NOVEL BENZAMIDE DERIVATIVES USEFUL AS POTASSIUM CHANNEL MODULATORS

TECHNICAL FIELD

This invention relates to novel benzamide derivative that are found to be potent modulators of potassium channels and, as such, are valuable candidates for the treatment of diseases or disorders as diverse as those which are responsive to the modulation of potassium channels.

BACKGROUND ART

Ion channels are cellular proteins that regulate the flow of ions through cellular membranes of all cells and are classified by their selective permeability to the different of ions (potassium, chloride, sodium etc.). Potassium channels, which represent the largest and most diverse sub-group of ion channels, selectively pass potassium ions and, doing so, they principally regulate the resting membrane potential of the cell and/or modulate their level of excitation. Dysfunction of potassium channels, as well as other ion channels, generates loss of cellular control resulting in altered physiological functioning and disease conditions. Ion channel blockers and openers, by their ability to modulate ion channel function and/ or regain ion channel activity in acquired or inherited channelopathies, are being used in the pharmacological treatment of a wide range of pathological diseases and have the potential to address an even wider variety of therapeutic indications. For instance, the primary indications for potassium channel openers encompass conditions as diverse as diabetes, arterial hypertension, cardiovascular diseases, urinary incontinence, atrial fibrillation, epilepsy, pain, and cancer. Among the large number of potassium channel types, the large- conductance calcium-activated potassium channel subtype is an obvious site for pharmacological intervention and for the development of new potassium channel modulators. Their physiological role has been especially studied in the nervous system, where they are key regulators of neuronal excitability and of neurotransmitter release, and in smooth muscle, where they are crucial in modulating the tone of vascular, broncho-tracheal, urethral, uterine or gastrointestinal musculature.

Given these implications, small agents with BK-opening properties could have a potentially powerful influence in the modulation and control of numerous consequences of muscular and neuronal hyperexcitability, such as asthma, urinary incontinence and bladder spasm, gastroenteric hypermotility, psychoses, post-stroke neuroprotection, convulsions, epilepsy, anxiety and pain. As far as the cardiovascular system is concerned, the physiological function of these ion channels represents a fundamental steady state mechanism, modulating vessel depolarisation, vasoconstriction and increases of intravascular pressure, and the development of selective activators of BK channels is seen as a potential pharmacotherapy of vascular diseases, including hypertension, erectile dysfunction, coronary diseases and vascular complications associated with diabetes or hypercholesterolemia.

Postovskii et al. [Postovskii I Y, Vereshchagina N N: Benzodiazines. VIII. Covalent hydration and cleavage of quinazoline compounds; Khimiva Geterotsiklicheskikh Soedinenii 1967 (5) 944-947] describe certain N-tetrazolyl- phenyl-benzamide derivatives. A biological activity is not reported.

US 4147781 describes certain N-(2-Hydroxy-phenyl)-benzamide derivatives useful as pesticides.

Korbonits et al. [Korbonits D, Simon K, Kolonits P: A novel ring transformation: 1 ,2,4-oxadiazoles from pyhmidine-N-oxides; Tetrahedron Letters 1983 24 (51 ) 5763-5766] describe certain N-hydroxycarbamimidoyl-phenyl- benzamide derivatives. A biological activity is not reported.

WO 2004018461 describes certain N-oxadiazolyl-phenyl-benzamide derivatives useful as disinfectants and therapeutic agents. Whitehouse [Whitehouse M W: Biochemical properties of antiinflammatory drugs. Xl. Structure-action relation for the uncoupling of oxidative phosphorylation and inhibition of chymotrypsin by N-substituted anthranilates and related compounds; Biochemical Pharmacology 1967 16 (5) 753-760] describe certain phenyl-carbonyl-amino-benzenesulfonic acid derivatives. A biological activity is not reported.

However, the benzamide derivatives of the present invention have not been reported, and their activity as modulators of potassium channels certainly not suggested.

SUMMARY OF THE INVENTION

It is an object of the invention to provide novel benzamide derivatives useful as potassium channel modulators. The benzamide derivatives of the invention may be characterised by Formula I

a stereoisomer thereof or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein

R ¹ represents a heteroaryl group selected from 5-oxo-4,5-dihydro- [1 ,2,4]oxadiazolyl, tetrazolyl, hydroxy, sulfonyl, sulfamoyl and hydroxycarbamimidoyl; and

R ² , R ³ , R ⁴ and R ⁵ , independently of each other, represent hydrogen, halo, trifluoromethyl, hydroxy, phenyl, thfluoromethyl-phenyl, sulfonyl, sulfamoyl, /V-alkyl-sulfamoyl, λ/,λ/-dialkyl-sulfamoyl, piperidino-sulfonyl, morpholino-sulfonyl or piperazino-sulfonyl; or

R ⁴ and R ⁵ , together with the phenyl group to which they are attached, form a benzofused (naphthyl) ring, which benzofused (naphthyl) ring may optionally be substituted with halo or hydroxy; and R ² and R ³ are as defined above. In another aspect the invention provides pharmaceutical compositions comprising a therapeutically effective amount of a benzamide derivative of the invention.

