WO2005117862A1 - Treatment of urinary conditions including incontinence - Google Patents

Treatment of urinary conditions including incontinence Download PDF

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Publication number
WO2005117862A1
WO2005117862A1 PCT/IB2005/001529 IB2005001529W WO2005117862A1 WO 2005117862 A1 WO2005117862 A1 WO 2005117862A1 IB 2005001529 W IB2005001529 W IB 2005001529W WO 2005117862 A1 WO2005117862 A1 WO 2005117862A1
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WIPO (PCT)
Prior art keywords
incontinence
group
compound
carbon atoms
nociceptin receptor
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PCT/IB2005/001529
Other languages
French (fr)
Inventor
Simon J. Lewis
Simon Lempriere Westbrook
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Pfizer Limited,
Pfizer, Inc.
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Priority claimed from GB0412416A external-priority patent/GB0412416D0/en
Application filed by Pfizer Limited,, Pfizer, Inc. filed Critical Pfizer Limited,
Publication of WO2005117862A1 publication Critical patent/WO2005117862A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder

Definitions

  • the present invention relates the use of antagonists of the nociceptin receptor for the treatment of urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder, urgency, urge incontinence, frequency, nocturia and/or mixed urinary incontinence.
  • urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder, urgency, urge incontinence, frequency, nocturia and/or mixed urinary incontinence.
  • the present invention also relates to a method of treatment of urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder, urgency, urge incontinence, frequency, nocturia and/or mixed urinary incontinence.
  • the present invention also relates to a method of increasing bladder capacity.
  • the present invention also relates to assays to screen for compounds useful in the treatment of the above conditions.
  • the medical need is high for effective pharmacological treatments of urinary conditions such as overactive bladder (OAB), urgency, urge incontinence, (urinary) frequency, nocturia, stress incontinence and mixed urinary incontinence.
  • OAB overactive bladder
  • Urinary incontinence is the complaint of any involuntary leakage of urine. It is a common condition, and often constitutes an embarrassment which can lead to social isolation, depression, loss of quality of life, and is a major cause for institutionalisation in the elderly population. In addition, feelings of urge to urinate, nocturia, and an increased frequency of urination are conditions which also seriously compromise the quality of life of patients, and are also especially prevalent in the elderly population.
  • nociceptin receptor antagonists may be expected to increase micturition reflex responses and reduce bladder capacity or to reverse conditions of retention due to dysfunction of the micturition reflex, indeed such antagonists have been suggested to be useful in the treatment of autonomic disorders including treatment of suppression of the micturition reflex (e.g. WO 03/000677; WO 03/064425; WO 05/016913).
  • nociceptin antagonists in vivo also have an effect to increase bladder capacity in animal models exploring bladder function.
  • a seminal finding of the present invention is therefore the ability to treat urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder (OAB), urgency, urge incontinence, frequency, nocturia, and/or mixed urinary incontinence, with an antagonist for the nociceptin receptor.
  • urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder (OAB), urgency, urge incontinence, frequency, nocturia, and/or mixed urinary incontinence, with an antagonist for the nociceptin receptor.
  • the invention relates to nociceptin receptor antagonists for use in the treatment of urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder (OAB), urgency, urge incontinence, frequency, nocturia, and/or mixed urinary incontinence.
  • the invention also relates to the use of nociceptin receptor antagonists for the manufacture of a medicament for the treatment of urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder (OAB), urgency, urge incontinence, frequency, nocturia, and/or mixed urinary incontinence.
  • the invention also relates to a method of treatment of urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder (OAB), urgency, urge incontinence, frequency, nocturia, and/or mixed urinary incontinence, with an antagonist to the nociceptin receptor.
  • urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder (OAB), urgency, urge incontinence, frequency, nocturia, and/or mixed urinary incontinence, with an antagonist to the nociceptin receptor.
  • One aspect of the invention is therefore a method of treating urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder (OAB), urgency, urge incontinence, frequency, nocturia, and/or mixed urinary incontinence, comprising the administration to a patient in need of such treatment of a therapeutically effective amount of a nociceptin receptor antagonist.
  • the urinary conditions that can be treated with a nociceptin receptor antagonist include overactive bladder, urgency, urge urinary incontinence, urinary frequency, nocturia, mixed urinary incontinence, stress urinary incontinence, and genuine stress urinary incontinence.
  • the terms "treating" or “treatment” include the palliative, curative and prophylactic treatment of the above conditions, as well as complications arising from the above conditions and other associated conditions, including lower urinary tract symptoms associated with benign prostatic hypertrophy.
  • overactive bladder refers to detrusor overactivity, i.e. overactivity of the bladder muscle. It includes the condition where the bladder contracts while it is filling.
  • incontinence or “urinary incontinence” refers to any involuntary leakage of urine.
  • Urge incontinence or "urge urinary incontinence” is the complaint of involuntary leakage accompanied by or immediately preceded by urgency.
  • frequency is the complaint by the patient who considers that he/she voids too often.
  • nocturia is the complaint that the individual has to wake at night one or more times to void.
  • stress incontinence or “stress urinary incontinence” (SUI) is the complaint of involuntary leakage upon anything that increases intraabdominal pressure, such as effort or exertion, sneezing or coughing.
  • mixed incontinence or “mixed urinary incontinence” refers to the case when a patient suffers from more than one form of urinary incontinence, e.g. stress incontinence and urge incontinence.
  • Overactive bladder can include symptoms of urgency, urge incontinence, frequency, nocturia, and/or mixed incontinence.
  • the nociceptin receptor antagonists preferably will have an IC 50 in a ligand binding assay of less than 100nM, more preferably an IC 50 of less than 10nM, even more preferably an IC 50 of less than 1 nM.
  • the IC 50 may be measured in a ligand binding assay, e.g. as described in Example 2, or in a functional assay, e.g. measuring the ability of the test compound to antagonise the inhibition of forskolin-stimulated cAMP formation (see e.g. Example 3b), or testing whether the test compound can inhibit agonist-stimulated binding of GTP ⁇ S (see, for example, Example 3a).
  • the nociceptin receptor antagonist will be at least 10 fold selective over the ⁇ opioid receptor, more preferably at least 100 fold selective over the ⁇ opioid receptor.
  • the nociceptin antagonist will be at least 10 fold selective over the K opioid receptor, more preferably at least 100 fold selective over the the K opioid receptor. More preferably the the nociceptin antagonist will be at least 10 fold selective over the ⁇ opioid receptor, more preferably at least 100 fold selective over the the ⁇ opioid receptor. More preferably, the nociceptin receptor antagonist will be at least 10 fold selective over ⁇ -, K- and ⁇ opioid receptors, even more preferably, the nociceptin receptor antagonist will be at least 100 fold selective over ⁇ -, K- and ⁇ opioid receptors.
  • Suitable nociceptin receptor antagonists include J-113397 (WO 98/54168; Kawamoto, H. et al (1999) J.Med.Chem. 42, 5061 -5063).
  • One aspect of the invention is the use of J- 113397 or a pharmaceutically acceptable salt or derivative thereof, in the preparation of a medicament for the treatment of urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress and mixed urinary incontinence, in particular overactive bladder, urgency, urge incontinence, frequency, nocturia and/or mixed urinary incontinence.
  • Suitable nociceptin receptor antagonists also include SB-612111 (Zaratin, P.F. et al. (2004) J Pharmacol Exp Ther, 308(2):454; WO 01/83454) and JTC-801 (WO 99/48492; Shinkai et al (2000) J. Med. Chem. 43, 4667-4677).
  • One aspect of the invention is the use of SB-612111 or JTC-801 or a pharmaceutically acceptable salt or derivative thereof, in the preparation of a medicament for the treatment of urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder, urgency, urge incontinence, frequency, nocturia and/or mixed urinary incontinence.
  • urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder, urgency, urge incontinence, frequency, nocturia and/or mixed urinary incontinence.
  • Suitable nociceptin receptor antagonists also include a compound of the following formula (la) or formula (lb), disclosed in US60/557598: (la)
  • R 1 and R 2 independently represent a hydrogen atom, a halogen atom or an alkyl group having from 1 to 3 carbon atoms;
  • R 3 (only in formula la) represents a hydrogen atom, a cycloalkyl group having from 3 to 6 carbon atoms, a tetrahydrofuranyl group, a tetrahydropyranyl group, an alkyl group having from 1 to 6 carbon atoms, which alkyl group is optionally substituted by 1 to 3 groups selected from a cyano group, a halogen atom, a hydroxy group, an alkoxy group having from 1 to 3 carbon atoms, an oxo group, an amino group and a mono- or di- alkylamino group each alkyl part having from 1 to 3 carbon atoms;
  • R 4 represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms; or (only in formula la) represents one of the following optionally substituted by 1 to 2 groups selected from an oxo group, a hydroxy group, a hydroxyalkyl group having from 1 to 3 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, an alkyl group having from 1 to 6 carbon atoms and an alkoxyalkyl group having a total of from 2 to 6 carbon atoms;
  • R 5 represents a phenyl group or a heteroaryl group and said heteroaryl group is a 5- to 6-membered hetero aromatic group having either from 1 to 4 ring nitrogen heteroatoms or 1 or 2 nitrogen ring heteroatoms and 1 oxygen or 1 sulfur ring heteroatom; said phenyl group and heteroaryl group are optionally substituted by 1 to 3 groups selected from a halogen atom, a hydroxy group, an alkyl group having from 1 to 3 carbon atoms
  • halogen means fluoro, chloro, bromo and iodo, preferably fluoro or chloro.
  • alkyl means straight or branched chain saturated radicals, including, but not limited to methyl, ethyl, n-propyl, /sopropyl.
  • alkoxy means alkyl-O-, including, but not limited to methoxy, ethoxy, ⁇ -propoxy, /sopropoxy.
  • alkanoyl means a group having carbonyl such as R'- C(O)- wherein R' is H, C 1-5 alkyl, phenyl or C 3 . 6 cycloalkyl, including, but not limited to formyl, acetyl, ethyl-C(O)-, n-propyl-C(O)-, /sopropyl-C(O)-, n-butyl-C(O)-, /so-butyl-
  • aryl means a monocyclic or bicyclic aromatic carbocyclic ring of 6 to 10 carbon atoms; including, but not limited to, phenyl or naphthyl, preferably phenyl.
  • cycloalkyl means a saturated carbocyclic radical ring of 3 to 6 carbon atoms, including, but not limited to, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • heteroaryl means a C-linked, hetero aromatic group having either from 1 to 4 ring nitrogen heteroatoms or 1 or 2 nitrogen ring heteroatoms and 1 oxygen or 1 sulfur ring heteroatom, including, but not limited to, pyrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, tetrazolyl, thiazolyl, isothiazolyl, imidazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrrolyl, thiophenyl, pyrazinyl, pyridazinyl, isooxazolyl, isothiazolyl, triazolyl, furazanyl, quinolyl, isoquinolyl, imidazopyridyl, benzimidazolyl, indolyl, and the like.
  • haloalkyl means an alkyl radical which is substituted by halogen atoms as defined above including, but not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2- trifluoroethyl, 2,2,2-trichloroethyl, 3-fluoropropyl, 4-fluorobutyl, chloromethyl, trichloromethyl, iodomethyl and bromomethyl groups and the like. Where the compounds of formula (la) or formula (lb) contain hydroxy groups, they may form esters.
  • esters examples include esters with a hydroxy group and esters with a carboxy group.
  • the ester residue may be an ordinary protecting group or a protecting group which can be cleaved in vivo by a biological method such as hydrolysis.
  • protecting group means a group, which can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis or photolysis.
  • Preferred compounds of formula (la) include:
  • Preferred compounds of formula (lb) include:
  • the compounds of formula la and lb of the present invention may be prepared according to known preparation methods, or General Procedures or preparation methods illustrated in the following reaction schemes. Unless otherwise indicated R 1 through R 6 and X, Y and n in the reaction schemes and discussion that follow are defined as above.
