AU2007201061A1 - Methods for modulating bladder function - Google Patents

Description

AUSTRALIA

Patents Act COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority Related Art: Name of Applicant: Wyeth Actual Inventor(s): Thomas Michael Argentieri, Jeffrey Howard Sheldon, Mark Robert Bowlby Address for Service and Correspondence: PHILLIPS ORMONDE FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA Invention Title: METHODS FOR MODULATING BLADDER FUNCTION Our Ref: 796077 POF Code: 460048/460161 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): -1- 6eOOq WO 02/32419 PCT/US01/32204 METHODS FOR MODULATING BLADDER FUNCTION The present application is a divisional application from Australian patent application number 2002211758, the entire disclosure of which is incorporated herein by reference.

This invention relates to novel methods for modulating bladder tissues utilizing compounds which modulate. the KCNQ family of potassium channels, particularly compounds which open or agonize the channels. The methods of this invention include the treatment, prevention, inhibition and amelioration of urge urinary incontinence also known as bladder instability, neurogenic bladder, voiding dysfunction, hyperactive bladder or detrusor overactivity. The methods of this invention also include the prevention and treatment of mixed stress and urge urinary incontinence, including that associated with secondary conditions such as prostate hypertrophy.

Background of the Invention U.S. Patent No. 5,384,330 (Dieter et al.) (EP 0554543B) teaches pharmacologically active 1 ,2,4-triaminobenzene derivatives of the General Formula: R4 N R Ar-Alk-(COK Ja N

NRIR

2 R

(I)

and their properties as anti-epileptic, muscle relaxing, fever-reducing and peripheral analgesic agents.

U.S. Patent No. 5,565,483 (Hewawasam et al.) (EP 07473548) teaches compounds of the formulae: R H

OR

R

(Il) 1A WO 02/32419 PCT/US01/32204 wherein: R is hydrogen, hydroxy or fluoro; R 2

R

3 and R 4 each are independently hydrogen, C 1 4 alkyl, halogen, trifluoromethyl, phenyl, p-methylphenyl or p-trifluoromethylphenyl; or R' and R 2

R

2 and R 3 or R 3 and R 4 are joined together to form a benzo fused ring; R 5 is hydrogen or C1.4 alkyl; and R 6 is chlorine or trifluoromethyl; or a nontoxic pharmaceutically acceptable salt, solvate or hydrate thereof, which are potassium channel openers useful for treating ischemia, convulsions and asthma.

The article Modulation of KCNQ2/3 Potassium Channels by the Novel Anticonvulsant Retigabine, Main et al., Molecular Pharmacology, 58: pp. 253-262, 2000, describes the actions of retigabine (D23129; N-[2-amino-4-(4-fluorobenzylamino)phenyl]carbamic acid ethyl ester) in modulating the KCNQ2/3 potassium channels in oocytes in a 3-fold manner, i.e. retigabine shifts the voltage dependence of channel activation to more hyperpolarized membrane potentials, increases the rate of channel activation and slows channel deactivation. The article "KCNQ4 Channel Inactivation by BMS-204352 and Retigabine" R L Schroder et al Neuropharmacology 40, 888-898 (2000) describes the activation of KCNQ4 channels in a reversible and concentrationdependent manner using retigabine and BMS-204352; (3S)-(+)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoro-methyl))-2H-indol-2-one.

U.S. Patent No. 5,849,789 and 5,852,053 (both to Rostock et al.) teache the use of retigabine for the treatment of neurodegenerative disorders, including those associated with stroke.

U.S. Patent No. 5,914,425 (Meisel et al.) teaches novel crystalline forms of retigabine.

U.S. Patent No. 6,117,900 teaches the use of retigabine, also known as N-[2amino-4-(4-fluorobenzylamino)-phenyl]carbamic acid ethyl ester, for the treatment of neuropathic pain.

Throughout the description and claims of this specification, use of the word "comprise" and variations of the word, such as "comprising" and "comprises", is not intended to exclude other additives, components, integers or steps.

The discussion of documents, acts, materials, devices, articles and the like is included in this specification solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all of these matters formed part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed in Australia before the priority date of each claim of this application.

W: iAmendmmens 8918659 Wyeth doc WO 02/32419 PCTIUS01/32204 Description of the Invention This invention comprises methods for modulating urinary bladder tissues in a mammal, particularly including uses thereof for maintaining urinary bladder control, the methods comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound which acts as an agonist or opener of the KCNQ family of potassium channels, including the KCNQ2, KCNQ3, KCNQ4, and KCNQ5 potassium channels, alone or in combination. A particular embodiment of this invention includes use in the methods described herein of one or more agonists or openers of KCNQ2/3 potassium channels. Another series of methods of this invention comprises use of one or more agonists or openers of KCNQ3/5 potassium channels.