In a third aspect the invention relates to the use of the benzamide derivatives of the invention for the manufacture of pharmaceutical compositions. In a further aspect the invention provides a method of treatment, prevention or alleviation of a disease or a disorder or a condition of a living animal body, including a human, which disorder, disease or condition is responsive to modulation of potassium channels, which method comprises the step of administering to such a living animal body in need thereof, a therapeutically effective amount of the benzamide derivative of the invention.

Other objects of the invention will be apparent to the person skilled in the art from the following detailed description and examples.

DETAILED DISCLOSURE OF THE INVENTION

In its first aspect the invention provides novel benzamide derivatives of

Formula I

a stereoisomer thereof or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein

R ¹ represents a heteroaryl group selected from 5-oxo-4,5-dihydro- [1 ,2,4]oxadiazolyl, tetrazolyl, hydroxy, sulfonyl, sulfamoyl and hydroxycarbamimidoyl; and

R ² , R ³ , R ⁴ and R ⁵ , independently of each other, represent hydrogen, halo, trifluoromethyl, hydroxy, phenyl, thfluoromethyl-phenyl, sulfonyl, sulfamoyl, /V-alkyl-sulfamoyl, λ/,λ/-dialkyl-sulfamoyl, piperidino-sulfonyl, morpholino-sulfonyl or piperazino-sulfonyl; or R ⁴ and R ⁵ , together with the phenyl group to which they are attached, form a benzofused (naphthyl) ring, which benzofused (naphthyl) ring may ooppttiioonnaally be substituted with halo or hydroxy; and R ² and R ³ are as defined above.

In a preferred embodiment the benzamide derivative of the invention is a compound of Formula Ia,

a stereoisomer thereof or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above. In a more preferred embodiment the benzamide derivative of the invention is a compound of Formula Ia, wherein

R ⁴ and R ⁵ both represent trifluoromethyl; and

R ¹ , R ² , R ³ , are as defined above.

In another preferred embodiment the benzamide derivative of the invention is a compound of Formula Ib,

a stereoisomer thereof or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ and R ⁴ are as defined in above.

In another preferred embodiment the benzamide derivative of the invention is a compound of Formula I, Ia or Ib, an stereoisomer thereof or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R ¹ represents a heteroaryl group selected from 5-oxo-4,5-dihydro- [1 ,2,4]oxadiazolyl, tetrazolyl, hydroxy, sulfonyl, sulfamoyl and hydroxycarbamimidoyl.

In a more preferred embodiment R ¹ represents 5-oxo-4,5-dihydro- [1 ,2,4]oxadiazolyl, sulfonyl or hydroxycarbamimidoyl. In another more preferred embodiment R ¹ represents a 5-oxo-4,5- dihydro-[1 ,2,4]oxadiazolyl group, and in particular 5-oxo-4,5-dihydro- [1 ,2,4]oxadiazol-3-yl.

In a third more preferred embodiment R ¹ represents a tetrazolyl group, and in particular 1 H-tetrazol-5-yl or 2H-tetrazol-5-yl. In a fourth more preferred embodiment R ¹ represents hydroxy.

In an even more preferred embodiment R ¹ represents hydroxy, and R2 represent sulfonyl.

In a fifth more preferred embodiment R ¹ represents sulfonyl (i.e. a -SO ₂ (OH) group). In a sixth more preferred embodiment R ¹ represents hydroxycarbamimidoyl.

In a third preferred embodiment the benzamide derivative of the invention is a compound of Formula I, an stereoisomer thereof or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R ² , R ³ , R ⁴ and R ⁵ , independently of each other, represent hydrogen, halo, trifluoromethyl, hydroxy, phenyl, thfluoromethyl-phenyl, sulfonyl, sulfamoyl, /V-alkyl-sulfamoyl, λ/,λ/-dialkyl-sulfamoyl, piperidino-sulfonyl, morpholino-sulfonyl or piperazino- sulfonyl.

In a more preferred embodiment R ² , R ³ , R ⁴ and R ⁵ , independently of each other, represent hydrogen, halo, trifluoromethyl, hydroxy, trifluoromethyl- phenyl, sulfonyl, sulfamoyl, λ/,λ/-dialkyl-sulfamoyl or morpholino-sulfonyl.

In a fourth preferred embodiment the benzamide derivative of the invention is a compound of Formula I, an stereoisomer thereof or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein

R ² and R ³ , independently of each other, represent hydrogen, halo, hydroxy, sulfonyl or thfluoromethyl-phenyl; and

R ⁴ and R ⁵ , independently of each other, represent hydrogen, halo, trifluoromethyl, sulfamoyl, λ/,λ/-dialkyl-sulfamoyl, thfluoromethyl-phenyl or morpholino-sulfonyl.

In a more preferred embodiment, the benzamide derivative of the invention is a compound of Formula I, Ia or Ib, an stereoisomer thereof or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R ² and R ³ , independently of each other, represent hydrogen, halo, hydroxy, sulfonyl or thfluoromethyl-phenyl.

In another more preferred embodiment one of R ² and R ³ represents hydrogen; and the other of R ² and R ³ represents halo, in particular chloro or bromo, thfluoromethyl-phenyl. In a third more preferred embodiment one of R ² and R ³ represents halo, in particular chloro; and the other of R ² and R ³ represents sulfonyl.

In a fourth more preferred embodiment R ¹ represents hydroxy; one of R ² and R ³ represents halo, in particular chloro; and the other of R ² and R ³ represents sulfonyl. In a fifth more preferred embodiment both of R ² and R ³ represent halo, in particular chloro or bromo.