  • the term "protecting group”, as used hereinafter, means a hydroxy or amino protecting group which is selected from typical hydroxy or amino protecting groups described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1999); The following reaction schemes illustrate the preparation of compounds of formula
  • G represents a hydrogen atom or a hydroxy group.
  • R a represents an alkyl group having from 1 to 4 carbon atoms.
  • L 1 represents a leaving group. Examples of suitable leaving groups include: halogen atoms, such as chlorine, bromine and iodine; sulfonic esters such as TfO (triflates), MsO (mesylates), TsO (tosylates); and the like.
  • Step 1A In this step, a compound of the formula 1-2 in which L 1 represents a halogen atom can be prepared by the halogenating the compound of the formula 1-1 in which G represents a hydrogen atom under halogenation conditions with a halogenating reagent in a reaction-inert solvent.
  • suitable solvents include: tetrahydrofuran, 1 ,4-dioxane, N,N- dimethylformamide, acetonitrile; alcohols, such as methanol or ethanol; halogenated hydrocarbons, such as dichloromethane, 1 ,2-dichloroethane, chloroform or carbon tetrachloride and acetic acid.
  • Suitable halogenating reagents include, for example, bromine, chlorine, iodine, ⁇ /-chlorosuccimide, ⁇ /-bromosuccimide, 1 ,3-dibromo-5,5- dimethylhydantoin, bis(dimethylacetamide)hydrogen tribromide, tetrabutylammonium tribromide, bromodimethylsulfonium bromide, hydrogen bromide-hydrogen peroxide, nitrodibromoacetonitrile or copper(ll) bromide.
  • the reaction can be carried out at a temperature of from 0 °C to 200 °C, more preferably from 20 °C to 120 °C.
  • Reaction times are, in general, from 5 minutes to 48 hours, more preferably 30 minutes to 24 hours, will usually suffice.
  • the compound of the formula 1-2 in which L 1 represents a halogen atom or a sulfonic ester can also be prepared by the halogenating or sulfonating the compound of the formula 1-1 in which G represents a hydroxy group under conditions known to those skilled in the art.
  • the hydroxy group of the compound of formula 1 -1 may be converted to the halogen atom using a halogenating agent in the presence or absence of a reaction inert solvent.
  • halogenating agents include: chlorinating agents, such as thionyl chloride, oxalyl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride, hydrogen chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, or phosphorus reagents such as triphenylphosphine, tributyl phosphine or triphenylphosphite in the presence of halogen source such as carbon tetrachloride, chlorine, ⁇ /-chlorosuccinimide (NCS); brominating agents, such as hydrogen bromide, N- bromosuccinimide (NBS), phosphorus tribromide, trimethylsilyl bromide or phosphorus reagents such as triphenylphosphine, tributyl phosphine or triphenylphosphite in the presence of halogen
  • suitable solvents include: aliphatic hydrocarbons, such as hexane, heptane and petroleum ether; aromatic hydrocarbons, such as benzene, toluene, o-dichlorobenzene, nitrobenzene, pyridine, and xylene; halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1 ,2-dichloroethane; and ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and 1 ,4-dioxane.
  • aliphatic hydrocarbons such as hexane, heptane and petroleum ether
  • aromatic hydrocarbons such as benzene, toluene, o-dichlorobenzene, nitrobenzene, pyridine, and xylene
  • halogenated hydrocarbons such as dichloromethane, chloroform, carbon
  • This reaction may be carried out at a temperature in the range from -100 °C to 250 °C, more preferably from 0 °C to the reflux temperature for 1 minute to a day, more preferably from 20 minutes to 5 hours.
  • the hydroxy group of the compound of formula 1-1 may be converted to the sulfonate group using a sulfonating agent in the presence of, or absence of a base.
  • sulfonating agents include: p-toluenesulfonyl chloride, p- toluenesulfonic anhydride, methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, or the like in the presence or absence of a reaction- inert solvent.
  • Such bases include: an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, halide or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, potassium fluoride, sodium hydride or potassium hydride, or an amine such as triethylamine, tributylamine, diisopropylethylamine, pyridine or dimethylaminopyridine in the presence or absence of a reaction-inert solvent.
  • an alkali or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, potassium fluoride, sodium hydride or potassium hydride
  • an amine such as triethylamine, tributylamine, diisopropylethylamine, pyridine or
  • suitable solvents include: aliphatic hydrocarbons, such as hexane, heptane and petroleum ether; aromatic hydrocarbons, such as benzene, toluene, o- dichlorobenzene, nitrobenzene, pyridine, and xylene; halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride and 1 ,2-dichloroethane; and ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and 1 ,4-dioxane; N,N- dimethylformamide, and dimethylsulfoxide.
  • aliphatic hydrocarbons such as hexane, heptane and petroleum ether
  • aromatic hydrocarbons such as benzene, toluene, o- dichlorobenzene, nitrobenzene, pyridine, and xylene
  • Step 1 B a compound of formula 1-4 can be prepared by the alkylation of a compound of formula 1 -3 with the alkylating agent 1-2 in the presence of a base in a reaction-inert solvent.
  • suitable solvents include: tetrahydrofuran, N,N- dimethylformamide, dimethylsulfoxide, diethylether, toluene, ethylene glycol dimethylether generally or 1 ,4-dioxane.
  • Suitable bases include: alkyl lithiums, such as n-butyllithium, seo-butyllithium or tert-butyllithium; aryllithiums, such as phenyllithium or lithium naphtilide; methalamide such as sodium amide or lithium diisopropylamide; and alkali metal, such as potassium hydride or sodium hydride.
  • This reaction may be carried out at a temperature in the range from -50 °C to 200 °C, usually from -10 °C to 100 °C for 5 minutes to 72 hours, usually 30 minutes to 36 hours.
  • a compound of formula 1-6 can be prepared by the aldol condensation of a compound of formula 1-3 with an aldehyde compound 1 -5 in the presence of a base in a reaction-inert solvent.
  • suitable solvents include: tetrahydrofuran, N,N- dimethylformamide, dimethylsulfoxide, ether, toluene, ethylene glycol dimethylether or 1 ,4-dioxane.
  • Suitable bases include: lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, thallium(l) carbonate, sodium ethoxide, potassium terf-butoxide, potassium acetate, cesium fluoride, tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium iodide, pyridine, picoline, 4- ( ⁇ /, ⁇ /-dimethylamino)pyridine, triethylamine, tributylamine, diisopropylethylamine, N- methylmorphorine and ⁇ /-methylpiperidine.
  • Step 1 D the compound of formula 1 -4 can be prepared by the reduction of the olefin compound of formula 1-6 with a reducing agent in an inert solvent.
  • suitable solvents include: methanol, ethanol, ethyl acetate, tetrahydrofuran (THF) or mixtures thereof.
  • the reduction may be carried out under known hydrogenation conditions in the presence of a metal catalyst, e.g.
  • nickel catalysts such as Raney nickel, palladium catalysts such as Pd-C, platinum catalysts such as Pt ⁇ 2, or ruthenium catalysts such as RuCl2 ( h3P)3 under hydrogen atmosphere or in the presence of hydrogen sources such as hydrazine or formic acid.
  • the reaction is carried out under acidic conditions, e.g. in the presence of hydrochloric acid or acetic acid. This reaction may be carried out at a temperature in the range from -50 °C to 200 °C, usually from -10 °C to 100 °C for 5 minutes to 72 hours, usually 30 minutes to 36 hours.
  • a compound of formula 1-7 can be prepared by Horner-Emmons reaction of the compound of formula 1 -4 with formaldehyde or paraformaldehyde in the presence of a base in a reaction-inert solvent.
  • suitable solvents include: tetrahydrofuran, ⁇ /, ⁇ /-dimethylformamide, dimethylsulfoxide, diethylether, toluene, ethylene glycol dimethylether, water or 1 ,4-dioxane.
  • Suitable bases include: lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, thallium(l) carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, potassium hydride or sodium hydride. This reaction may be carried out at a temperature in the range from 0 °C to 200 °C, usually from 50 °C to 150 °C for 5 minutes to 72 hours, usually 30 minutes to 50 hours.
  • a compound of formula 1 -10 can be prepared by Michael reaction of a compound of formula 1 -8 with an enone compound of formula 1 -9 in the presence of a base in a reaction-inert solvent.
  • suitable solvents include: acetonitrile, tetrahydrofuran, ⁇ /, ⁇ /-dimethylformamide, dimethylsulfoxide, ether, toluene, ethylene glycol dimethylether, water or 1 ,4-dioxane.
  • Suitable bases include: triethylamine, tributylamine, diisopropylethylamine, pyridine, picoline, N- methylmorphorine and ⁇ /-methylpiperidine, sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate.
  • This reaction may be carried out at a temperature in the range from 0 °C to 200 °C, usually from 25 °C to 100 °C for 5 minutes to 60 hours, usually 30 minutes to 30 hours.
  • Step l G In this step, a compound of formula 1 -11 can be prepared by the alkylation of a compound of formula 1-10 with the alkylating agent 1 -2 in the presence of a base in a reaction-inert solvent.
  • suitable solvents include: tetrahydrofuran, diethylether, toluene, ethylene glycol dimethylether generally or 1 ,4-dioxane.
  • suitable bases include: lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, methalamide such as sodium amide or lithium diisopropylamide; and alkali metal, such as potassium hydride or sodium hydride.
  • this reaction may be carried out in the presence or absence of an additive such as ⁇ /,/V'-dimethylpropyleneurea (DMPU), hexamethylphosphoramide (HMPA), N,N,N',N'- tetramethylethylenediamine (TMEDA).
  • DMPU ⁇ /,/V'-dimethylpropyleneurea
  • HMPA hexamethylphosphoramide
  • TEDA N,N,N',N'- tetramethylethylenediamine
  • This reaction may be carried out at a temperature in the range from -100 °C to 200 °C, usually from -80 °C to 100 °C for 5 minutes to 72 hours, usually 30 minutes to 36 hours.
  • Step 1 H the compound of formula 1-11 can be prepared by Michael reaction of the compound of formula 1-8 with the enone compound of formula 1 -7 in the presence or absence of a base in a reaction-inert solvent.
  • Suitable solvents include: methanol, ethanol, tetrahydrofuran, ⁇ /, ⁇ /-dimethylformamide, dimethylsulfoxide, diethylether, toluene, ethylene glycol dimethylether, water or 1 ,4-dioxane.
  • suitable bases include: triethylamine, tributylamine, diisopropylethylamine, pyridine, picoline, ⁇ /-methylmorphorine and ⁇ /-methylpiperidine. This reaction may be carried out at a temperature in the range from 0 °C to 200 °C, usually from 25 °C to 100 °C for 1 hour to 2 weeks, usually 5 hours to 10 days.
  • an acid compound of formula 1-12 may be prepared by hydrolysis of the ester compound of formula 1-11 in a solvent.
  • the hydrolysis may be carried out by conventional procedures. In a typical procedure, the hydrolysis carried out under the basic condition, e.g. in the presence of sodium hydroxide, potassium hydroxide or lithium hydroxide.
  • Suitable solvents include, for example, alcohols such as methanol, ethanol, propanol, butanol, 2-methoxyethanol, and ethylene glycol; ethers such as tetrahydrofuran (THF), 1 ,2-dimethoxyethane (DME), and 1 ,4-dioxane; amides such as ⁇ /, ⁇ /-dimethylformamide (DMF) and hexamethylphospholictriamide; and sulfoxides such as dimethyl sulfoxide (DMSO).
  • This reaction may be carried out at a temperature in the range from -20 °C to 100 °C, usually from 20 °C to 75 °C for 30 minutes to 48 hours, usually 60 minutes to 30 hours.