Among the compounds useful in the methods of this invention are those disclosed in U.S. Patent No. 5,384,330 (Dieter et al.) and EP 0554543B, the contents of which are incorporated herein by reference. The compounds include those of the formula: N R 3 I 0 Ar-Alk-(CO aa N NR1R 2

I

wherein: R, is selected from hydrogen, C-C-alkyl, C2-C 6 -alkanoyl or the radical Ar;

R

2 is selected from hydrogen or C--C 6 -alkyl;

R

3 is selected from C---C 6 -alkoxy, NH 2

C

1

-C

6 -alkylamino, C--C-dialkylamino, amino substituted by the radical Ar, CI-C 6 -alkyl, C 2

-C

6 -alkenyl, Cz-C 6 alkynyl, the radical Ar or the radical ArO-;

R

4 is selected from hydrogen, C 1 -C-alkyl or the radical Ar; Rs is selected from hydrogen or C--C 6 -alkyl or the radical Ar; Alk indicates a straight or branched alkylene group with 1-9 carbon atoms, which can also be substituted by the radical Ar; WO 02/32419 WO 0232419PCT[USOI/32204 Ar is a phenyl radical substituted by the radicals R 6

R

7 and/or R 8 where these radicals R 6

R

7 and R 8 are the same or different and represent H, C 1

-C

6 alkyl, C 3 -C7-cycloalkyl, hydroxy, 0 1

-C

6 -alkoxy, C 2 -0 6 -alkanoyloxy, halogen, hydroxy, C 1

-C

6 -halogenoalkyl, -CN, -NH 2

-NH--G

1

-C

6 -alkyl, -N(Cl-C 6 -alkyl) 2

-CO

2 H, -CO-Cl-C 6 -alkyl, -CO---0-C 6 -alkyl, -COAr, -CO-OAr, -CONH 2

-CONH-G

1

-C

6 -alkyl, -CON(Ci-C 6 -alkyl) 2 -CONHAr, -NH-CO-Cl-C 6 -alkyl, -NHCO-Ar, -NHCO-Cl-C 6 -alkoxy, -N-H-CO-Ar,

-NHCO-NH

2 -NHCO-N(-C-C-alkyl) 2 -NHCO-NHAr, -NH-S0 2 -Ci -06alkyl, -NH-SO 2 Ar, -NH-S0 2 -nitrophenyl, -S0 2 -OH, -S0 2

-G-C

6 -alkyl,

-SO

2 -Ar, -S0 2 -0 1 -Cf 6 -alkoxy, -S0 2 -OAr, -S0 2

-NH

2 -S0 2 -NH-Cl-C 6 -alkyl, -S0 2

-N(C-C

6 -alkyl) 2 -S0 2 -NHAr, -S0 2 -Cl-C 6 -alkoxy; n is 0 or 1; or a pharmaceutically acceptable salt thereof.

The alkyl groups, halogenalkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylamino groups, alkanoyl amino groups, alkanoyloxy groups and aikanoyl groups in general can be straight or branched. The same also applies to alkyl and alkyloxy groups (=alkoxy groups) if these are components of more complicated radicals for example in the form of a monoalkyl- or dialkylamino group, alkanoylamino group, carbaikoxy group, alkylcarbonyl group and analogous groups. The C 3

-C

7 -cycloalkyl group is preferably cyclopentyl or cyclohexyl. C 2

-C

6 -alkenyl preferably represents allyl.

CZ-C

6 -alkynyl preferably represents propargyl.

The halogen atoms are chlorine, bromine or fluorine, in particular chlorine of fluorine. The alkyl and alkoxy groups as such or as components of groups of more complicated radicals consist in particular of 1-4 carbon atoms, preferably 1 or 2 carbon atoms. Alkanoyl groups, such as alkanoylamino groups or alkanoyloxy groups consist in particular of 2-4, preferably 2-3 carbon atoms. Alk consists in particular of 1-3, preferably 1 or 2 carbon atoms.

Among the more preferred compounds of this group are: 2-Amino-4-(4-fluorobenzyiamino)-1 -ethoxycarbonylaminobenzene; 2-Amino-4-(4-trifluoromethylbenzylamino)-1 -ethoxycarbonylamino-benzene; -4- WO 02/32419 WO 0232419PCTIIJSOI/32204 2-Amino-4-benzylamilo-1 -ethoxycarbonylamilo-beflzefe; 2-Amino-4-(3,5-dichlorobenzylamino)-1 -ethoxycarbonylamino benzene; 2-Amino-4-(3,5-dichlorobenzylamilo)-1 -propyloxycarbonylamino benzene; 2-Amino-(2-chlorobelzylanino)-1 -(di ethyl ca rbamoylam iflo) benzene; 2-Amino-4-(2,4-dichlorobelzylamfino)-1 -(dimethylcarbamoylamilO) benzene; and 1 ,2-Diacetylamino-4-(4-fluorobelzylamilo) benzene.

Among the most preferred compounds for use in the methods of this invention are N-[2-amino-4-(4-fluorobenzylanminQ)-phenyIIcarbamic acid and its pharmaceutically acceptable salts and ester forms. 0f particular preference is retigabine, also known as N-[2-amino-4-(4-fluorobenzylamino)-phenyllcarbamic acid ethyl ester (CAS Registry No.

