BRPI0708777A2 - chemical compound, pharmaceutical composition, and use of a compound - Google Patents

Abstract

CHEMICAL COMPOUND, PHARMACEUTICAL COMPOSITION, AND USE OF A COMPOUND. The present invention relates to new diphenylurea derivatives of the formula (I) useful as chloride channel blockers or BK-Ca ~ channel modulators. In other respects, the invention relates to the use of these compounds in a method for therapy, and to pharmaceutical compositions comprising the compounds of the invention.

Description

"CHEMICAL COMPOUND, PHARMACEUTICAL COMPOSITION, AND USE OF A COMPOUND"

TECHNICAL FIELD

The present invention relates to novel diphenylurea derivatives useful as chloride channel blockers or

In other aspects the invention relates to the use of these compounds in a method for therapy, and to pharmaceutical compositions comprising the compounds of the invention.

TECHNICAL BACKGROUNDS

Chloride channels serve a wide variety of specific cell functions and contribute to the normal function of i.e. skeletal and smooth muscle cells. Chloride channels are likely to be found in each cell from bacteria to mammals. Its physiological tasks range from cell volume regulation to membrane potential stabilization, transepithelial or transcellular transport and acidification of intracellular organelles.

Similarly, Ca-activated BK channels are present in many cells including. Most central and peripheral nerve cells, striated muscle cells, cardiac cells, airway, vasculature, gastrointestinal tract, and bladder smooth cells in the endo- and exocrine glands including the

pancreatic B cells and renal tubules. There is a continuing strong need to provide

active compounds such as chloride channel blockers or BKca channel modulators and with an optimized pharmacological profile. In addition, there is a strong need to find compounds effective without the unwanted side effects associated with older compounds.

WO 2005/023237 and WO 2005/023238 (Poseidon Pharmaceuticals A / S) describe the use of ERG channel openers for the treatment of hyperexcitability-related neuronal diseases of cardiac arrhythmias. Among the disclosed compounds is 1- (3-trifluoromethyl-phenyl) -3- [2- (5-oxo-4,5-dihydro [1,2,4] oxadiazol-3-yl) -4- (4 '-N, N-dimethyl carbamoyl) biphenyl] urea.

SUMMARY OF THE INVENTION

It is an object of the invention to provide novel compounds which act as chloride channel blockers or BKca channel modulators.

Another object of the invention is to provide compounds with better selectivity. Yet another goal is to provide decomposed with better power.

Another object of the invention is to provide compounds that act on cell or tissue specific chloride channels or BKca channels. Yet another object is to provide compounds that act on specific groups or subtypes of chloride channels.

Yet another goal is the provision of compound most optimal pharmacodynamic properties such as kinetic behavior, bioavailability, solubility and efficacy.

In its first aspect, the invention provides a compound of general formula I,

<formula> formula see original document page 3 </formula>

any of its isomers or any mixture of its isomers, or a pharmaceutically acceptable salt thereof, wherein R 0, R 5 R 5, R 2, R 3, R 45 R 5 and R 6 are as defined below.

In its second aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, any of its isomers or any mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, together with at least one carrier, excipient or pharmaceutically acceptable diluent.

In another aspect, the invention provides the use of a compound of the invention, any of its isomers or any mixture of its isomers, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for the treatment, prevention or alleviation of a disease or a disorder or condition of a mammal, including a human, disease, disorder or condition which is responsive to blocking chloride channels or modulating BKca channels, or for the manufacture of a medicament useful for enhancing blood-brain barrier openness.

In yet another aspect, the invention relates to a method for treating, preventing or alleviating a disease or disorder or condition of a living animal body, including a human, disorder, disease or condition that is responsive to dechannel blockage. of chloride or channel modulation of BKca, which method comprises the step of administering to such a living animal body in need thereof a therapeutically effective amount of a compound of the invention, any of its isomers or any mixture of its isomers, or a pharmaceutically acceptable salt. the same.

Other objects of the invention will be apparent to the skilled person from the following detailed description and examples. DETAILED DESCRIPTION OF THE INVENTION

Diphenylurea derivatives

In its first aspect, the invention provides a chemical compound of formula I,

<formula> formula see original document page 5 </formula>

any of its isomers or any mixture of its isomers, or a pharmaceutically acceptable salt thereof; on what

R °, Rm, Rp, R2, R3, R4, R5 and R6 independently of one another represent hydrogen, halo, trifluoromethyl, trifluoromethoxy, alkyl or alkoxy.

In one embodiment of the compound of formula I, R ° represents hydrogen; Rm represents hydrogen; and Rp represents halo, trifluoromethyl, trifluoromethoxy, alkyl or alkoxy. In another derealization form, R 0 represents hydrogen; Rm represents hydrogen; and R represents halo or trifluoromethyl. In a special embodiment, RP represents trifluoromethyl.

In yet another embodiment, R 3, R 4, R 5 and R 6 represent hydrogen; and R2 represents halo, trifluoromethyl, trifluoromethoxy, alkyl or alkoxy. In a special embodiment R2 represents halo such as chlorine.