  • the hydrolysis may also be carried out under the acidic condition, e.g. in the presence of hydrogen halides, such as hydrogen chloride and hydrogen bromide; sulfonic acids, such as p-toluenesulfonic acid and benzenesulfonic acid; pyridium p- toluenesulfonate; and carboxylic acid, such as acetic acid and trifluoroacetic acid.
  • hydrogen halides such as hydrogen chloride and hydrogen bromide
  • sulfonic acids such as p-toluenesulfonic acid and benzenesulfonic acid
  • pyridium p- toluenesulfonate such as acetic acid and trifluoroacetic acid.
  • Suitable solvents include, for example, alcohols such as methanol, ethanol, propanol, butanol, 2-methoxyethanol, and ethylene glycol; ethers such as tetrahydrofuran (THF), 1 ,2-dimethoxyethane (DME), and 1 ,4-dioxane; halogenated hydrocarbons, such as dichloromethane, 1 ,2-dichloroethane, amides such as ⁇ /, ⁇ /-dimethylformamide (DMF) and hexamethylphospholictriamide; and sulfoxides such as dimethyl sulfoxide (DMSO).
  • alcohols such as methanol, ethanol, propanol, butanol, 2-methoxyethanol, and ethylene glycol
  • ethers such as tetrahydrofuran (THF), 1 ,2-dimethoxyethane (DME), and 1 ,4-dioxane
  • an amide compound of formula (la) may be prepared by the coupling reaction of an amine compound of formula 1 -13 with the acid compound of formula 1-12 in the presence or absence of a coupling reagent in an inert solvent. If desired, this reaction may be carried out in the presence or absence of an additive such as 1 -hydoroxybenzotriazole (HOBt) or 1 -hydroxyazabenzotriazole.
  • an additive such as 1 -hydoroxybenzotriazole (HOBt) or 1 -hydroxyazabenzotriazole.
  • Suitable solvents include: acetone, nitromethane, ⁇ /, ⁇ /-dimethylformamide (DMF), sulfolane, dimethyl sulfoxide (DMSO), 1- methyl-2-pirrolidinone (NMP), 2-butanone, acetonitrile; halogenated hydrocarbons, such as dichloromethane, 1 ,2-dichloroethane, chloroform; and ethers, such as tetrahydrofuran and 1 ,4-dioxane.
  • DMF ⁇ /, ⁇ /-dimethylformamide
  • DMSO dimethyl sulfoxide
  • NMP 1- methyl-2-pirrolidinone
  • 2-butanone 2-butanone
  • halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform
  • ethers such as tetrahydrofuran and 1 ,4-dioxane.
  • Suitable coupling reagents are those typically used in peptide synthesis including, for example, diimides (e.g., dicyclohexylcarbodiimide (DCC), water soluble carbodiimide (WSC)), O-benzotriazol-1 - yl- ⁇ /, /, ⁇ /', ⁇ /'-tetramethyluronium hexafluorophosphate (HBTU), 2-ethoxy- ⁇ /- ethoxycarbonyl-1 ,2-dihydroquinoline, 2-bromo-1 -ethylpyridinium tetrafluoroborate (BEP), 2-chloro-1 ,3-dimethylimidazolinium chloride, benzotriazol-1 -yloxy- tris(DCC), water soluble carbodiimide (WSC)), O-benzotriazol-1 - yl- ⁇ /, /, ⁇ /', ⁇ /'-tetramethyluronium hexafluor
  • the reaction may be carried out in the presence of a base such as, ⁇ /, ⁇ /-diisopropylethylamine, N- methylmorpholine, 4-(dimethylamino)pyridine and triethylamine.
  • a base such as, ⁇ /, ⁇ /-diisopropylethylamine, N- methylmorpholine, 4-(dimethylamino)pyridine and triethylamine.
  • the amide compound of formula (I) may be formed via an acylhalide, which may be obtained by the reaction with halogenating agents such as oxalylchloride, phosphorus oxychloride and thionyl chloride.
  • the resulting acylhalide may be converted to the corresponding amide compound by treating with the amine compound of formula 1-13 under the similar conditions as described in this step.
  • Step 2A a compound of formula 2-2 may be prepared by Michael reaction of the compound of formula 1-8 with an enone compound of formula 2-1. This reaction is essentially the same as and may be carried out in the same manner as and using the same reagents and reaction conditions as Step 1 H in Scheme 1.
  • Step 2B an acid compound of formula 2-3 may be prepared by hydrolysis of the compound of formula 2-2. This reaction is essentially the same as and may be carried out in the same manner as and using the same reagents and reaction conditions as Step 11 in Scheme 1.
  • Step 2C In this step, an amide compound of formula 2-4 may be prepared by coupling of the amine compound of formula 1 -13 with the acid compound of formula 2-3.
  • Step 2D the compound of formula 2-4 may be converted to a compound with a leaving group L 1 of formula 2-5 under conditions known to those skilled in the art.
  • This reaction is essentially the same as and may be carried out in the same manner as and using the same reagents and reaction conditions as Step 1 A in Scheme 1.
  • Step 2E the compound of formula (I) can be prepared by replacement of the leaving group of the compound of formula 2-5 with a compound of formula R 5 H in the presence of a base in a reaction-inert solvent.
  • Suitable solvents include: acetonitrile, tetrahydrofuran, /, ⁇ /-dimethylformamide, dimethylsulfoxide, ether, toluene, ethylene glycol dimethylether or 1 ,4-dioxane.
  • Suitable bases include: lithium hydroxide, sodium hydroxide, potassium hydroxide, barium- hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, thallium(l) carbonate, sodium ethoxide, potassium tert-butoxide, potassium acetate, cesium fluoride, tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium iodide, pyridine, picoline, 4-( ⁇ /,/V-dimethylamino)pyridine, triethylamine, tributylamine, diisopropylethylamine, ⁇ /-methylmorphorine and N- methylpiperidine. This reaction may be carried out at a temperature in the range from 0 °C to 250 °C, usually from -10 °C to 150 °C for 5 minutes to 72 hours, usually 30 minutes to 36 hours.
  • Step 3A the compound of formula 2-2 may be converted to a compound with a leaving group L 1 of formula 3-1 under conditions known to those skilled in the art. This reaction is essentially the same as and may be carried out in the same manner as and using the same reagents and reaction conditions as Step 2D in Scheme 2.
  • Step 3B a compound of formula 3-2 can be prepared by replacement of the leaving group of the compound of formula 3-1 with the compound of formula R 5 H. This reaction is essentially the same as and may be carried out in the same manner as and using the same reagents and reaction conditions as Step 2E in Scheme 2.
  • Step 3C a compound of formula 3-3 may be prepared by hydrolysis of the compound of formula 3-2.
  • This reaction is essentially the same as and may be carried out in the same manner as and using the same reagents and reaction conditions as Step 11 in Scheme 1.
  • Step 3D In this step, which applies only to the preparation of compounds of formula (la), the compound of formula (la) may be prepared by coupling of the amine compound of formula 1 -13 with the acid compound of formula 3-3.
  • This reaction is essentially the same as and may be carried out in the same manner as and using the same reagents and reaction conditions as Step 1 J in Scheme 1.
  • suitable solvents include a mixture of any two or more of those solvents described in each step.
  • the starting materials in the aforementioned general syntheses are commercially available or may be obtained by conventional methods known to those skilled in the art.
  • the compounds of formula (I), and the intermediates above-mentioned preparation methods can be isolated and purified by conventional procedures, such as recrystallization or chromatographic purification.
  • the various general methods described above may be useful for the introduction of the desired groups at any stage in the stepwise formation of the required compound, and it will be appreciated that these general methods can be combined in different ways in such multi-stage processes.
  • the sequence of the reactions in multi-stage processes should of course be chosen so that the reaction conditions used do not affect groups in the molecule which are desired in the final product.
  • Suitable nociceptin receptor antagonists also include compounds of formula (II) as claimed in WO 03/064425:
  • R 12a and R 13a taken together with the three ring atoms of the dihydro- or tetrahydroquinoline ring separating said substituents form a five to seven membered ring which is partially or fully unsaturated, wherein the ring atom not shared with the dihydro- or tetrahydroquinoline ring and adjacent to the nitrogen atom in the dihydro- or tetrahydroquinoline ring is a carbon atom; the remaining one to three ring atoms not shared with the dihydro- or tetrahydroquinoline ring are carbon atoms, one of said carbon atoms being optionally replaced with a nitrogen, oxygen or sulfur atom; and one or two of the carbon and nitrogen atoms not shared with the dihydro- or tetrahydro- quinoline ring are optionally substituted with substituents independently selected from oxo; hydroxy; (d-C 6 )alkyl; (C C 6 )alkyl substituted with one to five
  • Preferred nociceptin receptor antagonists are compounds of formula (II) wherein both R 14a and R 15a are hydrogen.
  • Other preferred nociceptin receptor antagonists are compounds wherein R 14a and R 15a taken together form oxo.
  • nociceptin receptor antagonists are compounds of formula (II) wherein R a , R a , R 3a and R 4a are all hydrogen.
  • nociceptin receptor antagonists are compounds of formula (II) wherein R 5a , R 6a , R 7a and R 8a are all hydrogen.
  • nociceptin receptor antagonists are compounds of formula (II) wherein
  • nociceptin receptor antagonists of formula (II) are selected from: 2,3-dihydro-1 '-[(2-oxo-1 ,2,3,4-tetrahydro-3-quinolinyl)methyl]spiro[1 H-indene-1 ,4'- piperidine];
  • X 1b represents an oxygen atom; or N-R 12b wherein R 12b is selected from the group consisting of a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkanoyl group having 1 to 6 carbon atoms, an alkylaminocarbonyl group having 1 to 6 carbon atoms in the alkyl group, an aryl group as defined below, an arylalkyl group having 1 to 6 carbon atoms in the alkyl part and the aryl part as defined below, a heteroaryl group as defined below and a heteroarylalkyl group having 1 to 6 carbon atoms in the alkyl part and heteroaryl part as defined below;
  • R 1 and R 2 each independently represent a hydrogen atom; an alkyl group having 1 to 6 carbon atoms; an alkoxy group having 1 to 6 carbon atoms; an alkanoyl group having 1 to 6 carbon atoms; an alkylcarbonylamino group having 1 to 6 carbon atoms in the alkyl part; an alkylaminocarbonyl group having 1 to 6 carbon atoms in the alkyl part; a mono-hydroxyalkyl group having 1 to 6 carbon atoms; a mono-aminoalkyl having 1 to 6 carbon atoms; or an alkoxyalkyl group having 1 to 6 carbon atoms in the alkoxy group and 1 to 6 carbon atoms in the alkyl part; or R 1b and R 2b taken together form oxo;
  • R 3b , R 45 , R 5b and R 6b each independently represent a hydrogen atom; a halogen atom; a hydroxy group; an alkyl group having 1 to 6 carbon atoms; an alkoxy group having 1 to 6 carbon atoms; an alkanoyl group having 1 to 6 carbon atoms; a mono-hydroxyalkyl group having 1 to 6 carbon atoms; a mono-aminoalkyl group having 1 to 6 carbon atoms; an alkylcarbonylamino group having 1 to 6 carbon atoms in the alkyl part; an alkylaminocarbonyl group having 1 to 6 carbon atoms in the alkyl part; an alkylaminosulfonyl group having 1 to 6 carbon atoms in the alkyl part; an aryl group as defined below which is linked directly to the benzene ring or is attached via a spacer group to the benzene ring, and the spacer group is defined as below; or a heteroaryl group as
  • R 7b and R 8b both represent hydrogen atoms or taken together form oxo
  • R 9b , R 10 and R 11b each independently represent a hydrogen atom, a halogen atom or an alkyl group having 1 to 6 carbon atoms;
  • X 2 , X 3b and X 4 each independently represent methylene, an oxygen atom, NR 13b , where R 3b is defined as a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, or carbonyl, provided that at least one of X 2b , X 3b and X 4 must represent methylene or carbonyl; or
  • X 4b represents a bond and X 2 and X 3b each independently represent methylene, an oxygen atom, NR 13b , where R 13b is defined as a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, carbonyl, provided that at least one of X 2b and X 3b must be methylene or carbonyl;
  • methylene in the definitions of X 2b , X 3b and X is each independently unsubstituted or substituted by at least one alkyl groups having 1 to 6 carbon atoms;
  • X 5b represents a -CR 14b or a nitrogen atom wherein R 14b represents a hydrogen atom, a halogen atom or an alkyl group having 1 to 6 carbon atoms; Said amino parts of the alkylcarbonylamino groups and alkylaminocarbonyl groups in the definitions of R 1b through R 6 and R 12b are unsubstituted or substituted by an alkyl group having 1 to 6 carbon atoms;
  • Said aryl groups and aryl parts of aralkyl groups referred to in the definitions of R 1 through R 6b and R 12b are aromatic hydrocarbon groups having 5 to 14 carbon atoms;
  • Said heteroaryl groups and heteroaryl parts of the heteroarylalkyl groups referred to in tthhee ddeeffiinniittiioonnss ooff RR 33bb tthhrroouugghh RR 66bb aanndd RR 11 aarree 55-- ttoo 77-- ⁇ membered heteroaryl groups containing 1 to 3 oxygen, sulfur and/or nitrogen atoms; and SSaaiidd ssppaacceerr ggrroouuppss rreeffeerrrreedd ttoo iinn tthhee ddeeffiinniittiioonnss ooff RR 11bb aamnd R 2 are
  • Suitable compounds of formula (III) are selected from:
  • nociceptin receptor antagonists are included in patent application WO 03/000677, preferably the compounds exemplified in WO 03/000677, or a pharmaceutically acceptable salt or solvate thereof.