150812-12-7), having the formula:

HNH

F

NH

2 Also useful in the methods of this invention are the metabolite forms of retigabine which may be isolated from blood, urine or feces of recipients of N-[2-amino-4-(4fluorobenzylamino)-phenyl]carbamic acid ethyl ester. The metabolites include the glucoside of retigabine, [4(-loobnyaio--34,-rhdoy6hdoyehl tetrahydropyran-2-ylamilo)-phenyl]-carbamic acid ethyl ester, as well as its two glucoronide analogs, 6-2Ehxcroyaio5(-loobnyaio-hnlmn] 3,4,5tiyrx- tayr-yan2croyi acid and 6-[(3-Amino-4-ethoxycarbonylamino-phenyl)-(4-fluoro-benzyl)-amino]-3, 4 ,5-trihydroxy-tetrahyd ro-pyran-2-carboxylic acid. Further metabolites include M 2-mio4(- or-ezlaio pey] acetamide, its cyclized analog Fl uoro-benzyl)-2-m ethyl -1 H-benzoi mid azol- 5-yl) amine and the glucoronidle analogs of N-2Aio4(-loobnyaio-hnlaeaie 6-(-ctlmn--mn-hnl-4fur-ezl-mnl345tiyrx-erhdo pyran-2-carboxylic acid and 6-2Aeya no5 4tu o enya o pey mn] 3,4,5-trihydroxy-tetrahydro-pyran-2-carboxylic acid.

WO 02/32419 PCT/US01/32204 Also useful in the methods of this invention are the compounds disclosed in U.S.

Patent No. 5,565,483 (Hewawasam et which issued on October 15, 1996, and EP 0747354B, the contents of which are incorporated herein by reference. These compounds include the substituted 3-phenyl oxindole compounds having the formulae:

R

1

N

R R

R

4

OR

R

(II)

wherein: R is hydrogen, hydroxy or fluoro;

R

2

R

3 and R 4 each are independently hydrogen, C1-4 alkyl, halogen, trifluoromethyl, phenyl, p-methylphenyl or p-trifluoromethylphenyl; or R' and R 2

R

2 and

R

3 or R 3 and R 4 are joined together to form a benzo fused ring;

R

5 is hydrogen or C1i alkyl; and

R

6 is chlorine or trifluoromethyl; or a nontoxic pharmaceutically acceptable salt, solvate or hydrate thereof, and optical forms thereof.

One group of the substituted 3-phenyl oxindole compounds useful with this invention include those described above wherein R is hydrogen. Another subgroup of these compounds include those in which R 2

R

3 and R 4 are each independently selected from H, C1 to C 4 alkyl, halogen or trifluoromethyl, and when R' and R 4 are H; R 2 or R 3 is phenyl, p-methoxyphenyl or trifluormethylphenyl; or R 1 and R 2

R

2 and R 3 or R 3 and R 4 are joined together to form a benzo fused ring; R5 is H or Ci to C4 alkyl; and R 6 is chlorine or trifluoromethyl, or a pharmaceutically acceptable salt form thereof.

Non-limiting examples of these substituted 3-phenyl oxindole compounds are: (±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2one; (±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-6-(trifluoromethyl)-2H-indol-2-one; -6- WO 02/32419 WO 0232419PCT/USOI/32204 (5-Chlo ro-2-hydroxyphelyl)-1, ,3-dihyd ro-3-hydroxy-6-(trifiluoromethyl)-2H-ildol-2one; (5-Choro-2-hydroxyphel)-, ,3-dihyd ro-6-(trif luoromethyl)-2H-il-2-ole; ro-2-hydroxyphelyl)-4,6-dichoro- 1 ,3-dihydro-3-hydroxy-2- H-il-2-ole; (5-Chloro-2-hyd roxyphenfly)-1, ,3-dihydro-3-hyd roxy-7-(trifIluoromethyI)-2H-ifl-2 one; (±)-3-(5-Chloro-2-hydroxyphel)-1 ,3-dihydro-3-hydroxy-4-trifIluoromethyI)2H-ifdld-2-ofe; 1,3Dhdo3hdoy3[-yrx--ti lurmty~hnl--(rflooehlindol-2-one; (±)-3-(5-Chloro-2-hydroxyphenyl)-1 ,3-dihydro-3-hydroxy-4,6-bis(trif luoromethy)-2H-il 2-one; (-)-3-(5-Chloro-2-methoxyphenyl)-, ,3-dihydro-3-hyd roxy-6-(trif luoromethYl)-2H-iflO 2 one; (±)-3-(5-Chloro-2-hydroxyphel)-, ,3-dihyd ro-3-hydroxy-6-(trif luoromethyl)-2H-ifdld02one; oro-2- hyd roxyphelyl) 1 3-d ihyd ro-3- hyd roxy-6-(t ril uoromethYl)-2H-ind0- 2 one; (±)-3-(5-Chloro-2-methoxyphenyl)-1 ,3.dihydro-3-f luoro-6-(trif luoromethy)-2H-indol-2-one; (±)-3-(5-Chloro-2-hydroxyphenyl)-1 ,3-dihydro-3-hydroxy-2H-benz[glindol-2one; (±)-3-(5-Chloro-2-hydroxyphenYI)-1 ,3-dihydro-6-pheny-2H-indol-2-one; (±)-3-(5-Chloro-2-hydroxyphenyl)-1 ,3-dihydro-2H-benz[gindol-2-one; (±)-3.(5-Chloro-2-methoxyphelyl)- 1, 3-dihydro-3-f luoro-6-pheny-2 H-indol-2-one; (±)-3-(5-Ghloro-2-methoxyphenyl)-1 ,3-dihydro-3-fluoro-6-iodo-2H-indol-20le; (±)-3-(5-Chloro-2-hydroxyphel)-1 ,3-dihydro-6-(4-methylphenyl)-2H-indol-2-fle; (5-Chloro-2-methoxyphelyl)-1, ,3-dihydro-3-f luo ro-7-(trifluorom ethyl) -2H-i ndol 2-ofe; (±)-3-(5-Chloro-2-hydroxyphelyl)-1 ,3-dihydro-2H-benz[e]indol-2-one; (±)-3-(5-Ghloro-2-methoxyphenyl)- 1 ,3-dihydro-3-f luoro-5-methy-2H-indoI-2-one; (±)-3-(5-Chloro-2.methoxyphenyl)- I ,3-dihydro-3-f luoro-4,6-bistrif luoromethy)-2H-il- 2-one; (±)-5-Bromo-3-(5-chloro-2-methoxyphel)-1 ,3-dihyd ro-3-f luoro-2H-ifl-2one; (±)-3-(5-Chloro-2-hyd roxyphenyl)- 1 ,3-dihyd ro-6-[4-(trif luoromethy)phenyl]-2H-indoI 2 one; WO 02/32419 WO 02/24 19PCT/USOI/32204 (±)-3-(5-Chloro-2-hydroxyphenyl)-1 ,3-dihydro-2H-indol-2-one; (±)-5-Bromo-3-(5-chloro-2-methoxyphenyl)-1 ,3-dihydro-3-hydroxy-2H-indol-2-one; (±)-3-(5-Chloro-2-hydroxyphenyl)-4,6-dichloro- 1 ,3-dihydro-2H-indol-2-one; (±)-3-(5-Chloro-2-methoxyphenyl)-1 ,3-dihydro-3-hydroxy-6-iodo-2H-indol-2-one; (±)-3-(5-Chloro-hydroxyphenyl)-1 ,3-dihydro-6-iodo-2H-indoi-2-one; (±)-3-(5-Chloro-2-methoxyphenyl)-1 ,3-dihydro-3-hydroxy-2H-benz[flindol-2one; (±)-3-(5-Ghloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-2H-benz[flindol-2one; and (±)-3-(5-Chloro-2-hydroxyphenyl)-1 ,3-dihydro-2H-benz[flindol-2-one; and the pharmaceutically acceptable salt forms thereof.