In another embodiment, R 2, R 4, R 5 and R 6 represent hydrogen; and R3 represents halo, trifluoromethyl, trifluoromethoxy, alkyl or alkoxy. In a special embodiment R 3 represents halo such as bromine.

In yet another embodiment, R 2, R 5 and R 6 represent hydrogen; and R3 and R4 independently of one another are halo, trifluoromethyl, trifluoromethoxy, alkyl or alkoxy. In another embodiment, R 3 and R 4 independently of one another are halo or trifluoromethyl. In a special embodiment, one of R3 and R4 represents halo, such as chlorine, and the other of R3 and R4 represents trifluoromethyl. In another embodiment, R representsatrifluoromethyl and R4 represents halo, such as chlorine.

In another embodiment, R2, R4 is hydrogen; and R 3 and R 5 independently of each other represent halo, trifluoromethyl, trifluoromethoxy, alkyl or alkoxy. In a special embodiment, R3 and R5 independently of each other represent halo. In another embodiment, R 3 represents fluorine and R 5 represents fluorine.

In a special embodiment the compound of the invention

It's

N- (3,5-Difluoro-phenyl) -N '- [3- (5-oxo-4,5-dihydro [1,2,4] oxadiazol-3-yl) -4-trifluoromethyl-biphenyl-4 -yl] urea;

N- (4-Chloro-3-trifluoromethyl-phenyl) -N '- [3- (5-oxo-4,5-dihydro [1,2,4] oxadiazol-3-yl) -4'-trifluoromethyl -biphenyl-4-yl) -urea;

N- (3-Bromo-phenyl) -N '- {3- (5-oxo-4,5-dihydro [1,2,4] oxadiazol-3-yl) -4'-trifluoromethylbiphen-4-yl ] urea;

N- (2-Chloro-phenyl) -N '- {3- (5-oxo-4,5-dihydro [1,2,4] oxadiazol-3-yl) -4'-trifluoromethylbiphenyl-4-yl ] urea;

or a pharmaceutically acceptable salt thereof.

Definition of Replacers

In the context of this invention halo represents fluorine, chlorine, bromine or iodine.

Alkyl means a straight chain or branched chain of one such carbon atom, including but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, and hexyl; methyl, ethyl, propyl and isopropyl are preferred groups.

Alkoxy is O-alkyl, where alkyl is as defined above. Pharmaceutically Acceptable Salts

The chemical compound of the invention may be provided in any suitable form for intended administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salts, and pre or prodrug forms of the inventive chemical compound.

Examples of pharmaceutically acceptable addition salts include, without limitation, non-toxic inorganic and organic acid addition salts such as hydrochloride, hydrobromide, nitrate, perchlorate, ofphosphate, sulfate, formate, acetate, aconate, scorbate, obenzenesulfonate, benzoate, cinnamate, citrate, embonate, enanthate, fumarate, glutamate, glycolate, lactate, maleate, malonate, omandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, toluene-p-sulfonate, and others. Such salts may be formed by procedures well known and described in the art.

Other acids such as oxalic acid, which may not be considered pharmaceutically acceptable, may be useful in the preparation of such salts useful as intermediates in obtaining an inventive chemical compound and its pharmaceutically acceptable acid addition salt.

Examples of pharmaceutically acceptable cationic salts of a chemical compound of the invention include, without limitation, sodium, opotassium, calcium, magnesium, zinc, aluminum, lithium, choline, lysinium, and ammonium salt, and others of a chemical compound of the invention contained an anionic group. Such cation salts may be formed by procedures well known and described in the art. In the context of this invention "compound salts" containing N are also considered to be pharmaceutically acceptable salts. Preferred "onium salts" include alkyl-onium salts, cycloalkyl-onium salts, and cycloalkylalkyl-onium salts.

Examples of pre-compound or prodrug forms of the chemical compound of the invention include examples of suitable prodrugs of the substances according to the invention including compounds modified in one or more reactive groups or derivatives of the compound precursor. Of particular interest are compounds modified on a group carboxyl, a hydroxyl group, or an amino group. Examples of suitable derivatives are esters or amides.

The chemical compound of the invention may be provided in dissolvable or indissoluble forms together with a pharmaceutically acceptable solvent such as water, ethanol, and the like. Dissolvable forms may also include hydrated forms such as monohydrate, dihydrate, semihydrate, trihydrate, tetrahydrate, and others. In general, dissoluble forms are considered equivalent to indissoluble forms for the purposes of this invention.

It will be appreciated by those skilled in the art that the compounds of the present invention may exist in different stereoisomeric forms - including enantiomers, diastereomers and cis-trans-isomers.

The invention includes all such isomers and any mixtures including racemic mixtures.

Methods for resolving optical isomers known to those skilled in the art may be used, and will be apparent to the average skilled worker in the art. Such methods include those described by J. Jaques, A. Collet, and S. Wilen in "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New York (1981). Optical activity compounds can also be prepared from materials. or optically reactive intermediates.