In a sixth more preferred embodiment the benzamide derivative of the invention is a compound of Formula I or Ia, an stereoisomer thereof or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R ⁴ and R ⁵ , independently of each other, represent hydrogen, halo, trifluoromethyl, sulfamoyl, λ/,λ/-dialkyl-sulfamoyl or morpholino-sulfonyl.

In a seventh more preferred embodiment the benzamide derivative of the invention is a compound of Formula I or Ia, an stereoisomer thereof or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R ⁴ and R ⁵ , independently of each other, represent hydrogen, halo, trifluoromethyl, sulfamoyl, λ/,λ/-dialkyl-sulfamoyl, thfluoromethyl-phenyl or morpholino-sulfonyl.

In an eight more preferred embodiment the benzamide derivative of the invention is a compound of Formula I or Ia, an stereoisomer thereof or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein one of

R ⁴ and R ⁵ represents hydrogen; and the other of R ⁴ and R ⁵ represents sulfamoyl, λ/,λ/-dialkyl-sulfamoyl or morpholino-sulfonyl.

In a ninth more preferred embodiment the benzamide derivative of the invention is a compound of Formula I or Ia, an stereoisomer thereof or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein both of R ⁴ and R ⁵ represent trifluoromethyl. In a fifth preferred embodiment the benzamide derivative of the invention is a compound of Formula I or Ia, an stereoisomer thereof or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R ² and R ³ are as defined above; and R ⁴ and R ⁵ , together with the phenyl group to which they are attached, form a benzofused (naphthyl) ring, which benzofused (naphthyl) ring may optionally be substituted with halo, and in particular bromo, or hydroxy.

In a more preferred embodiment the benzamide derivative of the invention is a compound of Formula I or Ia, an stereoisomer thereof or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R ⁴ and R ⁵ , together with the phenyl group to which they are attached, form a benzofused (naphthyl) ring.

In another more preferred embodiment the benzamide derivative of the invention is a compound of Formula I or Ia, an stereoisomer thereof or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R ⁴ and R ⁵ , together with the phenyl group to which they are attached, form a benzofused (naphthyl) ring, which benzofused (naphthyl) ring is substituted with halo, and in particular bromo, or hydroxy.

In a third more preferred embodiment the benzamide derivative of the invention is a compound of Formula I or Ia, an stereoisomer thereof or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R ⁴ and R ⁵ , together with the phenyl group to which they are attached, form a benzofused (naphthyl) ring, which benzofused (naphthyl) ring is substituted with halo, and in particular bromo.

In a fourth more preferred embodiment the benzamide derivative of the invention is a compound of Formula I or Ia, an stereoisomer thereof or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R ⁴ and R ⁵ , together with the phenyl group to which they are attached, form a

benzofused (naphthyl) ring, which benzofused (naphthyl) ring is substituted with hydroxy.

In a sixth preferred embodiment the benzamide derivative of the invention is a compound of Formula Ib (i.e. a compound of Formula I wherein R ⁵ represents hydrogen), an stereoisomer thereof or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein

R ² and R ³ , independently of each other, represent hydrogen, halo, hydroxy, sulfonyl or thfluoromethyl-phenyl; and

R ⁴ represents halo, trifluoromethyl, sulfamoyl, λ/,λ/-dialkyl-sulfamoyl, thfluoromethyl-phenyl or morpholino-sulfonyl.

In a more preferred embodiment the benzamide derivative ia a compound of Formula Ib (i.e. a compound of Formula I wherein R ⁵ represents hydrogen), an stereoisomer thereof or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R ² and R ³ , independently of each other, represent hydrogen or halo; and

R ⁴ represents sulfamoyl, λ/,λ/-dialkyl-sulfamoyl or morpholino-sulfonyl.

In a most preferred embodiment the benzamide derivative of the invention is λ/-[3-(1 /-/-Tetrazol-5-yl)-4'-trifluoromethyl-biphenyl-4-yl]-3,5-bis - trifluoromethyl-benzamide;

λ/-[5-Chloro-2-(1 /-/-tetrazol-5-yl)-phenyl]-3,5-bis-trifluoromethyl- benzamide;

λ/-[2,4-Dibromo-6-(1/-/-tetrazol-5-yl)-phenyl]-3,5-bis-t rifluoromethyl- benzamide;

/V-[4-Bromo-2-(2H-tetrazol-5-yl)-phenyl]-3,5-bis-trifluor omethyl- benzamide;

λ/-[4-Bromo-2-(λ/-hydroxycarbamimidoyl)-phenyl]-3,5-bis - trifluoromethyl-benzamide; λ/-[5-Chloro-2-(5-oxo-4,5-dihydro-[1 ,2,4]oxadiazol-3-yl)-phenyl]-3,5-bis- trifluoromethyl-benzamide;

1 -Hydroxy-naphthalene-2-carboxylic acid [5-chloro-2-(1 H-tetrazol-5-yl)- phenyl]-amide;

Naphthalene-2-carboxylic acid [5-chloro-2-(5-oxo-4,5-dihydro- [1 ,2,4]oxadiazol-3-yl)-phenyl]-amide;

2-[(6-Bromo-naphthalene-2-carbonyl)-amino]-4-chloro-benze nesulfonic acid;