Among the more preferred compounds of this group are: Cl

F

\-F

(±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-6-(trifluoromethyl)-2H-indol-2-one;

CI

HO;FF

HO-C

F

H

lo ro-2-hyd roxyphenyl)-1 ,3-dihydro-3-hyd roxy-6-(trif luoromethyl)-2 H-indol-2-one; Cl _IX F

H

(±)-3-(5-Chloro-2-methoxyphenyl)- 1 3-dihydro-3-fluoro-6-(trif luoromethyl)-2 H-indol-2-one; WO 02/32419 PCT/US01/32204 H

CI

(±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-2H-benz[g]indol-2-one; Cl

HO

H

(+)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-6-phenyl-2H-indol-2-one; and I CI

HO

(±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-2H-benz[f]indol-2-one.

Pharmaceutically acceptable salt forms of these substituted 3-phenyl oxindole compounds include those formed as base addition, including those formed using suitable inorganic bases, such as alkali and alkaline earth metal bases, such as sodium, potassium, magnesium and calcium metallic cations. The compounds may be administered as described in U.S. Patent No. 5,565,483. A pharmaceutically effective amount in mammals, including man, may be from about 0.1 gg/kg to about 100 mg/kg of body weight. Parenteral administration may be completed at an effective dose of from about 1 pg/kg to about 10 mg/kg of body weight.

WO 02/32419 PCT/US01/32204 The methods of this invention are useful for inducing, assisting or maintaining desirable bladder control in a mammal experiencing or susceptible to bladder instability or urinary incontinence. These methods include prevention, treatment or inhibition of bladder-related urinary conditions and bladder instability, including noctumrnal enuresis, nocturia, voiding dysfunction and urinary incontinence. Also treatable or preventable with the methods of this invention is bladder instability secondary to prostate hypertrophy. The compounds described herein are also useful in promoting the temporary delay of urination whenever desirable. The compounds of this invention may also be utilized to stabilize the bladder and treat or prevent incontinence which urge urinary incontinence, stress urinary incontinence or a combination of urge and stress incontinence in a mammal, which may also be referred to as mixed urge and stress incontinence. These methods include assistance in preventing or treating urinary incontinence associated with secondary conditions such as prostate hypertrophy.

These methods may be utilized to allow a recipient to control the urgency and frequency of urination. The methods of this invention include the treatment, prevention, inhibition and amelioration of urge urinary incontinence also known as bladder instability, neurogenic bladder, voiding dysfunction, hyperactive bladder, detrusor overactivity, detrusor hyper-reflexia or uninhibited bladder.

As described above, methods of this invention include treatments, prevention, inhibition or amelioration of hyperactive or unstable bladder, neurogenic bladder or hyperreflexic bladder. These uses include, but are not limited to, those for bladder activities and instabilities in which the urinary urgency is associated with prostatitis, prostatic hypertrophy, interstitial cystitis, urinary tract infections or vaginitis. The methods of this invention may also be used to assist in inhibition or correction of the conditions of Frequency-Urgency Syndrome, and lazy bladder, also known as infrequent voiding syndrome.