Labeled Compounds

The compounds of the invention may be used in their labeled or unlabelled form. In the context of this invention the labeled compound has one or more atoms substituted by one atom having a different atomic mass or mass number than the atomic mass or mass number usually found in nature. Labeling will allow easy quantitative detection of said compound.

The labeled compounds of the invention may be useful as diagnostic tools, tracers, or monitoring agents in various diagnostic methods, and for invective receptor imaging.

The labeled isomer of the invention preferably contains at least one radionuclide as a label. Radionuclides that emit empositrons are all candidates for use. In the context of this invention oradionuclide is preferably selected from H (deuterium), H (tritium), C'14C131P125I '123I, and 18F.

The physical method for detecting the labeled isomer of the present invention can be selected from Position Emission Tomography (PET), Single Photon Imaging Computed Tomography (SPECT) 5 Magnetic Resonance Spectroscopy (MRS), Magnetic Resonance Imaging ( MRI), and Axial Computed X-ray Tomography (CAT), or combinations thereof.

Preparation Methods

The compounds of the invention may be prepared by conventional methods by chemical synthesis, for example those described in the working examples. Starting materials for the processes described in the present application are known or can be readily prepared by conventional methods from commercially available chemicals.

Also a compound of the invention may be converted to another compound of the invention using conventional methods.

The end products of the reactions described herein may be isolated by conventional techniques, for example by extraction, crystallization, distillation, chromatography, etc.

Biological activity

The compounds of the present invention are useful as chloride channel blockers or BKca-channel modulators.

Preferred compounds of the invention show a biological activity in the submicromolar and micromolar range, that is, from below 1 to about 100 μΜ.

Example types of chloride channels are volume-regulated anionic channels (VRAC) or osteoclast or erythrocyte chloride channels. To measure compound activity, several chloride channel blocker assays known in the art may be used.

Thus in another aspect, the compounds of the invention are considered useful for the treatment, prevention or alleviation of a disease, disorder or condition responsive to chloride channel blockage.

In a special embodiment, the inventive compounds are considered useful for the treatment, prevention or alleviation of:

• a metabolic bone disease, such as an osteoclast-related bone disease, such as osteoporosis, postmenopausal osteoporosis, secondary osteoporosis, bone metastasis in mammastolytic cancer, osteolytic cancer invasion, or bone Paget's disease;

• diseases that are responsive to inhibition of angiogenesis, such as diseases involving tumor cell proliferation, such as cancer, metastatic cancer, prostate cancer, lung cancer, breast cancer, bladder cancer, kidney cancer, colonic cancer, gastric cancer, pancreatic cancer ovarian cancer, melanoma, hepatoma, sarcoma, lymphoma;

• diseases related to ophthalmic angiogenesis, such as exudative macular degeneration, age-related macular degeneration (AMD), retinopathy, diabetic retinopathy, diabetic proliferative retinopathy, diabetic macular edema (MSD), ischemic retinopathy (eg, retinal vein or artery occlusion) retinopathy of prematurity, neovascular glaucoma, and corneal neovascularization; and

• disease, disorder or condition that is responsive to intraocular pressure reduction, such as ocular hypertension, open-angle glaucoma, chronic open-angle glaucoma, angle-closure glaucoma, and ciliary injection caused by angle-closure glaucoma,

• rheumatoid arthritis, psoriasis and

• sickle cell anemia.

In another aspect, the compounds of the invention are considered useful for the treatment, prevention or alleviation of a disease, disorder or condition responsive to modulation of BKcA channels.

In a special embodiment, the inventive compounds are considered useful for the treatment, prevention or alleviation of:

• a cardiovascular disease, such as atherosclerosis, ischemia, reperfusion injury, hypertension, restenosis, arterial inflammation, ischemic heart disease or ischemic heart disease;

• an obstructive or inflammatory airway disease, such as airway hyperreactivity, pneumoconiosis, aluminosis, anthracosis, asbestosis, calicosis, pylose, siderosis, silicosis, tabacose, biscosis, sarcoidosis, beryliosis, pulmonary emphysema, acute respiratory distress syndrome (ARDS). ), acute lung injury (ALI), acute or chronic infectious lung disease, chronic obstructive pulmonary disease (COPD), bronchitis, bronchitecronic, panting bronchitis, exacerbation of airway hyperreactivity or cystic fibrosis, or cough including chronic cough, exacerbation of airway hyperreactivity , pulmonary fibrosis, pulmonary hypertension, inflammatory pulmonary diseases, or acute or chronic respiratory infectious diseases,

• urinary incontinence; psychosis, epilepsy or pain. In addition, the compounds of the invention may also be adapted to facilitate the transport of therapeutic substances across the blood-brain barrier, and in particular to facilitate the transverse release of chemotherapeutic agents and viral particles to tumor cells and other abnormal brain tissues.

Therefore, in another aspect, the invention relates to the use of a compound of the invention as a facilitating agent, useful for enhancing blood-brain barrier permeability, and thus capable of facilitating the transport of a therapeutic substance through the blood-brain barrier, including the blood-brain barrier. tumor found in brain tumors.