4-Chloro-2-[(naphthalene-2-carbonyl)-amino]-benzenesulfon ic acid;

λ/-[5-Chloro-2-(1 H-tetrazol-5-yl)-phenyl]-4-dipropylsulfamoyl- benzamide;

3-(3,5-Bis-trifluoromethyl-benzoylamino)-5-chloro-2-hydro xy- benzenesulfonic acid; /V-[4-Chloro-2-(1 /-/-tetrazol-5-yl)-phenyl]-4-dipropylsulfamoyl- benzamide;

/V-[5-Chloro-2-(5-oxo-2,5-dihydro-[1 ,2,4]oxadiazol-3-yl)-phenyl]-4- dipropylsulfamoyl-benzannide;

/V-[5-Chloro-2-(1 /-/-tetrazol-5-yl)-phenyl]-4-sulfamoyl-benzannide; /V-[5-Chloro-2-(5-oxo-4,5-dihydro-[1 ,2,4]oxadiazol-3-yl)-phenyl]-4-

(morpholine-4-sulfonyl)-benzannide;

/V-[5-Chloro-2-(5-oxo-4,5-dihydro-[1 ,2,4]oxadiazol-3-yl)-phenyl]-4- diethylsulfamoyl-benzannide;

/V-[5-Chloro-2-(1 H-tetrazol-5-yl)-phenyl]-4-(morpholine-4-sulfonyl)- benzamide;

/V-[5-Chloro-2-(1 /-/-tetrazol-5-yl)-phenyl]-4-diethylsulfamoyl-benzannide; or

/V-[5-Chloro-2-(1 H-tetrazol-5-yl)-phenyl]-2-hydroxy-5-(morpholine-4- sulfonyl)-benzamide; or a stereoisomer thereof or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof.

Any combination of two or more of the embodiments described herein is considered within the scope of the present invention.

Definition of Substituents

In the context of this invention halo represents fluoro, chloro, bromo or iodo.

In the context of this invention an alkyl group designates a univalent saturated, straight or branched hydrocarbon chain. The hydrocarbon chain preferably contain of from one to eighteen carbon atoms (Ci--i ₈ -alkyl), more preferred of from one to six carbon atoms (d- ₆ -alkyl; lower alkyl), including pentyl, isopentyl, neopentyl, hexyl and isohexyl. In a preferred embodiment alkyl represents a Ci _-4 -alkyl group, including butyl, isobutyl, secondary butyl, and tertiary butyl. In another preferred embodiment of this invention alkyl represents a C-ι- ₃ -alkyl group, which may in particular be methyl, ethyl, propyl or isopropyl.

Pharmaceutically Acceptable Salts

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

Examples of pharmaceutically acceptable salts include, without limitation, the non-toxic inorganic and organic acid addition salts such as the hydrochloride, the hydrobromide, the nitrate, the perchlorate, the phosphate, the sulphate, the formate, the acetate, the aconate, the ascorbate, the benzene- sulphonate, the benzoate, the cinnamate, the citrate, the embonate, the enantate, the fumarate, the glutamate, the glycolate, the lactate, the maleate, the malonate, the mandelate, the methanesulphonate, the naphthalene-2-sulphonate derived, the phthalate, the salicylate, the sorbate, the stearate, the succinate, the tartrate, the toluene-p-sulphonate, and the like. Such salts may be formed by procedures well known and described in the art.

Examples of pharmaceutically acceptable cationic salts of a benzamide derivative of the invention include, without limitation, the sodium, the potassium, the calcium, the magnesium, the lithium, and the ammonium salt, and the like, of a benzamide derivative of the invention containing an anionic group. Such cationic salts may be formed by procedures well known and described in the art.

Steric Isomers

It will be appreciated by those skilled in the art that the compounds of the present invention may exist in different stereoisomer^ forms, including enantiomers, diastereomers, as well as geometric isomers (cis-trans isomers).

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

Racemic forms can be resolved into the optical antipodes by known methods and techniques. One way of resolving racemates into the optical antipodes is based upon chromatography on an optical active matrix. Racemic compounds of the present invention can thus be resolved into their optical antipodes, e.g., by fractional crystallisation of D- or L- (tartrates, mandelates, or camphorsulphonate) salts for example.

Additional methods for the resolving the optical isomers are known in the art. Such methods include those described by Jaques J, Collet A, & Wilen S in

"Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New York

(1981 ).

Optical active compounds can also be prepared from optically active starting materials or intermediates.

Methods of Preparation The compounds according to the invention may be prepared by conventional methods for chemical synthesis, e.g. those described in the working examples.