The methods of this invention may also be used to treat, prevent, inhibit, or limit the urinary incontinence, urinary instability or urinary urgency associated with or resulting from administrations of other medications, including diuretics, vasopressin antagonists, anticholinergic agents, sedatives or hypnotic agents, narcotics, alpha-adrenergic agonists, alpha-adrenergic antagonists, or calcium channel blockers.

WO 02/32419 PCT/US01/32204 The methods of this invention are useful for inducing or assisting in urinary bladder control or preventing or treating the maladies described herein in humans in need of such relief, including adult and pediatric uses. However, they may also be utilized for veterinary applications, particularly including canine and feline bladder control methods. If desired, the methods herein may also be used with farm animals, such as ovine, bovine, porcine and equine breeds.

The applications may utilize conventional oral, rectal, parenteral or intravenous delivery methods as conventionally utilized in veterinary practice. Most preferable in most instance for home use with companion animals are oral tablets or capsules or neat compound or powdered or granular pharmaceutical formulations which may be mixed with chewable or liquid veterinary formulations or food materials or liquids acceptable to the animal in question.

As used herein, the terms "pharmaceutically effective amount" or "therapeutically effective amount" mean the total amount of each active component of the pharmaceutical composition or method that is sufficient to show a meaningful patient benefit, treatment, prevention or amelioration of urinary incontinence or the excessive or undesirable urge to urinate, or a decrease in the frequency of incidence of urinary incontinence. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.

The methods of this invention may be accomplished with a daily dose of the active compounds described above from U.S. Patent No. 5,384,330 of from about 0.1 mg/kg to about 10 mg/kg. Doses may be administered as a single regimen, such as only prior to bedtime or before travel, or as a continuous regimen divided by two or more doses over the course of a day. Human administration may be at dosages of from about mg BID to about 1000 mg BID, preferably from about 50 mg BID to about 500 g.

BID, more preferably at a dose of from about 100 mg BID to about 300 mg BID.

-11- WO 02/32419 PCT/US01/32204 The KCNQ potassium channel agonists of this invention may also be administered in the methods of this invention in combination with pharmaceutically effective amounts of other medicinal agents useful for bladder control or the treatment or inhibition of urinary incontinence. For instance, the compounds may be administered with desmopressin acetate, available as DDAVP" Nasal Spray and DDAVP® tablets from Aventis Pharmaceuticals, as well as a desmopressin acetate rhinal tube from Ferring Pharmaceuticals Inc. Other combination products include tolterodine tartrate (available as DETROL T tablets from Pharmacia Upjohn), oxybutinin chloride (available in the form of DITROPAN® tablets and syrup and DITROPAN XL® extended release tablets from ALZA Pharmaceuticals), propanthaline bromide (available in tablet form from Roxane Laboratories, Inc.), hyoscyamine and hyoscyamine sulfate (available, respectively, as CYSTOPAZ e tablets and CYSTOPAZ-Me timed release capsules from PolyMedica Pharmaceuticals Inc.), hyoscyamine hydrobromide, flavoxate HCI (available in URISPAS® 100 mg tablets from ALZA Pharmaceuticals), imipramine HCI (available in 10 mg, 25 mg and 50 mg tablets from Geneva Pharmaceuticals, Inc.), phenylpropanolamine, midodrine HCI (available in 2.5 mg and 5 mg PROAMATINE tablets from Shire US Inc.), phenoxybenzamine HCI (available as DIBENZYLINE capsules from WellSpring Pharmaceuticals Corporation), and prazosin HCI (available in MINIPRESS® capsules from Pfizer Inc.). Each of these medicaments may be administered in the pharmaceutically effective amounts and regimens known in the art, including those listed in the Physicians' Desk Reference, 55 Edition, 2001, published by Medical Economics Company, Inc. at Monvale, NJ 07645-1742, the relevant portions of which are incorporated herein by reference. The KCNQ channel agonists of this invention may also be used in conjunction with one or more compounds which act as vasopressin agonists including, but not limited to those described in U.S. Patent No.

6,194,407 (Failli et U.S. Patent No. 6,090,803 (Failli et U.S. Patent No.

6,096,736 (Ogawa et and U.S. Patent No. 6,096,735 (Ogawa et al.).

Compounds as described in U.S. Patent No. 5,384,330, including retigabine, can be administered orally using conventional pharmaceutical excipients or carriers, preferably coated or contained in hard or soft gelatin capsules. Examples of oral formulations contained in hard gelatin capsules can include those in which the active compound comprises from about 45% to 50%, by weight, of the formulation.