In one embodiment of this aspect the inventive compound is used to facilitate agents to an abnormally detained cerebral brain region physiologically affected by injury, trauma, infection, cerebrovascular accident, or ischemia. This abnormal brain region is a detained region of benign or malignant tumor or other neoplastic diseases or conditions. The particular malignant tumor may be a glioma, glioblastoma, oligodendroglioma, astrocytoma, ependymoma, primitive tumoururoectodermal, atypical meningioma, malignant meningioma, neuroblastoma, sarcoma, melanoma, lymphoma or carcinoma.

When used as a facilitating agent, the inventive compound may be co-administered with the therapeutic agent by any appropriate route in any convenient manner. Preferably, the facilitating agent is administered simultaneously (i.e., contemporary or concurrently) or substantially simultaneously (i.e. within about one hour, preferably within 30 minutes, even more preferably within 15 minutes) with the therapeutic agent.

Agents for use according to the invention, that is, both the facilitating agent and the therapeutic agent, may be administered by any appropriate route by which the agent is released into the bloodstream. This is preferably done by intravenous, intramuscular or intraarterial injection or infusion.

The therapeutic agent for use according to the invention may be any agent or medicament. However, preferred therapeutic agents or drugs for use according to the invention are antineoplastic agents, chemotherapeutic agents, cytotoxic agents, DNA expression vectors, proteins, oligonucleotides, nucleotide analogs, antimicrobial agents, interferons, cytokines, cytokine agonists, cytokine, immunotoxins, immunosuppressants, deboro compounds, monoclonal antibodies, adrenergic agents, anticonvulsants, ischemia protective agents, anti-trauma agents, chemotherapeutic anti-cancer agents and diagnostic agents.

Preferred chemotherapeutic agents for use according to the invention include:

• alkylating agents such as nitrogen mustards (eg mechlorethamine, cyclophosphamide, ifosamide, melphalan echlorambucil), ethylenimines and methylmelamines (eg hexamethylmelamine and thiotepa), alkyl sulfonates (eg busulfan), nitrosoureas (eg BC carmustines) ), lomustine (CCNU), semustine (methyl-CCNU) and streptozocine), triazenes (e.g. dacarbazine (DTlC));

Antimetabolites such as folic acid analogs (eg methotrexate), pyrimidine analogs (eg fluorouracil, floxuridine and cytarabine), purine analogs and related inhibitors (eg mercaptopurine, thioguanine and pentostatin); and

• natural antimitotic products such as vinca alkaloids (eg vinblastine and vincristine), epipodophyllotoxins (eg etoposide and teniposide), antibiotics (eg dactinomycin, daunorubicin, doxorubicin, bleomycin, plicamycin and mitomycin), enzymes (eg asparaginase), a daplatin coordinating complex (eg cisplatin and carboplatin) and respostabiological modifiers such as interferons (eg interferon-a).

In another preferred embodiment the DNA expression vector is a viral vector, preferably a deadenovirus derived vector or herpes simplex virus derived vector.

In yet another preferred embodiment the diagnostic agent for use according to the invention may be in particular an imaging or contrast agent, and may in particular be a radiolabeled substance, a gallium-labeled substance, or an agent. contrast agent selected from the group consisting of ferrous, fluorescent, luminescent and iodinated magnetic contrast agents.

When used as a facilitating agent, the inventive compound may preferably be co-administered with the therapeutic agent to physiologically direct regions of brain tissue affected by a physical or biochemical injury, for example Alzheimer's disease, Parkinson's disease, Parachinsonism, trauma , infection, stroke, cerebral ischemia, or neoplastic growth regions within the brain, such as benign or malignant brain tumor tissues.

Therapy Methods

In another aspect the invention provides a method for treating, preventing or alleviating a disease or disorder or condition of a living animal body, including a human, disease, disorder or condition which is responsive to blockage of the chloride channel or modulation of BKca channels, and which method comprises administering to such a live animal body, including a human, in need thereof an effective amount of a chemical compound of the invention.

Preferred medical indications considered in accordance with the invention are those set forth above.

It is hereby considered that the appropriate dosage ranges are from 0.1 to 1000 milligrams daily, 10 to 500 milligrams daily, and especially from 30 to 100 milligrams daily, depending as usual on the exact mode of administration, the form in which it is administered, of indication for which administration is directed, the patient involved and the body weight of the patient involved, as well as the preference and experience of the attending physician or veterinarian. When administered in combination with compounds known in the art for the treatment of diseases, the dosage regimen may be reduced.

Combination Therapy

The use of the compounds of the invention may be combined with the use of other compounds useful for the treatment, prevention or alleviation of a chloride channel block responsive disease, disorder or condition.

As an example, the compounds may be used in combination with one or more additional drugs useful for the treatment, prevention or alleviation of a disease responsive to inhibiting angiogenesis, such as compounds useful for anti-metastatic treatment. Such additional drugs include cytotoxic compounds, antimitotic compounds. and antimetabolites.

Examples of cytotoxic compounds (including cytotoxic alkylating agents) include carmustine (BCNU), photemustine, temozolomide (temodal), ifosfamide and cyclolosfamide.