Biological Activity The benzamide derivatives of the invention have been found to possess potassium channel modulating activity as measured by standard electrophysiological methods. Due to their activity at the potassium channels, the benzamide derivatives of the invention are considered useful for the treatment of a wide range of diseases and conditions. In a special embodiment, the benzamide derivatives of the invention are considered useful for the treatment, prevention or alleviation of a respiratory disease, epilepsy, partial epilepsy, convulsions, seizures, absence seizures, vascular spasms, coronary artery spasms, motor neuron diseases, myokymia, renal disorders, polycystic kidney disease, bladder hyperexcitability, bladder spasms, urinogenital disorders, urinary incontinence, bladder outflow obstruction, erectile dysfunction, gastrointestinal dysfunction, gastrointestinal hypomotility disorders, gastrointestinal motility insufficiency, postoperative ileus, constipation, gastroesophageal reflux disorder, secretory diarrhoea, an obstructive or inflammatory airway disease, ischaemia, cerebral ischaemia, ischaemic heart disease, angina pectoris, coronary heart disease, ataxia, traumatic brain injury, stroke, Parkinson's disease, bipolar disorder, psychosis, schizophrenia, autism, anxiety, mood disorders, depression, manic depression, psychotic disorders, dementia, learning deficiencies, age related memory loss, memory and attention deficits, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dysmenorrhoea, narcolepsy, sleeping disorders, sleep apnoea, Reynaud's disease, intermittent claudication, Sjogren's syndrome, xerostomia, cardiovascular disorders, hypertension, myotonic dystrophy, myotonic muscle dystrophia, spasticity, xerostomia, diabetes Type II, hyperinsulinemia, premature labour, cancer, brain tumours, inflammatory bowel disease, irritable bowel syndrome, colitis, colitis Crohn, immune suppression, hearing loss, migraine, pain, neuropathic pain, inflammatory pain, trigeminal neuralgia, vision loss, rhinorrhoea, ocular hypertension (glaucoma) or baldness.

In a more preferred embodiment, the benzamide derivatives of the invention are considered useful for the treatment, prevention or alleviation of a respiratory disease, urinary incontinence, erectile dysfunction, anxiety, epilepsy, psychosis, schizophrenia, bipolar disorder, depression, amyotrophic lateral sclerosis (ALS), Parkinson's disease or pain.

In another more preferred embodiment, the benzamide derivatives of the invention are considered useful for the treatment, prevention or alleviation of psychosis, schizophrenia, bipolar disorder, depression, epilepsy, Parkinson's disease or pain. In a third more preferred embodiment, the benzamide derivatives of the invention are considered useful for the treatment, prevention or alleviation of pain, mild or moderate or severe pain, pain of acute, chronic or recurrent character, pain caused by migraine, postoperative pain, phantom limb pain, inflammatory pain, neuropathic pain, chronic headache, central pain, pain related to diabetic neuropathy, to postherpetic neuralgia, or to peripheral nerve injury.

In a fourth more preferred embodiment, the benzamide derivatives of the invention are considered useful for the treatment, prevention or alleviation of cardiac ischemia, ischemic heart disease, hypertrophic heart, cardiomyopathy or failing heart. In a fifth more preferred embodiment, the compounds of the invention are considered useful for the treatment, prevention or alleviation of a cardiovascular disease. In a more preferred embodiment the cardiovascular disease is atherosclerosis, ischemia/reperfusion, hypertension, restenosis, arterial inflammation, myocardial ischaemia or ischaemic heart disease. In an sixth more preferred embodiment, the compounds of the invention are considered useful for obtaining preconditioning of the heart. Preconditioning, which includes ischemic preconditioning and myocardial preconditioning, describes short periods of ischemic events before initiation of a long lasting ischemia. The compounds of the invention are believed having an effect similar to preconditioning obtained by such ischemic events. Preconditioning protects against later tissue damage resulting from the long lasting ischemic events.

In a seventh more preferred embodiment, the benzamide derivatives of the invention are considered useful for the treatment, prevention or alleviation of schizophrenia, depression or Parkinson's disease. In an eighth more preferred embodiment, the compounds of the invention are considered useful for the treatment, prevention or alleviation of an obstructive or inflammatory airway disease. In a more preferred embodiment the obstructive or inflammatory airway disease is respiratory failure, adult respiratory

distress syndrome, asthma, nocturnal asthma, exercise induced bronchospasm, chronic obstructive pulmonary disease, giant bullae, acute bronchitis, chronic bronchitis, emphysema, reversible obstructive airway disease, bronchiectasis, bronchiolitis, cystic fibrosis, eatelectasis, pulmonary embolism, pneumonia, gastroesophageal reflux disease (GERD), lung abscess, hypersensitivity of the lung, hypersensitivity pneumonitis, eosinophilic pneumonias, allergic bronchopulmonary aspergillosis, or Goodpasture's syndrome. In an even more preferred embodiment the obstructive or inflammatory airway disease is an airway hyperreactivity, a pneumoconiosis such as aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis, a chronic obstructive pulmonary disease (COPD), bronchitis, excerbation of airways hyperreactivity or cystic fibrosis.

In its most preferred embodiment the obstructive airway disease is chronic obstructive pulmonary disease (COPD). In a ninth more preferred embodiment the compound of the invention is used in a combination with conventional bronchodilators, in particular the beta(2)- adrenoceptor agonists. Examples of bronchodilator drugs for use according to the invention include salbutamol (Albuterol, Ventolin) and formoterol (Foradil).

In a tenth more preferred embodiment the benzamide derivatives of the invention are considered useful for the treatment, prevention or alleviation of a sexual dysfunction, incl. male sexual dysfunction and female sexual dysfunction, and incl. male erectile dysfunction.

In an even more preferred embodiment the benzamide derivatives of the invention may be co-administered with a phosphodiesterase inhibitor, in particular a phosphodiesterase 5 (PDE5) inhibitor, e.g. sildenafil, tadalafil, vardenafil and dipyridamole, or with an agent that potentiates endothelium- derived hyperpolarizing factor-mediated responses, in particular calcium dobesilate or similar 2,5-dihydroxybenzenesulfonate analogs.