-12- WO 02/32419 PCT/US01/32204 Microcrystalline cellulose comprises from about 43% to about 47%, povidone comprises from about 3% to about and silicon dioxide and magnesium stearate each comprise from about 0.3% to about each by weight. Specific examples of capsules containing 50 mg, 100 mg and 200 mg may be formulated utilizing the following lists of components.

mg Retiqabine Capsules Ingredient Retigabine Microcrystalline Cellulose, NF Povidone, USP Silicon Dioxide, Colloidal, anhydrous, NF Magnesium Stearate, EP Theoretical Fill Weight Amount/Capsule 50.0 mg 45.5 mg 3.5 mg 0.5 mg 0.5 mg 100.0 mg 100 mo Retigabine Capsules Ingredient Retigabine Microcrystalline Cellulose, NF Povidone, USP Silicon Dioxide, Colloidal, anhydrous, NF Magnesium Stearate, EP Theoretical Fill Weight Amount/Capsule 100.0 mg 91.0 mg 7.0 mg 1.0 mg 1.0 mg 200.0 mg 200 mq Retiqabine Capsules Ingredient Retigabine Microcrystalline Cellulose, NF Povidone, USP Silicon Dioxide, Colloidal, anhydrous, NF Magnesium Stearate, EP Theoretical Fill Weight Amount/Capsule 200.0 mg 182.0 mg 14.0 mg 2.0 mg 2.0 mg 400.0 mg -13- WO 02/32419 PCTIUS01/32204 The ingredients in the formulations above can be prepared using the following steps.

1) Weigh separately the active ingredient (retigabine), preferably screened through an 800 micron screen, and the microcrystalline cellulose components.

2) Prepare a granulation solution by dissolving the Povidone, USP in purified L water.

3) Place the ingredients from Step 1 into a suitable blender and mix thoroughly.

4) Screen the mixture from Step 3 through a 1000 4m screen and place the screened mixture into the vessel of a fluidized bed granulator.

Heat the ingredients in the fluid bed granulator up to 270C product temperature while mixing.

6) Add the granulation solution from Step 2 to the fluid bed.

7) Dry the granulate in the fluid bed.

8) Weigh the colloidal silicon dioxide component, preferably screened through a 1000 pm screen, and the magnesium stearate component, preferably screened through a 600 p.m screen.

9) Add the silicon dioxide and magnesium stearate components to the fluid bed granulator's vessel containing the dried granulate from Step 7 and mix the components thoroughly.

Screen the mixed components from Step 9, preferably through a 800j.m screen.

11) Transfer the final screened components into a suitable blender and mix thoroughly.

-14- WO 02/32419 PCT/US01/32204 The final component mixture from Step 11 can then be coated, encapsulated or compressed into tablets utilizing conventional tablet excipients or carriers, as desired. It will be understood that oral dosage forms within the scope of this invention can be prepared using the components listed above in respective amounts according the dose of active ingredient in the particular formulation. For veterinary uses, the final mixture of Step 11 can be administered neat or mixed into foods acceptable to the animal in question. Further, the mixtures can be formulated into tablets, capsules or coated products, as described above, or integrated into conventional veterinary medicaments or food products.

For intravenous administration, the compounds from U.S. Patent No. 5,384,330 described herein may be prepared and maintained in conventional lyophylized formulations and reconstituted prior to administration with an intravenously acceptable saline solution, such as a 0.9% saline solution. The pH of the intravenous formulation can be adjusted, as needed, with an intravenous and pharmaceutically acceptable acid, such as methanesulfonic acid.

KNCQ1, 3 and 5 expression and M-current activity in rat urinary bladder Using quantitative rtPCR, the expression of KCNQ1, KCNQ3 and potassium channels was identified in the rat urinary bladder. The highest levels of expression were seen in KCNQ5 (0.2±0.1ng KCNQ5 mRNA/GAPDH mRNA). To further probe M-current activity in the bladder, retigabine (lOpM, M-current agonist) was tested in isolated bladder smooth muscle cells using standard patch-clamp techniques.

Exposure to retigabine significantly increased an outward current that was insensitive to iberiotoxin and was associated with a membrane hyperpolarization of 17.8 3.0 mV This hyperpolarization was reversed by the addition of linopirdine (50pM an Mcurrent antagonist) to the tissue bath. Retigabine relaxed isolated carbachol contracted rat bladder strips with an IC50 of 3.5±0.9 pM This relaxation was reversed by the M-current blockers linopirdine and XE-991.

Claims (16)

1. A method of inducing or maintaining bladder control in a mammal, the method comprising administering to a mammal in need thereof a pharmacologically effective amount of a KCNQ potassium channel agonist.

2. A method of treatment or prevention of urinary incontinence in a mammal, the method comprising administering to a mammal in need thereof a pharmacologically effective amount of a KCNQ potassium channel agonist.

3. A method according to Claim 2 wherein the urinary incontinence is urge incontinence.-

4. A method according to Claim 2 wherein the urinary incontinence is secondary to prostate hypertrophy. A method according to Claim 2 wherein the urinary incontinence is mixed urge and stress incontinence.

6. A method according to any one of Claims 1 to 5 wherein the KCNQ potassium channel is a KCNQ4 potassium channel.

7. A method according to any one of Claims 1 to 5 wherein the KCNQ potassium channel is a KCNQ2/3 potassium channel.

8. A method according to any one of Claims 1 to 5 wherein the KCNQ potassium channel is a KCNQ3/5 potassium channel.

9. A method according to any one of Claims 1 to 8 wherein the mammal is a human. A method-according to any-one of Claims 1 to 8 wherein the mammal is feline or canine. -16- WO 02/32419 WO 0232419PCT[USOI/32204