Examples of antimitotic compounds include paclitaxel (taxol) and docetaxel. An example of antimetabolites includes methotrexate.

In addition, the pharmaceutical composition for use according to the invention may be used or administered in combination with other treatments or therapies. Examples of other treatments or therapies include radiotherapy and surgery.

Also, the use of the compounds of the invention may be combined with the use of other bone metabolism controlling compounds for the treatment of bone metabolic disease. Such compounds that control known bone metabolism include bisphosphonates such as optionally combined calcium hydrochloride, pamidronate or clodronate; estrogen receptor active compounds such as estrogen ie estradiol and ethyl estradiol, calcitonin, 1,25-dihydroxyvitamin D and its metabolites, fluoride, growth hormone, parathyroid hormone, triiodothyroxine, collagen degrading enzymes such as daprotease inhibitors or therapeutic agents against cancer.

Also, the use of the compounds of the invention may be combined with the use of one or more additional medicaments useful for the treatment, prevention or alleviation of a disease, disorder or condition that is responsive to the reduction of intraocular pressure. Such additional medications include beta-blockers, para-sympathomimetic myotics, sympathomimetics and carbonic anhydrase inhibitors.

In addition, the use of the compounds of the invention may be combined with other treatments or therapies.

Treatment of diseases and disorders may be in chronic or long-term treatment as well as treatment of sudden onset and disorder.

Pharmaceutical Compositions In another aspect the invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of the chemical compound of the invention.

Although a chemical compound of the invention for use in therapy may be administered in the form of the crude chemical compound, it is preferred to introduce the active ingredient, optionally as a physiologically acceptable, into a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents and / or other usual pharmaceutical aids.

In a preferred embodiment, the invention provides pharmaceutical compositions comprising the inventive chemical compound, or a pharmaceutically acceptable salt or derivative thereof, together with one or more pharmaceutically acceptable carriers, and optionally other known and used therapeutic and / or prophylactic ingredients. Natechnic. The carrier (s) must be "acceptable" in the sense that it is compatible with the other ingredients of the formulation and not harmful to its recipient.

The pharmaceutical compositions of the invention may be those suitable for oral, rectal, bronchial, nasal, pulmonary, topical (including buccal and sublingual), transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, injection or infusion). intracerebral, intraocular) or those in a form suitable for administration by inhalation or insufflation, including aerosol administration of powders and liquids, or by extended release systems. Suitable examples of sustained release systems include semipermeable arrays of solid hydrophobic polymers containing the compound of the invention, which arrays may be in the form of formed articles, for example, films or microcapsules.

The chemical compound of the invention, together with a conventional adjuvant, carrier or diluent, can thus be formed into pharmaceutical decompositions and their unit dosage. Such forms include solids, and in particular tablets, filled capsules, powder or pellet forms, eliquids, in particular aqueous and non-aqueous solutions, suspensions, emulsions, elixirs and capsules filled therewith, all for oral use, suppositories for administration. and sterile injectable solutions for parenteral use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional compounds or active ingredients, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be used.

The chemical compound of the present invention may be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, a chemical compound of the invention or a pharmaceutically acceptable salt of a chemical compound of the invention.

To prepare pharmaceutical compositions of a chemical compound of the present invention, the pharmaceutically acceptable carriers may be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, seals, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component.

In tablets, the active ingredient is mixed with the carrier to provide the required binding capacity in appropriate proportions and compacted to the desired shape and size.

The powders and tablets preferably contain from five or ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, carboxymethylcellulosesodium, a low melting wax, cocoa butter and the like. The term "preparation" is intended to include the formulation of the carrier-encapsulating active compound as a carrier by providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus associated with it. Similarly, stamps and tablets are included. Tablets, powders, capsules, pills, seals, and lozenges may be used as solid forms suitable for oral administration.

To prepare suppositories, a low melt wax, such as a mixture of fatty acid glyceride or cocoa butter, is first melted and the active component is homogeneously dispersed therein as by agitation. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.

Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

Liquid preparations include solutions, suspensions and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations may be formulated as solutions in aqueous polyethylene glycol solution.

The chemical compound according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form obtained by aseptic isolation of the sterile solid or by lyophilization of the solution for constitution with a suitable vehicle, for example pyrogen-free sterile water, prior to use.

Aqueous solutions suitable for oral use may be prepared by dissolving the active component in water and adding suitable coloring, flavoring, stabilizing and thickening agents as desired.

Aqueous suspensions suitable for oral use may be made by dispersing the finely divided active component in water with viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.

Also included are solid form preparations intended for conversion immediately prior to use for liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. In addition to the active component such preparations may comprise colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilising agents and the like.

For topical administration to the epidermis the inventive chemical compound may be formulated as ointments, creams or lotions, or as a transdermal patch. Ointments and creams, for example, may be formulated with an aqueous or oily base with the addition of suitable thickening and / or gel forming agents. Lotions may be formulated with an aqueous or oily base and in general will also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents or coloring agents.