In a most preferred embodiment the benzamide derivatives of the invention is used in a combination therapy together with sildenafil, tadalafil, vardenafil or calcium dobesilate.

It is at present contemplated that a suitable dosage of the active pharmaceutical ingredient (API) is within the range of from about 0.1 to about 1000 mg API per day, more preferred of from about 10 to about 500 mg API per day, most preferred of from about 30 to about 100 mg API per day, dependent, however, upon the exact mode of administration, the form in which it is administered, the indication considered, the subject and in particular the body

weight of the subject involved, and further the preference and experience of the physician or veterinarian in charge.

Preferred benzamide derivatives of the invention show a biological activity in the sub-micromolar and micromolar range, i.e. of from below 1 to about 5 100 μM.

Pharmaceutical Compositions

In another aspect the invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of a benzamide0 derivative of the invention.

While a benzamide derivative of the invention for use in therapy may be administered in the form of the raw chemical compound, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptable salt, in a pharmaceutical composition together with one or more5 adjuvants, excipients, carriers, buffers, diluents, and/or other customary pharmaceutical auxiliaries.

In a preferred embodiment, the invention provides pharmaceutical compositions comprising the benzamide derivative of the invention together with one or more pharmaceutically acceptable carriers therefore, and, optionally, other0 therapeutic and/or prophylactic ingredients know and used in the art. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.

The pharmaceutical composition of the invention may be administered by any convenient route, which suits the desired therapy. Preferred routes of5 administration include oral administration, in particular in tablet, in capsule, in drage, in powder, or in liquid form, and parenteral administration, in particular cutaneous, subcutaneous, intramuscular, or intravenous injection. The pharmaceutical composition of the invention can be manufactured by any person skilled in the art, by use of standard methods and conventional techniques,0 appropriate to the desired formulation. When desired, compositions adapted to give sustained release of the active ingredient may be employed.

Further details on techniques for formulation and administration may be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, PA). 5 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 titration of the dosage to the particular circumstances of this invention to produce the desired therapeutic effect. However, it is presently contemplated that

pharmaceutical compositions containing of from about 0.1 to about 500 mg of active ingredient per individual dose, preferably of from about 1 to about 100 mg, most preferred of 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 can, in certain instances, be obtained at a dosage as low as 0.1 μg/kg i.v. and 1 μg/kg p.o. The upper limit of the dosage range is presently considered to be about 10 mg/kg i.v. and 100 mg/kg p.o. Preferred ranges are from about 0.1 μg/kg to about 10 mg/kg/day i.v., and from about 1 μg/kg to about 100 mg/kg/day p.o.

Methods of Therapy

In another aspect the invention provides a method of treatment, prevention or alleviation of a disease, disorder or condition of a living animal body, including a human, which disorder, disease or condition is responsive to activation of a potassium channel, which method comprises the step of administering to such a living animal body in need thereof, a therapeutically effective amount a compound capable of activating the potassium channel, or a pharmaceutically acceptable salt thereof. The preferred medical indications contemplated according to the invention are those stated above.

It is at present contemplated that a suitable dosage of the active pharmaceutical ingredient (API) is within the range of from about 0.1 to about 1000 mg API per day, more preferred of from about 1 to about 500 mg API per day, most preferred of from about 1 to about 100 mg API per day, dependent, however, upon the exact mode of administration, the form in which it is administered, the indication considered, the subject and in particular the body weight of the subject involved, and further the preference and experience of the physician or veterinarian in charge.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention is further illustrated by reference to the accompanying drawing, in which Fig. 1A and 1 B show the effect of Compound 12 (i.e. N-fδ-Chloro^-fiH-tetrazol-δ-y^-phenylJ-^dipropylsulfamoyl- benzamide) on the voltage dependence of BK _Ca channels expressed in Xenopus Oocytes:

Fig. 1A shows conductance (μS) vs. membrane potential (mV) in the absence (Control) of Compound 12 and in the presence of 0.01 to 31.6 μM of Compound 12; and

Fig. 1 B shows the concentration-response relationship for the left-shift of the BKca-activation curve induced by Compound 12; i.e. δV (mV) vs. log [c] (M). The calculated EC ₅₀ -value is 1.3 μM and the maximal left-shift for the BK- activation curve is -110 mV.

EXAMPLES

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

Example 1

Preparatory Example

General experimental procedure

The synthetic pathway of the compounds of the invention involves coupling between the suitable acetyl-chlohde (A) (1 equivalent), commercially available or prepared from the corresponding commercial carboxylic acids upon treatment with an excess of thionyl chloride, and a number of ortho-acidic-

substituted anilines (B) (1 equivalent). The anilines (B), when not commercially- available, were synthesised by conventional methods as those described in US 2002-0037905 and in Valgeirsson et al. in Journal of Medicinal Chemistry 2004 47 (27) 6948-6957. It is preferred that this reaction is carried out overnight, in a mixture of toluene and pyridine and at room temperature or under heating up to reflux (Method A). The usual work-up consists of evaporation to dryness of the reaction mixture and the crude residue is then washed with HCI 1 N and water, and finally purified either by crystallisation or flash chromatography (60-100% yield). Alternatively, the compounds of the invention have been synthesized by mixing directly the commercially-available carboxylic acids (C) (1 equivalent), dichloromethane (DCM), 1 -ethyl-3-(3-dimethylaminopropyl) carbodiimide HCI (EDCηCI) (2 eq) and 4-(dimethylamino)pyridine (DMAP) (3 eq). It is preferred that the resulting mixture is stirred at room temperature for 10 min and then the suitable anilines B (1 eq) are added. The mixture is usually stirred at room temperature overnight, diluted with DCM, washed with 1.5 N HCI and water, dried and evaporated to dryness, to afford the amides of the invention, which are purified either by crystallisation or flash chromatography (50-100% yield).