  • nociceptin receptor antagonists can be found in WO 03/095432, especially the preferred compounds listed in WO 03/095432, such as:
  • Suitable nociceptin receptor antagonists can also be found in patent applications WO 98/54168, US 6,258,825, WO 99/29696, WO 00/31061 , WO 00/34280, WO 01/012195, WO 01/32178, WO 01/036418, WO 01/83454, WO 02/40019, WO 02/088089, WO 02/26714, WO 02/090317, WO 02/090330, WO 03/008371 , WO 03/095427, WO 04/022558, WO 04/058248, WO 05/001693, WO 05/005411 , EP 963985, EP 963987, EP 970957, JP 2000
  • Yet a further aspect of the invention is a method of screening for compounds useful for treating urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder, urgency, urge incontinence, frequency, nocturia and/or mixed urinary incontinence, comprising screening compounds for antagonist activity against the nociceptin receptor, and selecting compounds with an IC 50 of less than 100nM, preferably with an IC 50 of less than 10nM, even more preferably with an IC 50 of less than 1 nM.
  • Another aspect of the invention is a process for providing a medicament for the treatment of urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder, urgency, urge incontinence, frequency, nocturia and/or mixed urinary incontinence, comprising the following steps:
  • step (b) selecting a compound with an IC 50 of less than 100 nM; (c) formulating a compound with the same structure as that selected in step (b), or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier or excipient; the process may also comprise the additional steps of:
  • step (d) packaging the formulation of step (c);
  • step (e) making the package of step (d) available to a patient suffering from a urinary condition mentioned above.
  • the compound selected in step (b) will have an IC 50 of less than 10nM, even more preferably it will have an IC 50 of less than 1 nM.
  • Yet another aspect of the invention is a process for providing a medicament for the treatment of urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder, urgency, urge incontinence, frequency, nocturia and/or mixed urinary incontinence, comprising the following steps:
  • step (c) formulating a compound with the same structure as that selected in step (b), or a pharmaceutically acceptable carrier or excipient; the process may also comprise the additional steps of:
  • step (d) packaging the formulation of step (c); and (e) making the package of step (d) available to a patient suffering from a urinary condition mentioned above.
  • the assay in step (a) measures the inhibition of the nociceptin receptor agonist-mediated inhibition of forskolin-stimulated cAMP responses. Even more preferably, the assay in step (a) measures the inhibition of agonist-stimulated GTP ⁇ S binding.
  • the compound selected in step (b) will have an IC 50 of less than 10 nM, even more preferably it will have an IC 50 of less than 1 nM.
  • Another aspect of the invention is a process for preparing a medicament for the treatment of urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder, urgency, urge incontinence, frequency, nocturia and/or mixed urinary incontinence, comprising the steps of (a) testing compounds in a ligand binding assay against nociceptin receptor or testing compounds in an assay, measuring inhibition of the agonist stimulated second messenger response of the nociceptin receptor; (b) identifying one or more compounds capable of antagonising the nociceptin receptor with an IC 5 o of less than 100nM; and (c) preparing a quantity of those one or more identified compounds.
  • the compound(s) selected in step (b) will have an IC 50 of less than 10 nM, even more preferably it/they will have an IC 50 of less than 1 nM.
  • Another aspect of the invention is a method of preparing a composition for treating a urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder, urgency, urge incontinence, frequency, nocturia and/or mixed urinary incontinence, which comprises: (a) identifying a compound which specifically binds to the nociceptin receptor by a method which comprises contacting cells expressing the nociceptin receptor or membranes prepared from such cells with a radiolabelled nociceptin receptor ligand in the presence or absence of a test compound, measuring the radioactivity bound to the cells or membranes, comparing the radioactivity bound to the cells or membranes in the presence and absence of test compound, whereby a compound which causes a reduction in the radioactivity bound is a compound specifically binding to the nociceptin receptor; and (b) admixing said compound with a carrier.
  • a urinary conditions such as overactive bladder, urgency, urge incon
  • Yet another aspect of the invention is a method of preparing a composition for treating urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder, urgency, urge incontinence, frequency, nocturia and/or mixed urinary incontinence, which comprises: (a) identifying a compound which specifically binds to and inhibits the activation of the nociceptin receptor by a method which comprises separately contacting cells expressing the nociceptin receptor on their surface and producing a second messenger response in response to a nociceptin receptor agonist, e.g.
  • nociceptin or a membrane preparation of such cells, with both the compound and an agonist of nociceptin receptor, and with only the agonist, under conditions suitable for activation of the nociceptin receptor, and measuring the second messenger response in the presence of only the agonist for the nociceptin receptor and in the presence of the agonist and the compound, a smaller change in the second messenger response in the presence of both agonist and compound than in the presence of the agonist only indicating that the compound inhibits the activation of the nociceptin receptor; and (b) admixing said compound with a carrier.
  • the invention relates to the use of a nociceptin receptor antagonist for the treatment of urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder, urgency, urge incontinence, frequency, nocturia and/or mixed urinary incontinence alone, or in combination with one or more other agents such as
  • Alpha adrenergic receptor agonist or partial agonist • Serotonin and Noradrenalin reuptake inhibitor (SNRI)
  • 5HT2C agonist see WO 04/096196
  • alpha2delta ligand such as gabapentin or pregabalin.
  • Reference to a compound, an antagonist, an agonist or an inhibitor shall at all times be understood to include all active forms of such agents, including the free form thereof (e.g. the free and/or base form) and also all pharmaceutically acceptable salts, polymorphs, hydrates, silicates, stereo-isomers (e.g. diastereoisomers and enantiomers) and so forth. Active metabolites of any of the compounds, in any form, are also included.
  • compositions of the compounds for either oral delivery or for topical application are included in the invention.
  • a formulation comprising a compound or combination of compounds as defined herein, preferably a formulation which is a creme or a gel, is also included in the invention.
  • the nociceptin receptor was first identified as an orphan G-protein coupled receptor with sequence homology to opioid receptors, and was named opioid receptor-like- 1 (ORL-1 ) (see Mollereau, C. et al (1994) FEBS Lett. 341 , 33-38). It was later identified as the receptor for nociceptin (Meunier, J-C et al (1995) Nature 377, 532-535; Reinscheid, R.K. et al (1995) Science 270, 792-794), and has also been called Orphanin FQ receptor.
  • ORL-1 opioid receptor-like- 1
  • ORL-1 receptors may also be used in the methods of the invention, including rat, mouse (Nishi, M et al (1994) Biochem Biophys Res Comms 205, 1353-1357), guinea pig (SwissProt accession P47748), pig (Osinski, M et al (1999) Eur J Pharmacol 365, 281 -289; SwissProt accession P79292), and others.
  • amino acid sequence is synonymous with the term “polypeptide” and/or the term “protein”. In some instances, the term “amino acid sequence” is synonymous with the term “peptide”. In some instances, the term “amino acid sequence” is synonymous with the term “protein”.
  • a homologous sequence is taken to include an amino acid sequence which may be at least 75, 85 or 90% identical to the amino acid sequence of the human nociceptin receptor sequence shown in Mollereau, C. et al ((1994) FEBS Lett. 341 , 33-38), preferably at least 95 or 98% identical.
  • homology should typically be considered with respect to those regions of the sequence known to be essential for an activity.
  • homology can also be considered in terms of similarity (i.e. amino acid residues having similar chemical properties/functions), in the context of the present invention it is preferred to express homology in terms of sequence identity.
  • sequence homology/identity can be easily assessed by publicly or commercially available bioinformatics software, such as Blast2 (Altschul, S.F. et al (1997) Nucl. Acids Res. 25, 3389-3402), or programs included in the GCG software package (Devereux et al (1984) Nucl. Acids Res. 12, 387; Wisconsin Package Version 10, Genetics Computer Group (GCG, Madison, Wisconsin), such as Bestfit or Gap. In most cases, the default parameters offered by the software, e.g. Bestfit or Gap, for Gap Penalties etc. are suitable for this assessment.
  • “Potency” as used herein is a measure of how effective a compound is at producing the desired response and can be expressed in terms of the concentration of compound which produces a particular level of the response attainable.
  • Affinity as used herein is a measure of how well a compound binds to or becomes associated with a receptor.
  • the affinity of a compound can be determined in a binding assay as described in Example 2 herein, and affinity in this context will refer to the IC 50 of the compound, i.e. to the concentration inhibiting 50% of the labelled compound from binding to the receptors, or to the Ki, which is the inhibition constant of the compound and can be calculated from the IC 50 , or can also refer to the K D , which is the dissociation constant of the compound.
  • the potency of a compound is related to its affinity but can also be determined in a functional assay such as an assay measuring the ability of the test compound to antagonise agonist-induced inhibition of forskolin-stimulated cAMP production, or agonist induced GTP ⁇ S formation (Example 3 herein), both of which will provide a functional measure of antagonist affinity/potency.
  • Potency could also, although not exclusively, be defined using an anaesthetised animal model to test the effect of compounds on bladder capacity as described in Example 1 herein.
  • the potency/efficacy in this case could refer to the ED 50 of the compound, i.e. the administered dose which shows 50% of the maximal response to that or another nociceptin receptor antagonist compound, or could refer to the dose of compound required to elicit a defined increase in bladder capacity or a defined change in any other measurable urological parameter.
  • “Selectivity” as used herein is a measure of the relative potency of a drug between two receptor subtypes for the same ligand. This can be determined in binding assays, e.g. as described in Example 2 herein, or in functional assays, e.g. as described in Example 3 herein.
  • the term "compound” may refer to a chemical or biological agent, and includes, for example, antibodies, antibody fragments, other proteins, peptides, sugars, any organic or inorganic molecules.
  • Compounds that may be used for screening include, but are not limited to, peptides such as, for example, soluble peptides, including but not limited to members of random peptide libraries; (see, e.g.,
  • antibodies including, but not limited to, polyclonal, monoclonal, humanized, anti-idiotypic, chimeric or single chain antibodies, and Fab, F(ab') 2 and Fab expression library fragments, and epitope-binding fragments thereof), and small organic or inorganic molecules.