Compositions suitable for topical administration in turnabout include lozenges comprising the active agent in a basearomatized, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as glycerine gelatin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The compositions may be provided in single or multiple dose form.

Administration to the respiratory tract may also be obtained by means of an aerosol formulation in which the active ingredient is supplied in a pressurized package with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, or other suitable carbon dioxide. . The aerosol may conveniently also contain a surfactant such as lecithin. The drug dose may be controlled by providing a metering valve.

Alternatively the active ingredients may be provided in the form of a dry powder, for example, a powder mixture of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropyl methyl cellulose and polyvinylpyrrolidone (PVP). will form a gel in the nasal cavity. Powdered composition may be presented in unit dose form for example in capsules or cartridges, for example gelatin, or blister packs from which the powder may be administered by means of an inhaler.

In compositions intended for administration to the tractors, including intranasal compositions, the compound will generally have a small particle size, for example of the order of 5 microns or less.

Such a particle size may be obtained by means known in the art, for example by micronization.

Where desired, compositions adapted to give extended release of the active ingredient may be used.

The pharmaceutical preparations are preferably in unit dosage form. In such forms, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form may be a packaged preparation, the package containing separate amounts of the preparation, such as tablets, capsules and packaged in vials or ampoules. Also, the unit dosage form may be a capsule, tablet, seal or tablet alone, or may be the appropriate number of either of these in packaged form.

Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.

Further details on the techniques for formulation and administration can be found in the latest edition of RemingtoniSharmaceutical Sciences (CMaack Publishing Co., Easton, PA).

A therapeutically effective dose refers to that amount of active ingredient that ameliorates symptoms or condition. Therapeutic efficacy and toxicity, for example, ED50 and LD50, may be determined by standard pharmacological procedures in cell cultures or experimental animals. The dose ratio between therapeutic and toxic effects is the therapeutic index and may be expressed as the LD50ZED50 ratio. Pharmaceutical compositions exhibiting large therapeutic indices are preferred. The naturally administered dose should be carefully adjusted for the age, weight and condition of the individual being treated, as well as for the route of administration, form and dosage regimen, and the desired result and dosage. Exactly of course must be determined by the technician.

The actual dosage depends on the nature and severity of the disease being treated, and is within the discretion of the physician, and may be varied by titrating the dosage to the particular circumstances of this invention to produce the desired therapeutic effect. However, it is presently considered that pharmaceutical compositions containing from about 0.1 to about 500 mg of active ingredient per individual dose, preferably about 1 to about 100 mg, most preferably from about 1 to about 10 mg, are suitable. for therapeutic treatments.

The active ingredient may be administered in one or several doses per day. A satisfactory result in certain cases may be obtained at a dosage as low as 0.1 mg / kg i.v. and 1 mg / kg p.o. The upper limit of the dosage range is presently considered to be about 10 mg / kg.v. and 100 mg / kg p.o. Preferred ranges are from about 0.1 mg / kg to about 10 mg / kg / day i.v., and from about 1 µg / kg to about 100 mg / kg / day, p.o.

EXAMPLES

The invention is further illustrated with reference to the following examples, which are not intended to be in any way limiting the scope of the invention as claimed.

Example 1

4-Amino-4,4-trifluoromethyl-biphenyl-3-carbonitrile

<formula> formula see original document page 23 </formula>

In 250 ml of water and 500 ml of 1,2-dimethoxyethane, 26.5 g of 4- (trifluoromethyl) benzeneboronic acid, 25 g of 2-amino-5-bromo-benzonitrile and 57.9 g of potassium carbonate were mixed. The mixture was sparged with nitrogen for 10 minutes, then 1 g of debis (triphenylphosphine) palladium (H) chloride was added and the reaction mixture was refluxed overnight. The reaction mixture was cooled to room temperature, 700 ml of water added and extracted with 800 ml of ethyl acetate. The organic phase was washed first with 300 ml of saturated sodium chloride, then 300 ml of 2 M calcium chloride and finally with 300 ml of water. The organic phase was dried with magnesium sulfate, evaporated to an oil and triturated with ether. Yield 30.5 g (92%)

Example 2

4-Amino-N-hydroxy-4Mrifluoromethyl-biphenyl-3-carboxamide

<formula> formula see original document page 24 </formula>

4-Amino-4'-trifluoromethyl-biphenyl-3-carbonitrile (10 g) was dissolved in 250 ml of methanol and 5.6 g of dehydroxylamine hydrochloride and 8.1 g of triethylamine were added. The reaction mixture was stirred at 50 ° C overnight, added 100 ml of water and 100 ml of ethyl acetate. It was extracted with 100 ml of ethyl acetate. The organic phases were washed with 100 ml water and then with 100 ml saturated sodium chloride. The organic phase was dried with magnesium sulfate and evaporated to an oil. Yield 10.8 g (96%).