As illustrative examples of Method A and Method B we report the preparation of the following compounds.

Method A

λ/-r5-Chloro-2-(5-oxo-4,5-dihvdro-π ,2,41oxadiazol-3-yl)-phenyl1-3,5-bis- trifluoromethyl- benzamide (Compound 1 ) To a stirred mixture of 3-(2-amino-4-chloro-phenyl)-4H-

[1 ,2,4]oxadiazol-5-one prepared as described by Valgeirsson et al. in Journal of Medicinal Chemistry 2004 47 (27) 6948-6957 (0.854 g, 1 eq) in pyridine (6 ml) and dry toluene (20 ml), a solution of commercial 3,5-bis-thfluoromethyl-benzoyl chloride (1 .12 g, 1 eq) in dry toluene (15 ml) is added portion wise and stirring is continued at room temperature overnight. The resulting reaction mixture is evaporated to dryness and the solid residue is washed with HCI 1 N and water, and then purified by crystallization from acetonitrile (0.823 g, 45% yield). LC-ESI- HRMS of [M-H]- shows 450.0067 Da. CaIc. 450.008005 Da, dev. -2.9 ppm.

Method B

λ/-r5-Chloro-2-(5-oxo-2,5-dihvdro-π ,2,41oxadiazol-3-yl)-phenyl1-4- dipropylsulfamoyl- benzamide (Compound 2)

A mixture of the commercially-available 4-dipropylsulfamoyl-benzoic acid (0.250 g, 1 eq), dichloromethane (DCM) (20 ml), 1 -ethyl-3-(3- dimethylaminopropyl) carbodiimide HCI (EDCηCI) (0.336 g, 2 eq) and 4-

(dimethylamino)pyridine (DMAP) (0.321 g, 3 eq). is stirred at room temperature for 10 min and then 3-(2-amino-4-chloro-phenyl)-4H-[1 ,2,4]oxadiazol-5-one (0.185 g,

1 eq) is added. The mixture is usually stirred at room temperature overnight, diluted with DCM, washed with 1.5 N HCI and water, dried and evaporated to dryness, to afford the title compound which is purified by crystallisation from a mixture of dymethyl formamide and water DCM (53% yield). LC-ESI-HRMS of [M+H]+ shows 479.1173 Da. CaIc. 479.115595 Da, dev. 3.6 ppm.

As further examples, the chemical-physical properties of a number of compounds of the invention, obtained as outlined above, are described below.

λ/-r3-(1 /-/-Tetrazol-5-yl)-4'-trifluoromethyl-biphenyl-4-yl1-3,5-bis -trifluoromethyl- benzamide (Compound 3)

LC-ESI-HRMS of [M-H]- shows 544.0804 Da. CaIc. 544.081987 Da, dev. -2.9 ppm.

λ/-r5-Chloro-2-(1 /-/-tetrazol-5-yl)-phenyl1-3,5-bis-trifluoromethyl-benzamide (Compound 4)

M.p. 247-249°C.

λ/-r2,4-Dibromo-6-(1 /-/-tetrazol-5-yl)-phenyl1-3,5-bis-trifluoromethyl-benzamide (Compound 5)

LC-ESI-HRMS of [M-H]- shows 555.8852 Da. CaIc. 555.884329 Da, dev. 1.6 ppm.

λ/-[4-Bromo-2-(2/-/-tetrazol-5-yl)-phenyl1-3,5-bis-trifl uoromethyl-benzamide (Compound 6)

LC-ESI-HRMS of [M-H]- shows 477.9743 Da. CaIc. 477.973816 Da, dev. 1 ppm.

λ/-[4-Bromo-2-(N-hvdroxycarbamimidoyl)-phenyl1-3,5-bis-t rifluoromethyl- benzamide (Compound 7)

LC-ESI-HRMS of [M-H]- shows 467.9787 Da. CaIc. 467.978233 Da, dev. 1 ppm.

1 -Hydroxy-naphthalene-2-carboxylic acid [5-chloro-2-(1 /-/-tetrazol-5-yl)-phenyl1- amide

(Compound 8)

M.p. 221 -225 ⁰ C.

Naphthalene-2-carboxylic acid [5-chloro-2-(5-oxo-4,5-dihvdrc)-[1 ,2,41oxadiazol-3- yJiz phenyli-amide (Compound 9)

LC-ESI-HRMS of [M+H]+ shows 366.0629 Da. CaIc. 366.064545 Da, dev. -4.5 ppm.

2-r(6-Bromo-naphthalene-2-carbonyl)-amino1-4-chloro-benze nesulfonic acid (Compound 10)

LC-ESI-HRMS of [M+H]+ shows 439.9377 Da. CaIc. 439.935896 Da, dev. 4.1 ppm.