  • nociceptin receptor e.g. one corresponding to extracellular loops or the extracellular domain
  • truncated nociceptin receptor polypeptides nociceptin receptor in which one or more domains, e.g. the transmembrane domain or cellular domain, has been deleted
  • functional equivalents of nociceptin receptor or mutants of nociceptin receptor e.g. the transmembrane domain or cellular domain
  • Such host animals may include but are not limited to rabbits, mice, hamsters, rats, goats, sheep, to name but a few.
  • Various adjuvants may be used to increase the immunological response, depending on the host species, including but not limited to Freund's (complete and incomplete), mineral gels such as aluminum hydroxide, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanin, dinitrophenol, and potentially useful human adjuvants such as BCG (bacille Calmette-Guerin) and Corynebacterium patvum.
  • Polyclonal antibodies are heterogeneous populations of antibody molecules derived from the sera of the immunized animals.
  • Monoclonal antibodies which are homogeneous populations of antibodies to a particular antigen, may be obtained by any technique which provides for the production of antibody molecules by continuous cell lines in culture. These include, but are not limited to, the hybridoma technique of Kohler and Milstein, ((1975) Nature 256, 495-497 and U.S. Patent No. 4,376,110), the human B-cell hybridoma technique (Kosbor et al. (1983) Immunology Today 4, 72; Coie et al. (1983) Proc. Natl. Acad. Sci. USA 80, 2026-2030), and the EBV-hybridoma technique (Cole et al. (1985) Monoclonal Antibodies And Cancer Therapy, Alan R.
  • Such antibodies may be of any immunoglobulin class including IgG, IgM, IgE, IgA, IgD and any subclass thereof.
  • the hybridoma producing the mAb of this invention may be cultivated in vitro or in vivo. Production of high titers of mAbs in vivo makes this the presently preferred method of production.
  • chimeric antibodies In addition, techniques developed for the production of "chimeric antibodies" (Morrison et al. (1984) Proc. Natl. Acad. Sci., 81 , 6851-6855; Neuberger et al. (1984) Nature, 312, 604-608; Takeda et al. (1985) Nature, 314, 452-454) by splicing the genes from a mouse antibody molecule of appropriate antigen specificity together with genes from a human antibody molecule of appropriate biological activity can be used.
  • a chimeric antibody is a molecule in which different portions are derived from different animal species, such as those having a variable region derived from a murine mAb and a human immunoglobulin constant region.
  • single chain antibodies can be adapted to produce single chain antibodies against nociceptin receptor gene products.
  • Single chain antibodies are formed by linking the heavy and light chain fragments of the Fv region via an amino acid bridge, resulting in a single chain polypeptide.
  • Antibody fragments which recognize specific epitopes may be generated by known techniques.
  • such fragments include but are not limited to: the F(ab') 2 fragments which can be produced by pepsin digestion of the antibody molecule and the Fab fragments which can be generated by reducing the disulfide bridges of the F(ab') 2 fragments or by papain digestion of antibody molecules.
  • Fab expression libraries may be constructed (Huse et al. (1989) Science, 246, 1275-1281 ) to allow rapid and easy identification of monoclonal Fab fragments with the desired specificity.
  • Antibodies to nociceptin receptor may also be obtained by generating anti-idiotype antibodies against a nociceptin receptor ligand, e.g. nociceptin itself, using techniques well known to those skilled in the art (see, e.g. Greenspan & Bona (1993) FASEB J 7, 437-444; and Nissinoff (1991 ) J. Immunol. 147, 2429-2438).
  • nociceptin receptor antagonist can be readily determined by evaluation of their potency and selectivity using methods such as those disclosed herein, followed by evaluation of their toxicity, pharmacokinetics (absorption, metabolism, distribution and elimination), etc in accordance with standard pharmaceutical practice.
  • Suitable compounds are those that are potent and selective, have no significant toxic effect at the therapeutic dose, and preferably are bioavailable following oral administration.
  • Oral bioavailablity refers to the proportion of an orally administered drug that reaches the systemic circulation.
  • the factors that determine oral bioavailability of a drug are dissolution, membrane permeability and hepatic clearance.
  • a screening cascade of firstly in vitro and then in vivo techniques is used to determine oral bioavailablity.
  • the solubilisation of the drug by the aqueous contents of the gastro-intestinal tract can be predicted from in vitro solubility experiments conducted at appropriate pH to mimic the GIT.
  • the nociceptin receptor antagonists Preferably have a minimum solubility of 50 ⁇ g/ml. Solubility can be determined by standard procedures known in the art such as described in Lipinski CA et al.; Adv. Drug Deliv. Rev. 23(1-3), 3-25, 1997.
  • Membrane permeability refers to the passage of a compound through the cells of the
  • the nociceptin receptor antagonists have a Log D 74 of -2 to +4, more preferably -1 to +3.
  • the Log D can be determined by standard procedures known in the art such as described in Stopher, D and McClean, S; J. Pharm. Pharmacol. 42(2), 144, 1990.
  • the nociceptin receptor antagonists have a Caco-2 flux of greater than 2x10 "6 cms '1 , more preferably greater than 5x10 '6 cms "1 .
  • the Caco-2 flux value can be determined by standard procedures known in the art such as described in Artursson, P and Magnusson, C; J. Pharm. Sci, 79(7), 595-600, 1990.
  • Metabolic stability addresses the ability of the GIT to metabolise compounds during the absorption process or the liver to do so immediately post-absorption: the first pass effect.
  • Assay systems such as microsomes, hepatocytes etc are predictive of metabolic lability.
  • Preferably nociceptin receptor antagonists show metabolic stability in the assay system that is commensurate with an hepatic extraction of less then 0.5. Examples of assay systems and data manipulation are described in Obach, RS; Curr. Opin. Drug Disc. Devel. 4(1 ), 36-44, 2001 and Shibata, Y et al.; Drug Met. Disp. 28(12), 1518-1523, 2000.
  • the compounds of the invention can be administered alone but will generally be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • the compounds of the invention can be administered orally, buccally or sublingually in the form of tablets, capsules, multi-particulates, gels, films, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.
  • the compounds of the invention may also be administered as fast-dispersing or fast- dissolving dosage forms or in the form of a high energy dispersion or as coated particles. Suitable formulations may be in coated or uncoated form, as desired.
  • Such solid pharmaceutical compositions may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably corn, potato or tapioca starch), disintegrants such as sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
  • excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably corn, potato or tapioca starch), disintegrants such as sodium starch glycollate, croscarmellose sodium and certain complex silicates, and
  • Active ingredient means a compound of the invention.
  • a tablet is prepared using the following ingredients : Active ingredient (50mg) is blended with cellulose (microcrystalline), silicon dioxide, stearic acid (fumed) and the mixture is compressed to form tablets.
  • An intravenous formulation may be prepared by combining active ingredient (100mg) with isotonic saline (1000ml)
  • the tablets are manufactured by a standard process, for example, direct compression or a wet or dry granulation process.
  • the tablet cores may be coated with appropriate overcoats.
  • Solid compositions of a similar type may also be employed as fillers in gelatin or HPMC capsules.
  • Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols.
  • the nociceptin receptor antagonists may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
  • Modified release and pulsatile release dosage forms may contain excipients such as those detailed for immediate release dosage forms together with additional excipients that act as release rate modifiers, these being coated on and/or included in the body of the device.
  • Release rate modifiers include, but are not exclusively limited to, hydroxypropylmethyl cellulose, methyl cellulose, sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate, polyethylene oxide, Xanthan gum, Carbomer, ammonio methacrylate copolymer, hydrogenated castor oil, camauba wax, paraffin wax, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, methacrylic acid copolymer and mixtures thereof.
  • Modified release and pulsatile release dosage forms may contain one or a combination of release rate modifying excipients.
  • Release rate modifying excipients may be present both within the dosage form i.e. within the matrix, and/or on the dosage form, i.e. upon the surface or coating.
  • Fast dispersing or dissolving dosage formulations may contain the following ingredients: aspartame, acesulfame potassium, citric acid, croscarmellose sodium, crospovidone, diascorbic acid, ethyl acrylate, ethyl cellulose, gelatin, hydroxypropylmethyl cellulose, magnesium stearate, mannitol, methyl methacrylate, mint flavouring, polyethylene glycol, fumed silica, silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, sorbitol, xylitol.
  • dispersing or dissolving as used herein to describe FDDFs are dependent upon the solubility of the drug substance used i.e. where the drug substance is insoluble a fast dispersing dosage form can be prepared and where the drug substance is soluble a fast dissolving dosage form can be prepared.
  • the compounds of the invention can also be administered parenterally, for example, intracavernosaly, intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion or needleless injection techniques.
  • parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • the aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary.
  • the dosage of the combination of the invention in such formulations will depend on its potency, but can be expected to be in the range of from 1 to 500mg of nociceptin receptor antagonist for administration up to three times a day.
  • a preferred dose is in the range 10 to 100mg (e.g. 10, 25, 50 and 100mg) of nociceptin receptor antagonist which can be administered once, twice or three times a day (preferably once).
  • the precise dose will be as determined by the prescribing physician and will depend on the age and weight of the subject and severity of the symptoms.
  • the daily dosage level of a compound of the invention will usually be from to 5 to 500mg/kg (in single or divided doses).
  • tablets or capsules may contain from 5mg to 250mg (for example 10 to 10Omg) of the compound of the invention for administration singly or two or more at a time, as appropriate.
  • the physician in any event will determine the actual dosage which will be most suitable for any individual patient and it will vary with the age, weight and response of the particular patient.
  • the above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention.
  • the compounds of the invention may be taken as a single dose as needed or desired (i.e. prn). It is to be appreciated that all references herein to treatment include acute treatment (taken as required) and chronic treatment (longer term continuous treatment).
  • the compounds of the invention can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomiser or nebuliser, with or without the use of a suitable propellant, e.g.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurised container, pump, spray, atomiser or nebuliser may contain a solution or suspension of the active compound, e.g.
  • Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of the compounds of the invention and a suitable powder base such as lactose or starch.
  • Aerosol or dry powder formulations are preferably arranged so that each metered dose or "puff" contains from 1 ⁇ g to 50mg of a compound of the invention for delivery to the patient.
  • the overall daily dose with an aerosol will be in the range of from 1 ⁇ g to 50mg which may be administered in a single dose or, more usually, in divided doses throughout the day.
  • the compounds of the invention can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder.
  • the compounds of the invention may also be dermally or transdermally administered, for example, by the use of a skin patch, depot or subcutaneous injection. They may also be administered by the pulmonary or rectal routes.
  • the compounds of the invention can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
  • they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the compounds of the invention may also be used in combination with a cyclodextrin.
  • Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Formation of a drug-cyclodextrin complex may modify the solubility, dissolution rate, bioavailability and/or stability property of a drug molecule. Drug- cyclodextrin complexes are generally useful for most dosage forms and administration routes.
  • the cyclodextrin may be used as an auxiliary additive, e.g. as a carrier, diluent or solubiliser.
  • Alpha-, beta- and gamma-cyclodextrins are most commonly used and suitable examples are described in published international patent applications WO91/11172, WO94/02518 and WO98/55148.
  • Oral administration of the compounds of the invention is a preferred route, being the most convenient.
  • the drug may be administered parenterally, sublingually or buccally.
  • Figure 1 demonstrates the effect of the nociceptin antagonist J-113397 on bladder capacity in anaesthetised spontaneously hypertensive rats (SHR's).
  • Figure 2 demonstrates the effect of a saline bolus on bladder capacity in anaesthetised SHR's.
  • FIG 3 shows the effect of SB-61211 1 on bladder capacity in anaesthetised female spontaneously hypertensive rats (SHRs).
  • Example 1 Assay showing the beneficial effect of a nociceptin receptor antagonist in the treatment of urinary incontinence
  • Urethane anaesthetised rats were cannulated at the carotid artery for blood pressure measurements, and at the jugular vein for intravenous infusions.