Example 3

3- (4-Amino-4,4-trifluoromethyl-biphenyl-3-yl) -4H [1- <2,41-oxadiazol-5-one <formula> formula see original document page 25 </formula>

Sodium (1.6 g) was stirred in 200 ml of dry ethanol until dissolved, to the solution was added 10.8 g of 4-amino-N-hydroxy-4'-trifluoromethyl biphenyl-3-carboxamide and 16 g of diethyl carbonate, the reaction mixture was stirred overnight at 85 ° C, evaporated to an oil, the residue was dissolved in ethyl acetate, the organic phase was extracted with 4N aqueous NaOH. The aqueous phase was made acidic with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with concentrated aqueous sodium chloride, dried with magnesium sulfate and evaporated to an oil. The residue was dissolved in 150 ml of ethanol and boiling. The solution was cooled to room temperature, crystallized, isolated by filtration and dried. Yield 5.1 g (45%).

Example 4

N- (3,5-Difluoro-phenyl-N--3- (5-oxo-4- (5-dihydro-β2,41oxadiazol-3-yl) -4,2-trifluoromethyl-biphenyl-4-ylurea)

<formula> formula see original document page 25 </formula>

5 g of 3- (4-amino-4'-trifluoromethyl-biphenyl-3-yl) -4H [1,2,4] oxadiazol-5-one and 2.5 g of isocyanate were suspended in 100 ml of dry toluene. 3,5-difluorophenyl were added, the reaction mixture was stirred at room temperature overnight, 1.3 g of 3,5-difluorophenyl isocyanate was added and stirring was continued overnight. difluorophenyl (1.3 g) and 100 ml of acetonitrile added, the reaction mixture was stirred at room temperature for 90 minutes and evaporated to dryness. The residue was dissolved in 100 ml of boiling deacetone, then cooled to 0 ° C and filtered. The precipitate was recrystallized from 200 ml of ethanol, after filtration while hot, to the solution was added 400 ml of water. The product was isolated by filtration. Yield 4 g (54%) mp. > 150 ° C decomp.

Analogously it was manufactured:

N- (4-Chloro-3-trifluoromethyl-phenyl) -N, - {3- (5-oxo-4,5-dihydro [1,2,4] oxadiazol-3-yl) -4'-trifluoromethyl -biphenyl-4-yl} urea:

> 139 ° C decomp.

N- (3-Bromo-phenyl) -N '- {3- (5-oxo-4,5-dihydro [1,2,4] oxadiazol-3-yl) -4'-trifluoromethyl-biphen-4-one il} urea.

> 200 ° C decomp.

N-Cl-Chloro-phenyl) -N '- {3-5-oxo-4,5-dihydro [1,2,4] oxadiazol-3-yl) -4'-trifluoromethyl-biphenyl-4-yl ] urea.

Mp 220-222 ° C.

Example 5

Chloride conductance in human erythrocyte in vitro

Chloride conductance was measured according to the procedure as described in the "Biology" paragraph of WO 00/24707. The parameter calculated from these studies is the IC50 value - concentration at which 50% of chloride channels are blocked.

The first compound of Example 4, N- (3,5-Difluoro-phenyl) -N '- [3- (5-oxo-4,5-dihydro [1,2,4] oxadiazol-3-yl) -4 '-trifluoromethyl-biphenyl-4-yl] urea shows an IC 50 value of 0.28 μΜ.

Example 6

Volume Regulated Anion Channel Effect (VRAC)

Volume Regulated Anion Channel (VRAC) activity was tested by the whole cell contact clamp technique using Human Embryonic Renal Cells (HEK293) as described in Helix etal, J Membr Biol. 2003 196 (2): 83-94 In summary, VRAC was activated by cell swelling in hypotonic extracellular saline (75% detonicity) extracellular saline and the anionic current elicited by voltage increases was measured vs. time. After current stabilization the compound to be tested was added to the extracellular solution and time dependent oblique was followed for the calculation of the KD value. The first compound of Example 4, N- (3,5-Difluoro-phenyl) -N '- [3- (5-oxo-4,5-dihydro [1,2,4] oxadiazol-3-yl) -4 '-trifluoromethyl-biphenyl-4-yl] urea showed a Kd value of 0.23 μΜExample 7

Human BK Channel Screening

The influence of a compound on membrane currents was electrophysiologically determined in Xenopus Oocytes capable of expressing human BK channels, and current through the channels was recorded using the classical two-electrode voltage clamp technique.

The first compound of Example 4, N- (3,5-Difluoro-phenyl) -N '- [3- (5-oxo-4,5-dihydro [1,2,4] oxadiazol-3-yl) -4 '-trifluoromethyl-biphenyl-4-yl] urea was subjected to this determination at a concentration of 0.3 μΜ decomposed test, and this caused an increase of BK current relative to basal current of more than 200%.