4-Chloro-2-[(naphthalene-2-carbonyl)-amino]-benzenesulfon ic acid (Compound

LC-ESI-HRMS of [M+H]+ shows 362.0255 Da. CaIc. 362.025383 Da, dev. 0.3 ppm.

λ/-r5-Chloro-2-(1 /-/-tetrazol-5-yl)-phenyl1-4-dipropylsulfamoyl-benzamide (Compound 12)

LC-ESI-HRMS of [M+H]+ shows 463.132 Da. CaIc. 463.131913 Da, dev. 0.2 ppm.

S-O.δ-Bis-tπfluoromethyl-benzoylamino^δ-chloro^-hvdrox y-benzenesulfonic acid (Compound 13)

LC-ESI-HRMS of [M-H]- shows 461 ,9646 Da. CaIc. 461 ,963766 Da, dev. 1 ,8 ppm.

λ/-r4-Chloro-2-(1 /-/-tetrazol-5-yl)-phenyl1-4-dipropylsulfamoyl-benzamide (Compound 14)

LC-ESI-HRMS of [M+H]+ shows 463,134 Da. CaIc. 463,131913 Da, dev. 4,5 ppm.

λ/-[5-Chloro-2-(1 H-tetrazol-5-yl)-phenyl1-4-sulfamoyl-benzamide (Compound 15)

LC-ESI-HRMS of [M-H]- shows 377.0221 Da. CaIc. 377.022363 Da, dev. -0.7 ppm.

/V-[5-Chloro-2-(5-oxo-4,5-dihvdro-[1 ,2λ1oxadiazol-3-yl)-phenyl]-4-(morpholine-4- sulfonvD-benzamide (Compound 16)

LC-ESI-HRMS of [M-H]- shows 463.0497 Da. CaIc. 463.04791 Da, dev. 3.9 ppm.

λ/-r5-Chloro-2-(5-oxo-4,5-dihvdro-π ,2,41oxadiazol-3-yl)-phenyl1-4- diethylsulfamoyl- benzamide (Compound 17)

LC-ESI-HRMS of [M-H]- shows 449.0681 Da. CaIc. 449.068645 Da, dev. -1.2 ppm.

λ/-[5-Chloro-2-(1 /-/-tetrazol-5-yl)-phenyl1-4-(morpholine-4-sulfonyl)-benzami de (Compound 18)

LC-ESI-HRMS of [M-H]- shows 447.064 Da. CaIc. 447.064228 Da, dev. -0.5 ppm.

λ/-[5-Chloro-2-(1 /-/-tetrazol-5-yl)-phenyl1-4-diethylsulfamoyl-benzamide (Compound 19)

LC-ESI-HRMS of [M-H]- shows 433.0862 Da. CaIc. 433.084963 Da, dev. 2.9 ppm.

λ/-[5-Chloro-2-(1 /-/-tetrazol-5-yl)-phenyl1-2-hvdroxy-5-(morpholine-4-sulfony l)- benzamide (Compound 20)

LC-ESI-HRMS of [M-H]- shows 463.0605 Da. CaIc. 463.059143 Da, dev. 2.9 ppm.

Example 2

Biological Activity

In this example the BK channel opening activity of Compound 12 (i.e. N-fδ-Chloro^-fiH-tetrazol-δ-y^-phenylJ-^dipropylsulfamoyl- benzamide) is determined using BK channels heterologously expressed in Xenopus laevis oocytes.

The electrical current through the BK channel was measured using conventional two-electrode voltage clamp. BK currents were activated by repeating ramp protocols. In brief, the membrane potential was continuously

changed from -120 mV to +120 mV within a 2 s period. The threshold for BK activation is approximately +30 mV under control conditions. Compounds were applied for 100 s during which the ramp protocol was repeated 10 times with 10 s intervals. In between the ramp protocols the membrane potential was clamped at - 80 mV. The first three compound applications were control blanks where the current level is allowed to stabilize. During the subsequent 8 applications increasing concentrations (0.01-31 .6 μM) of Compound 12 was applied and a marked increase in the current level at depolarizing potentials was observed.

In order to evaluate the ability of the compounds to shift the BK activation curve towards lower membrane potentials, the BK current was transformed into conductance by using Ohm's law g = I / (E _mθmb - E _rθV ), where g is the conductance, I is the current, E _mθmb is the membrane potential and E _rθV is the reversal potential. The extracellular solution for these experiments contained 2.5 mM K+ and the intracellular K+ concentration of an oocyte was estimated to be 100 mM. Under those conditions, Nernst equation predicts a reversal potential of E _rθV = -93.2 mV. The control conductance level at a membrane potential of +100 mV was calculated, and the compound effect was evaluated as the potential difference, δV, to the membrane potential at which the same conductance level was obtained in the presence of compound. The concentration response curve for this potential difference was fitted to the sigmoidal logistic equation: δV = δV _max /(1 + (EC ₅ o/[compound]) ⁿ ), where δV _max represents the maximal left shift of the BK activation curve, EC ₅₀ is the concentration causing a half maximal response, and n is the slope coefficient.

The results of this determination are presented in Figs. 1A and 1 B. The calculated EC ₅₀ and δVmax values for Compound 12 were 1 .3 μM and -1 10 mV, respectively.