquid material which acts as a vehicle, or can be in the form of tablets, pills powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, containing, for example, up to 10% by weight of the active pharmaceutical composition, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

For oral administration, the active ingredient may be combined with an oral, and non-toxic, pharmaceutically-acceptable carrier, such as, without limitation, lactose, starch, sucrose, glucose, sodium carbonate, mannitol, sorbitol, calcium carbonate, calcium phosphate, calcium sulfate, methyl cellulose, and the like; together with, optionally, disintegrating agents, such as, without limitation, maize, starch, methyl cellulose, agar bentonite, xanthan gum, alginic acid, and the like; and optionally, binding agents, for example, without limitation, gelatin, natural sugars, beta- lactose, corn sweeteners, natural and synthetic gums, acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like; and, optionally, lubricating agents, for example, without limitation, magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodium benzoate, sodium acetate, sodium chloride, talc, and the like.

In powder forms, the carrier may be a finely divided solid which is in admixture with the finely divided active ingredient. The active ingredient may be mixed with a carrier having binding properties in suitable proportions and compacted in the shape and size desired to produce tablets. The powders and tablets preferably contain from about 1 to about 99 weight percent of the active ingredient which is the novel composition of the present invention. Suitable solid carriers are magnesium carboxymethyl cellulose, low melting waxes, and cocoa butter.

Sterile liquid formulations include suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carriers, such as sterile water, sterile organic solvent, or a mixture of both sterile water and sterile organic solvent. The active ingredient can also be dissolved in a suitable organic solvent, for example, aqueous propylene glycol. Other compositions can be made by dispersing the finely divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oil.

The formulation may be in unit dosage form, which is a physically discrete unit containing a unit dose, suitable for administration in human or other mammals. A unit dosage form can be a capsule or tablets, or a number of capsules or tablets. A "unit dose" is a predetermined quantity of the active pharmaceutical composition of the present invention, calculated to produce the desired therapeutic effect, in association with one or more excipients. The quantity of active ingredient in a unit dose may be varied or adjusted from about 0.1 to about 1000 milligrams or more according to the particular treatment involved.

Typical oral dosages of the present invention, when used for the indicated effects, will range from about O.Olmg/kg/day to about 100 mg/kg/day, preferably from 0.1 mg/kg/day to 30 mg/kg/day, and most preferably from about 0.5 mg/kg/day to about 10 mg/kg/day. In the case of parenteral administration, it has generally proven advantageous to administer quantities of about 0.001 to lOOmg/kg/day, preferably from 0.01 mg/kg/day to 1 mg/kg/day. The pharmaceutical compositions of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses, two, three, or more times per day. Where delivery is via transdermal forms, of course, administration is continuous.

For topical administration, the active ingredient may be used as is, or compositions may be formulated for topical delivery. Suitable pharmaceutically acceptable carriers for topical application include those suited for use as dispersions, emulsions, nebulae, powders and vapors.

Dispersions include, for example, solutions, suspensions, and colloidal dispersions. Emulsions include, for example, systems containing two immiscible liquids in which one is dispersed, in the form of very small globules, throughout the other. Nebulae include, for example, oily liquid preparations that may be broken up into fine droplets. Powders include solid component forms.

Vapors include solids or liquids converted into gaseous form.

Dispersions, emulsions, nebulae and powders may be formulated into aerosol compositions. Different regions of the respiratory tract may be targeted utilizing suitable aerosol compositions. These compositions may be composed of droplets or particles in a gas, using either gas and a powder or atomized bulk liquids. Aerosol compositions can be formulated into compositions with or without a propellant. The aerosol compositions preferably comprise from 25 to 99%, preferably 90 to 95%, of a suitable propellant. Examples of such propellants include fluorocarbons such as dichlorofluoromethane and dichlorotetrafluoroethane, and hydrocarbons such as propane, butane and isobutane. Dispersions, emulsions, nebulae, powders and vapors can be formulated into inhalant compositions. Inhalants can include finely powdered, liquid or vapor compositions carried by an air current into the respiratory passages. Components of inhalant compositions may include ethereal oils, highly volatile substances such as menthol and camphor, suitable surfactants/ dispersing agents such as oleic acid, lecithin or sorbitan trioleate, water or other co-solvents.

Pressurized or unpressurized nebulizers of both aqueous solutions and dry powders, may be used for the administration of compounds and compositions of the present invention as inhalants. Delivery to more distal regions of the respiratory tract can be accomplished using nebulizers which distribute composition components in a finely divided cloud. Examples of such nebulizers include jet nebulizers, spinning nebulizers and ultrasonic nebulizers. Inhalers may also be used.

Composition formulations for inhalers may include dimethyl ether-fluorocarbons blended with other components that are solvents and propellants.

Insufflators may also be used for the administration of compounds and compositions of the present invention. The compounds or compositions are blown into the nasal, oral or respiratory passages.

Dispersions, emulsions, nebulae, and powders can be formulated into nasal or oral sprays, the compositions being administered in the form of a spray of small droplet or particle size by ejecting the composition into the nasal or oral cavity. These compositions may be primarily aqueous or aqueous-organic and may contain other components such as sympathomimetics, antihistamines, local anesthetics and aromatics, such as menthol.