11. A method according to any one of Claims i to 10 in which the KCNQ potassium channel agonist is a compound of the formula IND 0 Ar-Alk-(Co) k N NR 1 R 2 wherein: R, is selected from hydrogen, Cl-C 6 -alkyl, C 2 -C 6 -alkanoyl or the radical Ar; R 2 is selected from hydrogen or C 1 -C 6 -alkyl; R 3 is selected from CI 1 -0 6 -alkoxy, NH 2 Cl-C 6 -akylamino, Ci- 6 -dialkylamino, amino substituted by the radical Ar, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, the radical Ar or the radical ArO-; R 4 is selected from hydrogen, CI-G 6 -alkyl or the radical Ar; R 5 is selected from hydrogen or C 1 -G 6 -alkyl or the radical Ar; Alk indicates a straight or branched alkylene group with 1-9 carbon atoms, which can also be substituted by the radical Ar; Ar is a phenyl radical substituted by the radicals R 6 R 7 and/or IRS where these radicals R 6 R 7 and R 8 are the same or different and represent H, C 1 -0 6 -alkyl, C 3 -0 7 cycloalkyl, hydroxy, Cl-0 6 -alkoxy, C 2 -0 6 -alkanoyloxy, halogen, hydroxy, C1-C6- halogenoalkyl, -CN, -NH 2 -NH--0 1 -C 6 -alkyl, -N(C 1 C 6 -alkYl) 2 -CO 2 H, -CO-C 1 -C 6 alkyl, -CO---0-C 1 -C 6 -alkyl, -COAr, -CO-OAr, -CONH 2 -CONH-Cl-C 6 -alkyl, -CON(Cl--0 6 -alkyl) 2 -CONHAr, C 1 -C 6 -alkyl, -NHCO-Ar, -NHCO- Cl-C 6 -alkoxy, -N-H-CO-Ar, -NHCO-NH 2 -NHCO-N(-Cl--C 6 -alkyl) 2 -NHCO- NHAr, -NH-S0 2 C-1 -G 6 -alkyl, -NH-SO 2 Ar, -NH-S0 2 -ntrophenyl, -S0 2 -OH, -S0 2 -G 1 -C 6 -alkyl, -S0 2 -Ar, -S0 2 -Cl-C 6 -alkoxy, -SO 2 OAr, -SO 2 -NH 2 -SO=- NH-Cl-C 6 -alkyl, -SO 2 -N(C 1 C 6 -alkyl) 2 -S0 2 -N HAr, -SO 2 -C 1 -C-alkoxy; n is 0ori1; or a pharmaceutically a cceptable salt thereof.

17- WO 02/32419 PCT/US01/32204 12. A method according to Claim 11 in which the compound of formula I is selected from the group of: 2 -Amino-4-(4-fluorobenzylamino)-1-ethoxycarbonylaminobenzene; 2 -Amino-4-(4-trifluoromethylbenzylamino)-1-ethoxycarbonylamino-benzene; 2 -Amino-4-benzylamino-1-ethoxycarbonylamino-benzene; 2 -Amino-4-(3,5-dichlorobenzylamino)-l-ethoxycarbonylamino benzene; 2 -Amino-4-(3,5-dichlorobenzylamino)-l-propyloxycarbonylamino benzene; 2 -Amino-(2-chlorobenzylamino)-1 -(diethylcarbamoylamino) benzene; 2 -Amino-4-(2,4-dichlorobenzylamino)-l-(dimethylcarbamoylamino) benzene; or 1, 2 -Diacetylamino-4-(4-fluorobenzylamino) benzene; or a pharmaceutically acceptable salt thereof. 13. A method according to Claim 11 in which the compound of formula I is N-[ 2 -amino-4-(4-fluorobenzylamino)-phenyl]carbamic acid or a pharmaceutically acceptable salt or ester form thereof. 14. A method according to Claim 13 wherein the pharmaceutically acceptable ester form is N-[ 2 -amino-4-(4-fluorobenzylamino)-phenyl]carbamic acid ethyl ester. 15. A method according to Claim 13 or Claim 14 wherein the pharmacologically effective amount is from about 0.1 mg/kg to about 10 mg/kg. 16. A method according to Claim 13 or Claim 14 wherein the pharmacologically effective amount is from about 10 mg BID to about 1000 mg BID. 17. A method according to Claim 13 or Claim 14 wherein the pharmacologically effective amount is from about 50 mg BID to about 500 mg BID.

18. A method according to Claim 13 or Claim 14 wherein the pharmacologically effective amount is from about 100 mg BID to about 300 mg BID. -18- WO 02/32419 WO 0232419PCT!USOI /32204