Claims (14)

1. Chemical compound, characterized in that it is of formula (I) <formula> formula see original document page 28 </formula> any of its isomers or any mixture of its isomers, or a pharmaceutically acceptable salt thereof; Rm, Rp, R2, R35 R4, R5 and R6 independently of one another represent hydrogen, halo, trifluoromethyl, trifluoromethoxy, alkyl or alkoxy. A compound according to claim 1, characterized in that R o represents hydrogen, R m represents hydrogen; e Rp represents halo, trifluoromethyl, trifluoromethoxy, alkyl or alkoxy. A compound according to claim 1, characterized in that R o represents hydrogen, R m represents hydrogen; eRp represents halo or trifluoromethyl. A compound according to any one of claims 1 to 3, characterized in that R 3, R 4, R 5 and R 6 represent hydrogen; R 2 represents halo, trifluoromethyl, trifluoromethoxy, alkyl or alkoxy. A compound according to any one of claims 1 to 3, characterized in that R 25 R 4, R 5 and R 6 represent hydrogen; and R3 represents halo, trifluoromethyl, trifluoromethoxy, alkyl or alkoxy. A compound according to any one of claims 1 to 3, characterized in that R 2, R 5 and R 6 represent hydrogen; and R 3 and R 4 independently of each other represent halo, trifluoromethyl, trifluoromethoxy, alkyl or alkoxy. A compound according to any one of claims 1 to 3, characterized in that R 2, R 4 and R 6 represent hydrogen; trifluoromethyl, trifluoromethoxy, alkyl or alkoxy. A compound according to claim 1, characterized in that it is N- (3,5-Difluoro-phenyl) -N '- [3- (5-oxo-4,5-dihydro [1,2,4]]. oxadiazol-3-yl) -4'-trifluoromethyl-biphenyl-4-yl] urea; N- (4-Chloro-3-trifluoromethyl-phenyl) -N '- {3- (5-oxo-4,5-dihydro) - [1,2,4] oxadiazol-3-yl) -4'-trifluoromethyl-biphenyl-4-yl} urea; N- (3-Bromo-phenyl) -N '- [3- (5-oxo-4, 5-dihydro [1,2,4] oxadiazol-3-yl) -4'-trifluoromethyl-biphen-4-yl} urea; N- (2-Chloro-phenyl) -N '- [3 - ( 5-oxo-4,5-dihydro [1,2,4] oxadiazol-3-yl) -4'-trifluoromethyl-biphenyl-4-yl] urea, or a pharmaceutically acceptable salt thereof. Pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of a compound as R 3 and R 6 independently of each other represent halo as defined in any one of claims 1 to 8, any of its isomers or any mixture of its isomers, or a pharmaceutically acceptable salt thereof, together with at least one carrier, excipient or diluent. pharmaceutically acceptable, Use of a compound as defined in any one of claims 1 to 9, any of its isomers or any mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is for the manufacture of a pharmaceutical composition for treatment. , prevention or alleviation of a disease or disorder or condition of a mammal, including a human, disease, disorder or condition which is responsive to chloride channel blockage or modulation of BKca-1 channels. Use according to claim 11, characterized in that the disease, disorder or condition responsive to chloride channel blockade or BKca channel modulation is a bone disease related to osteoclast, osteoporosis, postmenopausal osteoporosis, secondary osteoporosis, bone metastasis. in osteolytic breast cancer, invasion of osteosteolitic, bone Paget's disease, cancer, metastatic cancer, prostate cancer, lung cancer, bladder cancer, kidney cancer, colonic cancer, gastric cancer, pancreatic cancer, ovarian cancer, melanoma, hepatoma, sarcoma, lymphoma, exudative macular degeneration, age-related macular degeneration (AMD), retinopathy, diabetic retinopathy, diabetic proliferative retinopathy, diabetic macular edema (MSD), ischemic retinopathy, retinal vein or artery occlusion, neoplasm retinal disease, , corneal neovascularization, ocular hypertension air, open-angle glaucoma, chronic open-angle glaucoma, angle-closure glaucoma, ciliary injection caused by angle-closure glaucoma, rheumatoid arthritis, psoriasis, cell-cell anemia, atherosclerosis, ischemia, reperfusion injury, hypertension, restenosis, inflammation artery, myocardial ischemia, heart disease, airway hyperactivity, pneumoconiosis, aluminosis, anthracosis, asbestosis, kallikose, ptilose, siderosis, silicosis, tabacose, bisinosis, sarcoidosis, beryliosis, pulmonary emphysema, acute respiratory distress syndrome (ARDS), pulmonary injury (ALI), acute or chronic infectious lung disease, chronic obstructive pulmonary disease (COPD), bronchitis, chronic bronchitis, panting bronchitis, exacerbation of airway hyperactivity or cystic fibrosis, cough including chronic cough, exacerbation of airway hyperactivity, pulmonary fibrosis, pulmonary hypertension, pulmonary diseases i inflammatory, or acute or chronic respiratory infectious diseases, urinary incontinence, psychosis, epilepsy or pain. Use of a compound according to any one of claims 1 to 9, any of its isomers or any mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is for the manufacture of a medicament useful for increasing the blood-brain barrier permeability. 14. A method for treating, preventing or alleviating a disease or disorder or condition of a living animal body, including a human, disorder, disease or condition which is responsive to chloride channel blocking or modulation of BKca channels, characterized in that it comprises the step of administering to a body of a live animal in need thereof a therapeutically effective amount of a compound as defined in any one of claims 1 to 9, any of its isomers or any mixture of its isomers, or a salt. pharmaceutically acceptable thereof.