  • the bladder was catheterised, .and saline infused into the bladder at a rate of 45 ⁇ l/min. After the bladder trace had stabilised the bladder infusion was turned off. Three separate measurements of bladder capacity were then made with the bladder being emptied after each void, a bladder infusion rate of 150 ⁇ l/min was used. The mean of these three measurements was used as the baseline for all future measurements.
  • a 0.5ml bolus of saline or J- 113397 was then infused intravenously over 5 minutes. This was followed by a continuous infusion at 17 ⁇ l/min of saline or J-113397 to maintaine a plasma concentration of 500ng/ml or 10OOng/ml of J-1 13397.
  • Figure 1 demonstrates the effect of the nociceptin antagonist J-113397 on bladder capacity in anaesthetised SHR rats.
  • the Y axis is percentage change from intitial control readings.
  • the white bar is following saline infusion.
  • the checked bar is following an infusion of J-1 13397 targeting plasma levels of J-113397 at 500ng/ml.
  • the black bar is following an infusion of J-113397 targeting plasma levels of J-113397 at 1000ng/ml. Error bars are SE's.
  • the results demonstrate that J-113397 shows a dose-dependent increase in bladder capacity in these animals.
  • Figure 2 shows the result for time-matched control animals, receiving sequential infusions of saline instead of J-113397.
  • the Y axis is percentage change from initial control readings.
  • the white bar is following the first saline infusion
  • the checked bar is following the second saline infusion
  • the black bar is following the last saline infusion. Error bars are standard errors. Number of animals in each group was 5. The results demonstrate that the increase in bladder capacity in Figure 1 is not the result of the infusion of volume into the animals, but is clearly an effect of J-113397, the nociceptin receptor antagonist.
  • Figure 3 shows the effect of SB-612111 on bladder capacity in anaesthetised female spontaneously hypertensive rats. Note that after IV bolus dose administration of SB- 61211 1 the amount of saline required to be infused into the bladder in order to evoke a micturition response is greater than that required in the absence of SB-612111
  • Nociceptin receptor binding assay Competitive displacement analyses were performed in duplicate in a 96-well plate using a scintillation proximity assay (SPA). The membrane preparation (6.3 ⁇ g) was incubated for 45 min at 22°C with 0.4nM [ 3 H]nociceptin, 1.0 mg of WGA-SPA beads and 10-fold six different concentrations (0.01 nM to 1000 nM) of compounds in a final volume of 200 /I containing 50mM HEPES buffer pH7.4, 10mM
  • SPA scintillation proximity assay
  • Nociceptin was tested at three concentrations (0.1 ,1 ,10 nM) in order to validate this experiment. Non-specific binding was determined by the addition of 1 ⁇ M unlabeled nociceptin. Under these conditions, 98% specific binding was obtained. Each IC 50 value was calculated using a Excel CurveFit Macro program.
  • Example 3 Functional assays for detecting nociceptin receptor activity:
  • Cell membranes are prepared from HEK-293 cells transfected with human nociceptin receptor cDNA using standard technology. The membranes are then incubated with 400 pM [ 35 S]GTP ⁇ S, 10 or 50 nM nociceptin and various concentrations of test compounds in assay buffer (20mM HEPES, 100 mM NaCI, 5mM MgCI 2 , 1 mM EDTA, 5mM GDP, 1 mM DTT, pH 7.4), containing 1.5mg of wheat germ agglutinin-coated SPA beads for 60 to 90 minutes at 25°C in a final volume of 200 ⁇ l.
  • assay buffer 20mM HEPES, 100 mM NaCI, 5mM MgCI 2 , 1 mM EDTA, 5mM GDP, 1 mM DTT, pH 7.4
  • Basal binding is assessed in the absence of nociceptin and non-specific binding is defined by the addition of unlabelled 10mM GTP ⁇ S.
  • Membrane-bound radioactivity is detected by a Liquid Scintillation Counter.
  • HEK293 CRE- ⁇ lac cells are transfected with human nociceptin receptor cDNA in pcDNA3.1 Zeo using standard technology. Following Zeocin selection, clones are screened for nociceptin agonist-mediated inhibition of forskolin-stimulated cAMP responses using a commercial cAMP assay kit (Amersham BIOTRAK cAMP).
  • the nociceptin receptor is a GHinked GPCR. Stimulation of HEK293 CRE ⁇ -lac nociceptin receptor cells with forskolin leads to increased cAMP levels and hence increased ⁇ -lactamase. A nociceptin receptor agonist (i.e. nociceptin) will inhibit this stimulation, thus reducing ⁇ -lactamase levels. However, in the presence of a nociceptin receptor antagonist compound, the effect of nociceptin on ⁇ -lactamase production will be blocked. This screen therefore aims to identify antagonists of the nociceptin receptor.
  • Example 4 Selectivity assay: ⁇ -opioid receptor binding assay
  • Cell membranes prepared from CHO-K1 cells transfected to express the human ⁇ -opioid receptor were incubated for 45 minutes at 22°C with 1.0 nM [ 3 H]DAMGO, 1.0 mg of wheat germ agglutinin-coated SPA beads and various concentrations of test compounds in a final volume of 200 ⁇ l of 50mM Tris-HCL buffer pH7.4, containing 5 mM MgCI 2 .
  • Nonspecific binding was determined by the addition of 1 mM unlabelled DAMGO. After the reaction, the assay plate was centrifuged at 1 ,000rpm for 1 min and then the radioactivity was measured by a Liquid Scintillation Counter.
  • Each percent non-specific binding thus obtained is graphed as a function of compound concentration.
  • a sigmoidal curve is used to determine 50% binding (i.e. IC 50 values).
  • Nociceptin receptor antagonists demonstrating selectivity over ⁇ -opioid receptor demonstrate higher binding affinity for nociceptin receptors than for ⁇ -opioid receptors.

Abstract

The invention relates to the use of nociceptin receptor antagonists for the treatment of urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder, urgency, urge incontinence, frequency, nocturia and/or mixed urinary incontinence. The invention also relates to methods of screening for compounds for the use in the treatment of urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder, urgency, urge incontinence, frequency, nocturia and/or mixed urinary incontinence.

Description

Treatment of Urinary Conditions Including Incontinence
The present invention relates the use of antagonists of the nociceptin receptor for the treatment of urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder, urgency, urge incontinence, frequency, nocturia and/or mixed urinary incontinence.
The present invention also relates to a method of treatment of urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder, urgency, urge incontinence, frequency, nocturia and/or mixed urinary incontinence. The present invention also relates to a method of increasing bladder capacity.
The present invention also relates to assays to screen for compounds useful in the treatment of the above conditions.
The medical need is high for effective pharmacological treatments of urinary conditions such as overactive bladder (OAB), urgency, urge incontinence, (urinary) frequency, nocturia, stress incontinence and mixed urinary incontinence. This high medical need is a result of lack of efficacious pharmacological therapy coupled with high patient numbers.
Urinary incontinence is the complaint of any involuntary leakage of urine. It is a common condition, and often constitutes an embarrassment which can lead to social isolation, depression, loss of quality of life, and is a major cause for institutionalisation in the elderly population. In addition, feelings of urge to urinate, nocturia, and an increased frequency of urination are conditions which also seriously compromise the quality of life of patients, and are also especially prevalent in the elderly population.
It is increasingly recognised that both supraspinal and spinal sites contain key neuroanatomical areas involved in the control of micturition. Pharmacological therapy may target the bladder directly, as is the case with muscarinic receptor antagonists used to treat OAB, alternatively the pharmacological therapy may target neuronal pathways controlling micturition, for example when SNRI's are used to treat SUI. Previously much literature has been amassed showing that nociceptin/orphanin FQ (the natural agonist of the nociceptin receptor) when given intravenously or intracerebroventricularly in rats caused inhibition of the micturition reflex (Giuliani S et al (1998) Br J Pharmacol. 124, 1566-72; Lecci A et al (2000) J Urol. 163, 638-45; Lecci A et al (2000) Peptides 21 , 1007-21 ). Similar results have been shown clinically, two small trials investigating the effect of intravesical application of nociceptin on bladder function/micturition in neurogenically overactive bladder patients (Lazzeri M et al (2001 ) J Urol. 166, 2237-40; Lazzeri M et al (2003) Urology 61 , 946-50). As such nociceptin receptor antagonists may be expected to increase micturition reflex responses and reduce bladder capacity or to reverse conditions of retention due to dysfunction of the micturition reflex, indeed such antagonists have been suggested to be useful in the treatment of autonomic disorders including treatment of suppression of the micturition reflex (e.g. WO 03/000677; WO 03/064425; WO 05/016913). Surprisingly we have now shown that nociceptin antagonists in vivo also have an effect to increase bladder capacity in animal models exploring bladder function.
A seminal finding of the present invention is therefore the ability to treat urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder (OAB), urgency, urge incontinence, frequency, nocturia, and/or mixed urinary incontinence, with an antagonist for the nociceptin receptor.
Therefore the invention relates to nociceptin receptor antagonists for use in the treatment of urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder (OAB), urgency, urge incontinence, frequency, nocturia, and/or mixed urinary incontinence. The invention also relates to the use of nociceptin receptor antagonists for the manufacture of a medicament for the treatment of urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder (OAB), urgency, urge incontinence, frequency, nocturia, and/or mixed urinary incontinence. The invention also relates to a method of treatment of urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder (OAB), urgency, urge incontinence, frequency, nocturia, and/or mixed urinary incontinence, with an antagonist to the nociceptin receptor. One aspect of the invention is therefore a method of treating urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder (OAB), urgency, urge incontinence, frequency, nocturia, and/or mixed urinary incontinence, comprising the administration to a patient in need of such treatment of a therapeutically effective amount of a nociceptin receptor antagonist. The urinary conditions that can be treated with a nociceptin receptor antagonist include overactive bladder, urgency, urge urinary incontinence, urinary frequency, nocturia, mixed urinary incontinence, stress urinary incontinence, and genuine stress urinary incontinence. The terms "treating" or "treatment", include the palliative, curative and prophylactic treatment of the above conditions, as well as complications arising from the above conditions and other associated conditions, including lower urinary tract symptoms associated with benign prostatic hypertrophy.
The term "overactive bladder" refers to detrusor overactivity, i.e. overactivity of the bladder muscle. It includes the condition where the bladder contracts while it is filling.
The term "urgency" is the complaint of a sudden compelling desire to pass urine, which is difficult to defer.
The term "incontinence" or "urinary incontinence" refers to any involuntary leakage of urine.
The term "urge incontinence" or "urge urinary incontinence" is the complaint of involuntary leakage accompanied by or immediately preceded by urgency.
The term "frequency" is the complaint by the patient who considers that he/she voids too often. The term "nocturia" is the complaint that the individual has to wake at night one or more times to void.
The term "stress incontinence" or "stress urinary incontinence" (SUI) is the complaint of involuntary leakage upon anything that increases intraabdominal pressure, such as effort or exertion, sneezing or coughing. The term "mixed incontinence" or "mixed urinary incontinence" refers to the case when a patient suffers from more than one form of urinary incontinence, e.g. stress incontinence and urge incontinence.
Overactive bladder can include symptoms of urgency, urge incontinence, frequency, nocturia, and/or mixed incontinence.
The nociceptin receptor antagonists preferably will have an IC50 in a ligand binding assay of less than 100nM, more preferably an IC50 of less than 10nM, even more preferably an IC50 of less than 1 nM. The IC50 may be measured in a ligand binding assay, e.g. as described in Example 2, or in a functional assay, e.g. measuring the ability of the test compound to antagonise the inhibition of forskolin-stimulated cAMP formation (see e.g. Example 3b), or testing whether the test compound can inhibit agonist-stimulated binding of GTPγS (see, for example, Example 3a).