19. A method according to any one of Claims 1 to 10 in which the KGNQ potassium channel agonist is a compound of the formula HN 0 R R OR wherein: R is hydrogen, hydroxy or fluoro; R 1 R 2 R 3 and R 4 each are independently hydrogen, ClA alkyl, halogen, trifluoromethyl, phenyl, p-methylphenyl or p-trifluoromethylphenyl; or R' and R 2 R 2 and R 3 or R 3 and R 4 are joined together to form a benzo fused ring; R 5 is hydrogen or ClA alkyl; and R 6 is chlorine or triflIuorom ethyl; or a nontoxic pharmaceutically acceptable salt, solvate or hydrate thereof.. A method according to Claim 19 in which the compound of formula 11 is selected from the group of: (±)-3-(5-Chloro-2-methoxyphenyl)- 1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-ildol-2- one; (±)-3-(5-Chloro-2-methoxyphenyl)- 1,3-dihydro-6-(trifluoromethyl)-2H-indol-2-one; (±)-3-(5-Chloro-2-hydroxyphenyl)- 1,3-dihydro-3-hyd roxy-6-(trifluoromethyl)-2H-indol-2- one; (±)-3-(5-Chloro-2-hydroxyphenyl)-1 ,3-dihydro-6-(trifluoromethyl)-2H-indol-2-one; (±)-3-(5-Chloro-2-hydroxyphenyl)-4,6-dichloro- 1,3-dihydro-3-hydroxy-2-H-indol-2-one; (±)-3-(5-Chloro-2-hydroxyphenyl)-1 ,3-dihydro-3-hydroxy-7-(trifluoromethyl)-2H-ildol-2- one; -3-(5-Chloro-2-hydroxyphenyl)-1 ,3-dihydro-3-hydroxy-4-trifluoromethy1)2H-indol-2-one;,_ 4P25 3-ihdr--hdoy3[-yrx--(rfIuoomehl hnl 6(rfIurmehl- indol-2-one; -19- WO 02/32419 WO 0232419PCTJUSOII322O4 (±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-4,6-bis(trifluoromethyl)-2H-indol- 2-one; (-)-3-(5-Chloro-2-methoxyphenyl)- 1,3-dihydro-3-hydroxy-6-(trif luoromethyl)-2H-indol-2- one; (±)-3-(5-Chloro-2-hydroxyphenyl)- 1,3-dihydro-3-hydroxy-6-(trif luoromethyl)2H-indol-2- one; (-)-3-(5-Chloro-2-hydroxyphenyl)-1 ,3-dihydro-3-hydroxy-6-(trif luoromethyl)2H-indol-2- one; (±)-3-(5-Chloro-2-methoxyphenyl)- 1,3-dihydro-3-f luoro-6-(trif luoromethyl)2H-indol-2-one; (±)-3-(5-Chloro-2-hydroxypheny)- 1,3-dihydro-3-hydroxy-2H-benzglindol-2one; (±)-3-(5-Chloro-2-hydroxyphenyl)-1 ,3-dihydro-6-phenyl-2H-indol-2-one; (±)-3-(5-Chloro-2-hydroxyphenyl)-1 ,3-dihydro-2H-benz[g]indol-2-one; (±)-3-(5-Chloro-2-methoxyphenyl)- 1,3-dihydro-3-fluoro-6-phenyl-2H-indol-2-one; (±)-3-(5-Chloro-2-methoxyphenyl)-1 ,3-dihydro-3-fluoro-6-iodo-2H-indol-2one; (±)-3-(5-Chloro-2-hydroxyphenyl)-1 3-dihydro-6-(4-methylphenyl)-2H-indol-2-one; loro-2-methoxyphenyl)- 1,3-dihydro-3-f luoro-7-(trif luoromethyl)-2H-indol-2-one; (±)-3-(5-Chloro-2-hydroxyphenyl)-1 ,3-dihydro-2H-benz[e]indol-2-one; (±)-3-(5-Ghloro-2-methoxyphenyl)- 1,3-dihydro-3-fluoro-5-methyl-2H-indol-2-one; (±)-3-(5-Chloro-2-methoxypheny)- 1 ,3-dihydro-3-f luoro-4,6-bis(trif luoromethyl)-2H-indol- 2-one; (±)-5-Bromo-3-(5-chloro-2-methoxyphenyl)- 1 ,3-dihydro-3-f luoro-2H-indol-2one; (±)-3-(5-Chloro-2-hydroxyphenyl)-1 ,3-dihydro-6-[4-(trif luoromethyl)phenyll-2H-indol-2- one; (±)-3-(5-Chloro-2-hydroxyphenyl)-1 ,3-dihydro-2H-indol-2-one; (±)-5-Bromo-3-(5-chloro-2-methoxyphenyl)-1 ,3-dihydro-3-hydroxy-2H-indol-2-one; (±)-3-(5-Chloro-2-hydroxyphenyl)-4,6-dichloro-1 ,3-dihydro-2H-indol-2-one; (±)-3-(5-Chloro-2-methoxyphenyl)-1 3-dihydro-3-hydroxy-6-iodo-2H-indol-2-one; (±)-3-(5-Chlofo-hydroxypheny)-1 ,3-dihydro-6-iodo-2H-indol-2-one; (±)-3-(5-Chloro-2-methoxyphenyl)-1 ,3-dihydro-3-hydroxy-2H-benz[flindol-2one; (±)-3-(5-Chloro-2-hydroxyphenyl)-1 ,3-dihydro-3-hydroxy-2H-benz~flindol-2one; and (±)-3-(5-Chloro-2-hydroxyphenyl)-1 ,3-dihydro-2H-benz[Ilindol-2-one; and the pharmaceutically acceptable salt forms thereof. 20

21. Use of a KCNQ potassium channel agonist in the preparation of a medicament for inducing or maintaining bladder control in a mammal.

22. Use of a KCNQ potassium channel agonist in the preparation of a medicament for the treatment or prevention of urinary incontinence in a mammal. IND

23. described.

24. described. A method according to claim 1 or 2 substantially as hereinbefore Use according to claim 21 or 22 substantially as hereinbefore W:Bree\mendmen s\0o1659 Wyetl.doc