Dispersions, emulsions, nebulae, and powders can be formulated for administration to the upper and lower respiratory tract by incorporating the compounds or compositions of the present invention with air or other gasses. The formulations comprising droplets or particles for administration to the upper respiratory tract are preferably of an aerodynamic size (mean mass diameter) of from about 0.1 μm to about lOOμm, more preferably from about lOμm to about lOOμm, even more preferably from about 50μm to about lOOμm. Formulations particularly suited for administration to the lower respiratory tract are made by incorporating the compounds or compositions of the present invention with air or other gases to produce respiratory formulations. The term lower respiratory formulations as used herein means compounds or compositions of the present invention dispersed in air or other gasses to form discrete units with an aerodynamic size (mean mass diameter) of equal to or less than about lOμm. Preferred lower respiratory formulations have an aerodynamic size of from about 0.1 μm to about lOμm. More preferably, the lower respiratory formulations have an aerodynamic size of from about 0.5μm to about 7μm. Even more preferably, the lower respiratory formulations have an aerodynamic size of from about 1 μm to about 5μm. Dispersions, emulsions, nebulae and powders can be formulated into drops, gargles, rinses or jellies, lotions or creams by incorporating a safe and effective amount of a CMR-I compound or composition with a pharmaceutically-acceptable solubilizing and/or dispersing agent (such as polysorbates, Pluronics®, Brijs®, polyvinylpyrrolidone, phospholipids, alkyl sulfates, etc.) and water; and/or pharmaceutically-acceptable co-solvents such as ethanol, propylene glycol, glycerin and PEG. Preservatives such as benzalkonium chloride and alkyl parabens and the like; and thickening agents such as modified cellulose gums of carboxyvinyl polymers, can be included as optional ingredients.

The effect of the present pharmaceutical compositions was examined by the following assays and pharmacological tests.

Measurement of the menthol-induced Ca²⁺ influx in HEK293 Cell expressing CMR-I receptor (Assay 1).

A cell-based calcium influx assay using HEK293 cells stably expressing human CMR-I is used to identify CMR-I receptor-antagonists. Menthol, a CMR-I specific agonist, is used for stimulation of these cells, inducing an increase in intracellular calcium. This menthol-induced Ca²⁺ increase is traced by fluorescence measurement. Therefore the cells are loaded with fluo4-AM prior to stimulation. For testing inhibitors the cells are preincubated with various concentrations of the compound before menthol stimulation. The potency of potential CMR-I inhibitors is quantified by measuring decrease of fluorescence .

Measurement of the menthol-induced Ca²⁺ influx in primary cultured rat dorsal root ganglia neurons (Assay 2)

Since CMR-I is expressed on DRG (C-fibers), in which this receptor mediates the altered afferent information in overactive bladder; primary cultures of rat DRG are used as functional in vitro test. Stimulation of the cells is done with menthol and cold and the induced calcium influx is quantified by fluorescence in the presence or absence of CMR-I inhibitors.

Preparation of primary cultured rat DRG neurons: DRG are prepared from Zucker rats (30 days in age) and neuronal cells are dispersed in 0.1% collagenase. After removal of Schwann cells by adhering to a culture plate, non-adherent neuronal cells are recovered and cultured on laminin- and poly-D-lysine coated 384 well plates for 2 days in the presence of 50 ng/ml rat NGF and 50 μM 5- fluorodeoxyuridine. Measurement of Ca²⁺: Rat DRG neurons are suspended in a culture medium and seeded into 384- well plates (black walled clear-base / Nalge Nunc International). Following the culture for 48 hrs the medium is changed to 2 μM Fluo-4 AM (Molecular Probes) and 0.02% Puronic F-127 in assay buffer (Hank's balanced salt solution (HBSS), 17 mM HEPES (pH7.4), 1 mM Probenecid, 0.1% bovine serum albumin (BSA)) and the cells are incubated for 60 min at 25°C. After washing twice with assay buffer the cells are incubated with a test compound or vehicle (dimethylsulfoxide) for 20 min at 25⁰C. The fluorescence change indicating mobilization of cytoplasmic Ca²⁺ is measured for 60 sec after the stimulation with 50 μM menthol. The fluorescence change is calculated in the samples treated with a test compound and vehicle respectively. Inhibitory effect of the compound is calculated by a comparison of the values.

Claims

1. The use of a cold methanol receptor (CMR-I) modulator or a pharmaceutically acceptable salt thereof for treatment and/or prophylaxis of respiratory diseases or disorders in a mammal.

2. The use of claim 1 , wherein said respiratory diseases or disorders are chronic obstructive pulmonary disease or allergic rhinitis.

3. The use of claim 1, wherein said mammal is a human.

4. The use of claim 1, wherein said CMR-I modulator is administered in combination with a pharmaceutically acceptable carrier.

5. The use of a CMR-I modulator or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treatment and/or prophylaxis of respiratory diseases or disorders.

6. The use of claim 5, wherein said respiratory diseases or disorders are chronic obstructive pulmonary disease or allergic rhinitis.

7. A pharmaceutical composition comprising a CMR-I modulator or a pharmaceutically acceptable salt thereof for treatment and/or prophylaxis of respiratory diseases or disorders.

8. The pharmaceutical composition of claim 7, wherein said respiratory diseases or disorders are chronic obstructive pulmonary disease or allergic rhinitis.

9. A method for treatment and/or prophylaxis of respiratory diseases or disorders in a mammal, said method comprising administering to said mammal a therapeutically effective amount of a cold methanol receptor (CMR-I) modulator or a pharmaceutically acceptable salt thereof.

10. The method of claim 9, wherein said mammal is a human.

11. The method of claim 9, wherein said CMR-I modulator is administered in combination with a pharmaceutically acceptable carrier.

12. The use of claim 1, wherein said CMR-I modulator is a CMR-I antagonist.