Preferably the nociceptin receptor antagonist will be at least 10 fold selective over the μ opioid receptor, more preferably at least 100 fold selective over the μ opioid receptor. Preferably the nociceptin antagonist will be at least 10 fold selective over the K opioid receptor, more preferably at least 100 fold selective over the the K opioid receptor. More preferably the the nociceptin antagonist will be at least 10 fold selective over the δ opioid receptor, more preferably at least 100 fold selective over the the δ opioid receptor. More preferably, the nociceptin receptor antagonist will be at least 10 fold selective over μ-, K- and δ opioid receptors, even more preferably, the nociceptin receptor antagonist will be at least 100 fold selective over μ-, K- and δ opioid receptors.
Suitable nociceptin receptor antagonists include J-113397 (WO 98/54168; Kawamoto, H. et al (1999) J.Med.Chem. 42, 5061 -5063). One aspect of the invention is the use of J- 113397 or a pharmaceutically acceptable salt or derivative thereof, in the preparation of a medicament for the treatment of urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress and mixed urinary incontinence, in particular overactive bladder, urgency, urge incontinence, frequency, nocturia and/or mixed urinary incontinence.
Suitable nociceptin receptor antagonists also include SB-612111 (Zaratin, P.F. et al. (2004) J Pharmacol Exp Ther, 308(2):454; WO 01/83454) and JTC-801 (WO 99/48492; Shinkai et al (2000) J. Med. Chem. 43, 4667-4677). One aspect of the invention is the use of SB-612111 or JTC-801 or a pharmaceutically acceptable salt or derivative thereof, in the preparation of a medicament for the treatment of urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder, urgency, urge incontinence, frequency, nocturia and/or mixed urinary incontinence.
Suitable nociceptin receptor antagonists also include a compound of the following formula (la) or formula (lb), disclosed in US60/557598:
Figure imgf000006_0001
(la)
Figure imgf000006_0002
(Ib)
or a pharmaceutically acceptable ester of such a compound, or a pharmaceutically acceptable salt thereof, wherein
R1 and R2 independently represent a hydrogen atom, a halogen atom or an alkyl group having from 1 to 3 carbon atoms;
R3 (only in formula la) represents a hydrogen atom, a cycloalkyl group having from 3 to 6 carbon atoms, a tetrahydrofuranyl group, a tetrahydropyranyl group, an alkyl group having from 1 to 6 carbon atoms, which alkyl group is optionally substituted by 1 to 3 groups selected from a cyano group, a halogen atom, a hydroxy group, an alkoxy group having from 1 to 3 carbon atoms, an oxo group, an amino group and a mono- or di- alkylamino group each alkyl part having from 1 to 3 carbon atoms;
R4 (only in formula la) represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms; or
Figure imgf000006_0003
(only in formula la) represents one of the following
Figure imgf000006_0004
optionally substituted by 1 to 2 groups selected from an oxo group, a hydroxy group, a hydroxyalkyl group having from 1 to 3 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, an alkyl group having from 1 to 6 carbon atoms and an alkoxyalkyl group having a total of from 2 to 6 carbon atoms; R5 represents a phenyl group or a heteroaryl group and said heteroaryl group is a 5- to 6-membered hetero aromatic group having either from 1 to 4 ring nitrogen heteroatoms or 1 or 2 nitrogen ring heteroatoms and 1 oxygen or 1 sulfur ring heteroatom; said phenyl group and heteroaryl group are optionally substituted by 1 to 3 groups selected from a halogen atom, a hydroxy group, an alkyl group having from 1 to 3 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, an alkoxyalkyl group having a total of from 2 to 6 carbon atoms, a hydroxyalkyl group having from 1 to 3 carbon atoms, an amino group, a mono-or di-alkylamino group each alkyl part having from 1 to 3 carbon atoms, an aminocarbonyl group, a mono- or di- alkylaminocarbonyl group having from 1 to 3 carbon atoms in each alkyl group, an alkanoylamino group having from 2 to 3 carbon atoms and an alkylsulfonylamino group having from 1 to 3 carbon atoms; R6 represents a hydrogen atom, an alkyl group having from 1 to 3 carbon atoms, an alkanoyl group having from 2 to 3 carbon atoms or an alkylsulfonyl group having from 1 to 3 carbon atoms; -X-Y- represents a group of the formula -N(R7)C(=O)-, -C(=O)N(R7)-, -N(R7)CH2-, - CH2N(R7)-, -N(R7)SO2-, ,-SO2N(R7)-, -CH2CH2-, -CH=CH-, -CH(CH2OH)CH2-, - CH2CH(CH2OH)- ,-CH2CH(OH)-, -CH(OH)CH2-, -C(R7)(R8)-O- or -O-C(R7)(R8)-; R7 represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms; R8 represents a hydrogen atom, an alkyl group having from 1 to 3 carbon atoms or a hydroxyalkyl group having from 1 to 3 carbon atoms; and n represents an integer 0, 1 or 2
As used herein, the term "halogen" means fluoro, chloro, bromo and iodo, preferably fluoro or chloro. As used herein, the term "alkyl" means straight or branched chain saturated radicals, including, but not limited to methyl, ethyl, n-propyl, /sopropyl. As used herein, the term "alkoxy" means alkyl-O-, including, but not limited to methoxy, ethoxy, π-propoxy, /sopropoxy. As used herein, the term " alkanoyl" means a group having carbonyl such as R'- C(O)- wherein R' is H, C1-5 alkyl, phenyl or C3.6 cycloalkyl, including, but not limited to formyl, acetyl, ethyl-C(O)-, n-propyl-C(O)-, /sopropyl-C(O)-, n-butyl-C(O)-, /so-butyl-
C(O)-, secon a/y-butyl-C(O)-, fert/a/y-butyl-C(O)-, cyclopropyl-C(O)-, cyclobutyl-C(O)-, cyclopentyl-C(O)-, cyclohexyl-C(O)-, and the like. As used herein, the term "aryl" means a monocyclic or bicyclic aromatic carbocyclic ring of 6 to 10 carbon atoms; including, but not limited to, phenyl or naphthyl, preferably phenyl. As used herein, the term "cycloalkyl" means a saturated carbocyclic radical ring of 3 to 6 carbon atoms, including, but not limited to, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. As used herein, the term "heteroaryl" means a C-linked, hetero aromatic group having either from 1 to 4 ring nitrogen heteroatoms or 1 or 2 nitrogen ring heteroatoms and 1 oxygen or 1 sulfur ring heteroatom, including, but not limited to, pyrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, tetrazolyl, thiazolyl, isothiazolyl, imidazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrrolyl, thiophenyl, pyrazinyl, pyridazinyl, isooxazolyl, isothiazolyl, triazolyl, furazanyl, quinolyl, isoquinolyl, imidazopyridyl, benzimidazolyl, indolyl, and the like. As used herein, the term "haloalkyl", as used herein, means an alkyl radical which is substituted by halogen atoms as defined above including, but not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2- trifluoroethyl, 2,2,2-trichloroethyl, 3-fluoropropyl, 4-fluorobutyl, chloromethyl, trichloromethyl, iodomethyl and bromomethyl groups and the like. Where the compounds of formula (la) or formula (lb) contain hydroxy groups, they may form esters. Examples of such esters include esters with a hydroxy group and esters with a carboxy group. The ester residue may be an ordinary protecting group or a protecting group which can be cleaved in vivo by a biological method such as hydrolysis. The term "protecting group" means a group, which can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis or photolysis.
Preferred compounds of formula (la) include:
3-(2,3-Dihydro-1 Η-spiro[indene-1 ,4'-piperidin]-1 '-yl)-Λ/,Λ/-dimethyl-2-(pyridin-2- ylmethyl)propanamide ;
Λ/,Λ/-Dimethyl-3-(1 Η,3H-spiro[2-benzofuran-1 ,4'-piperidin]-1 '-yl)-2-(1 ,3-thiazol-4- ylmethyl)propanamide ;
3-(6-Fluoro-1 'H,3H-spiro[2-benzofuran-1 ,4'-piperidin]-1 '-yl)-Λ/,Λ/-dimethyl-2-(pyridin-2- ylmethyl)propanamide ; (-)-3-(6-Fluoro-1 ' - ,3H-spiro[2-benzofuran-1 ,4'-piperidin]-1 '-yl)-Λ/,Λ/-dimethyl-2-(pyridin-2- ylmethyl)propanamide ;
3-(6-Fluoro-1 ' - ,3H-spiro[2-benzofuran-1 ,4'-piperidin]-1 '-yl)-Λ/-(2-hydroxyethyl)-Λ/-methyl-
2-(pyridin-2-ylmethyl)propanamide ;
3-(6-Fluoro-1 Η,3H-spiro[2-benzofuran-1 ,4'-piperidin]-1 '-yl)-Λ/-(2-methoxyethyl)-/V-methyl- 2-(pyridin-2-ylmethyl)propanamide ; 3-(6-Fluoro-1 Η,3H-spiro[2-benzofuran-1 ,4'-piperidin]-1 '-yl)-Λ/,/V-dimethyl-2-(1 ,3-thiazol-4- ylmethyl)propanamide ;
(-)-3-(6-Fluoro-1 Η,3H-spiro[2-benzofuran-1 ,4'-piperidin]-1 '-yl)-Λ/,Λ/-dimethyl-2-(1 ,3- thiazol-4-ylmethyl)propanamide ; 3-(6-Fluoro-1 'H,3H-spiro[2-benzofuran-1 ,4'-piperidin]-1 '-yl)-Λ/-(2-methoxyethyl)-Λ/-methyl-
2-(1 ,3-thiazol-4-ylmethyl)propanamide ;
3-(5-Fluoro-1 -methyl-2-oxo-1 ,2-dihydro-1 'H-spiro[indole-3,4'-piperidin]-1 '-yl)-Λ/,Λ/- dimethyl-2-(pyridin-2-ylmethyl)propanamide ;
3-(3,3-Dimethyl-1 ' - ,3H-spiro[2-benzofuran-1 ,4'-piperidin]-1 '-yl)-Λ/,Λ/-dimethyl-2-(pyridin- 2-ylmethyl)propanamide ;
1 -[3-(6-Fluoro-1 'H,3/+spiro[2-benzofuran-1 ,4'-piperidin]-1 '-yl)-2-(1 ,3-thiazol-4- ylmethyl)propanoyl]-3-methylazetidin-3-ol ; /,Λ/-Dimethyl-3-(3-methyl-1 'H,3 --spiro[2-benzofuran-1 ,4'-piperidin]-1 '-yl)-2-(pyridin-2- ylmethyl)propanamide ; 3-(6-Fluoro-1 Η,3 -/-spiro[2-benzofuran-1 ,4'-piperidin]-1 '-yl)-Λ/,Λ/-dimethyl-2-(1 H-pyrazol-
1 -ylmethyl)propanamide ;
(-)-3-(6-Fluoro-1 'H,3H-spiro[2-benzofuran-1 ,4'-piperidin]-1 '-yl)-Λ/,Λ/-dimethyl-2-(1 H- pyrazol-1 -ylmethyl)propanamide ;
3-(6-Fluoro-1 Η,3H-spiro[2-benzofuran-1 ,4'-piperidin]-1 '-yl)-Λ/-(2-hydroxyethyl)-Λ/-methyl- 2-(1 ,3-thiazol-4-ylmethyl)propanamide ;
(-)-3-(6-Fluoro-1 ' -/,3H-spiro[2-benzofuran-1 ,4'-piperidin]-1 '-yl)-Λ/-(2-hydroxyethyl)-/V- methyl-2-(1 ,3-thiazol-4-ylmethyl)propanamide ;
3-(6-Fluoro-1 'H,3 -/-spiro[2-benzofuran-1 ,4'-piperidin]-1 '-yl)-Λ/-(2-methoxy-2- methylpropyl)-Λ/-methyl-2-(1 ,3-thiazol-4-ylmethyl)propanamide ; 1 -[3-(6-Fluoro-1 Η,3H-spiro[2-benzofuran-1 ,4'-piperidin]-1 '-yl)-2-(1 ,3-thiazol-4- ylmethyl)propanoyl]-3-methylpyrrolidin-3-ol ;
3-(6-Fluoro-1 '/-/,3H-spiro[2-benzofuran-1 ,4'-piperidin]-1 '-yl)-Λ/-(3-hydroxy-3-methylbutyl)-
Λ/-methyl-2-(1 ,3-thiazol-4-ylmethyl)propanamide ;
3-(6-Fluoro-1 'H,3H-spiro[2-benzofuran-1 ,4'-piperidin]-1 '-yl)-Λ/-methyl-Λ/-(tetrahydrofuran- 3-yl)-2-(1 ,3-thiazol-4-ylmethyl)propanamide ;
Λ/,Λ/-Dimethyl-3-(3-methyl-1 Η,3H-spiro[2-benzof uran-1 ,4'-piperidin]-1 '-yl)-2-(1 ,3-thiazol-
4-ylmethyl)propanamide ; and
1 '-[3-Azetidin-1 -yl-3-oxo-2-(1 ,3-thiazol-4-ylmethyl)propyl]-6-fluoro-3H-spiro[2-benzofuran-
1 ,4'-piperidine] ; 3-(6-Fluoro-1 Η,3H-spiro[2-benzofuran-1 ,4'-piperidin]-1 '-yl)-Λ/,Λ/-dimethyl-2-[(4-methyl-
1 H-pyrazol-1 -yl)methyl]propanamide; 3-(4-Chloro-1 H-pyrazol-1 -yl)-2-[(6-fluoro-1 Η,3/--spiro[2-benzofuran-1 ,4'-piperidin]-1 '- yl)methyl]-Λ/,Λ/-dimethylpropanamide;
(-)-3-(4-Chloro-1 H-pyrazol-1 -yl)-2-[(6-fluoro-1 'H,3H-spiro[2-benzofuran-1 ,4'-piperidin]-1 '- yl)methyl]-Λ/,Λ/-dimethylpropanamide; 3-(6-Fluoro-3,4-dihydro-1 '/-/-spiro[isochromene-1 ,4'-piperidin]-1 '-yl)-Λ/,Λ/-dimethyl-2-(1 H- pyrazol-1 -ylmethyl)propanamide; and
3-(6-Fluoro-3,4-dihydro-1 Η-spiro[isochromene-1 ,4'-piperidin]-1 '-yl)-Λ/,Λ/-dimethyl-2-(1 ,3- thiazol-4-ylmethyl)propanamide; or a pharmaceutically acceptable ester or salt thereof.
Preferred compounds of formula (lb) include:
2-Benzyl-3-(2,3-dihydro-1 Η-spiro[indene-1 ,4'-piperidin]-1 '-yl)propanoic acid trifluoroacetate;
2-(2-Chlorobenzyl)-3-(1 'H,3 --spiro[2-benzofuran-1 ,4'-piperidin]-1 '-yl)propanoic acid trifluoroacetate;
2-(5-{[tert-Butyl(dimethyl)silyl]oxy}-2-fluorobenzyl)-3-(1 ,H,3H-spiro[2-benzofuran-1 ,4'- piperidin]-1 '-yl)propanoic acid trifluoroacetate;
2-(2-Chloro-5-hydroxybenzyl)-3-(1 ' -/,3H-spiro[2-benzofuran-1 ,4'-piperidin]-1 '- yl)propanoic acid; 2-(2-Chlorobenzyl)-3-(1 -methyl-2-oxo-1 ,2-dihydro-1 '/--spiro[indole-3,4'-piperidin]-1 '- yl)propanoic acid;
2-(2-Chlorobenzyl)-3-(5-fluoro-1 -methyl-1 ,2-dihydro-1 '/--spiro[indole-3,4'-piperidin]-1 '- yl)propanoic acid;
2-(2-Fluoro-5-hydroxybenzyl)-3-(1 -methyl-2-oxo-1 ,2-dihydro-1 ' --spiro[indole-3,4'- piperidin]-1 '-yl)propanoic acid;
2-(2-Chlorobenzyl)-3-(6-fluoro-1 'H,3H-spiro[2-benzofuran-1 ,4'-piperidin]-1 '-yl)propanoic acid;
2-(2-Chloro-5-hydroxybenzyl)-3-(1 -methyl-2-oxo-1 ,2-dihydro-1 '/--spiro[indole-3,4'- piperidin]-1 '-yl)propanoic acid; 2-(5-{[ter -Butyl(dimethyl)silyl]oxy}-2-fluorobenzyl)-3-(5-fluoro-1 -methyl-1 ,2-dihydro-1 'H- spiro[indole-3,4'-piperidin]-1 '-yl)propanoic acid trifluoroacetate;
2-(5-{[fert-Butyl(dimethyl)silyl]oxy}-2-chlorobenzyl)-3-(5-fluoro-1 -methyl-1 ,2-dihydro-1 'H- spiro[indole-3,4'-piperidin]-1 '-yl)propanoic acid trifluoroacetate;
2-(2-Chloro-5-hydroxybenzyl)-3-(5-fluoro-1 -methyl-2-oxo-1 ,2-dihydro-1 Η-spiro[indole- 3,4'-piperidin]-1 '-yl)propanoic acid;
2-(2-Fluoro-5-hydroxybenzyl)-3-(5-fluoro-1 -methyl-2-oxo-1 ,2-dihydro-1 Η-spiro[indole-
3,4'-piperidin]-1 '-yl)propanoic acid; 2-(2-Chloro-5-hydroxybenzyl)-3-(2-hydroxy-2,3-dihydro-1'H-spiro[indene-1 ,4'-piperidin]-
1 '-yl)propanoic acid;
2-(2-chloro-5-hydroxybenzyl)-3-(3-methyl-1 'H,3H-spiro[2-benzofuran-1 ,4'-piperidin]-1 '- yl)propanoic acid; 2-(2-Chloro-5-hydroxybenzyl)-3-[3-(hydroxymethyl)-2,3-dihydro-1 ' --spiro[indene-1 ,4'- piperidin]-1 '-yl]propanoic acid; 2-(2-chloro-5-hydroxybenzyl)-3-(3-hydroxy-2,3-dihydro-
1 'H-spiro[indene-1 ,4'-piperidin]-1 '-yl)propanoic acid;
2-(2-Chloro-5-hydroxybenzyl)-3-(5-fluoro-1 ' -/,3/--spiro[2-benzofuran-1 ,4'-piperidin]-1 '- yl)propanoic acid; 3-(3-Methyl-1 'H,3H-spiro[2-benzofuran-1 ,4'-piperidin]-1 '-yl)-2-(pyridin-2- ylmethyl)propanoic acid;
3-(3-Methyl-1 'H,3H-spiro[2-benzofuran-1 ,4'-piperidin]-1 '-yl)-2-(1 ,3-thiazol-4- ylmethyl)propanoic acid trifluoroacetate;
3-(3,4-Dihydro-1 Η-spiro[isochromene-1 ,4'-piperidin]-1 '-yl)-2-(1 ,3-thiazol-4- ylmethyl)propanoic acid trifluoroacetate;
3-(5-Fluoro-1 -methyl-2-oxo-1 ,2-dihydro-1 'H-.spiro[indole-3,4'-piperidin]-1 '-yl)-2-(1 ,3- thiazol-4-ylmethyl)propanoic acid trifluoroacetate;
3-(2,3-Dihydro-1 Η-spiro[indene-1 ,4'-piperidin]-1 '-yl)-2-(1 ,3-thiazol-4-ylmethyl)propanoic acid trifluoroacetate; 3-(2,3-Dihydro-1 ' --spiro[indene-1 ,4'-piperidin]-1 '-yl)-2-(1 H-pyrazol-1 -ylmethyl)propanoic acid;
3-(6-Fluoro-3,4-dihydro-1 'H-spiro[isochromene-1 ,4'-piperidin]-1 '-yl)-2-(1 H-pyrazol-1 - ylmethyl)propanoic acid; and
3-(6-Fluoro-3,4-dihydro-1 'H-spiro[isochromene-1 ,4'-piperidin]-1 '-yl)-2-(1 ,3-thiazol-4- ylmethyl)propanoic acid trifluoroacetate; or a pharmaceutically acceptable ester or salt thereof.
General Synthesis: The compounds of formula la and lb of the present invention may be prepared according to known preparation methods, or General Procedures or preparation methods illustrated in the following reaction schemes. Unless otherwise indicated R1 through R6 and X, Y and n in the reaction schemes and discussion that follow are defined as above. The term "protecting group", as used hereinafter, means a hydroxy or amino protecting group which is selected from typical hydroxy or amino protecting groups described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1999); The following reaction schemes illustrate the preparation of compounds of formula
(I). Scheme 1 : This illustrates the preparation of compounds of formula (la) and formula (lb, 1-12).
Scheme 1 G R5 Step 1A ""R5 1-1 1-2
Figure imgf000012_0001
O R5 1-7 Step l H
Figure imgf000012_0002
In the above formula, G represents a hydrogen atom or a hydroxy group. Ra represents an alkyl group having from 1 to 4 carbon atoms. L1 represents a leaving group. Examples of suitable leaving groups include: halogen atoms, such as chlorine, bromine and iodine; sulfonic esters such as TfO (triflates), MsO (mesylates), TsO (tosylates); and the like. Step 1A In this step, a compound of the formula 1-2 in which L1 represents a halogen atom can be prepared by the halogenating the compound of the formula 1-1 in which G represents a hydrogen atom under halogenation conditions with a halogenating reagent in a reaction-inert solvent. Examples of suitable solvents include: tetrahydrofuran, 1 ,4-dioxane, N,N- dimethylformamide, acetonitrile; alcohols, such as methanol or ethanol; halogenated hydrocarbons, such as dichloromethane, 1 ,2-dichloroethane, chloroform or carbon tetrachloride and acetic acid. Suitable halogenating reagents include, for example, bromine, chlorine, iodine, Λ/-chlorosuccimide, Λ/-bromosuccimide, 1 ,3-dibromo-5,5- dimethylhydantoin, bis(dimethylacetamide)hydrogen tribromide, tetrabutylammonium tribromide, bromodimethylsulfonium bromide, hydrogen bromide-hydrogen peroxide, nitrodibromoacetonitrile or copper(ll) bromide. The reaction can be carried out at a temperature of from 0 °C to 200 °C, more preferably from 20 °C to 120 °C. Reaction times are, in general, from 5 minutes to 48 hours, more preferably 30 minutes to 24 hours, will usually suffice. The compound of the formula 1-2 in which L1 represents a halogen atom or a sulfonic ester can also be prepared by the halogenating or sulfonating the compound of the formula 1-1 in which G represents a hydroxy group under conditions known to those skilled in the art. For example, the hydroxy group of the compound of formula 1 -1 may be converted to the halogen atom using a halogenating agent in the presence or absence of a reaction inert solvent. Preferred halogenating agents include: chlorinating agents, such as thionyl chloride, oxalyl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride, hydrogen chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, or phosphorus reagents such as triphenylphosphine, tributyl phosphine or triphenylphosphite in the presence of halogen source such as carbon tetrachloride, chlorine, Λ/-chlorosuccinimide (NCS); brominating agents, such as hydrogen bromide, N- bromosuccinimide (NBS), phosphorus tribromide, trimethylsilyl bromide or phosphorus reagents such as triphenylphosphine, tributyl phosphine or triphenylphosphite in the presence of halogen source such as carbon tetrabromide, bromine or NBS; and iodinating agents, such as hydroiodic acid, phosphorus triiodide, or phosphorus reagents such as triphenylphosphine, tributyl phosphine or triphenylphosphite in the presence of halogen source such as iodine. Examples of suitable solvents include: aliphatic hydrocarbons, such as hexane, heptane and petroleum ether; aromatic hydrocarbons, such as benzene, toluene, o-dichlorobenzene, nitrobenzene, pyridine, and xylene; halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1 ,2-dichloroethane; and ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and 1 ,4-dioxane. This reaction may be carried out at a temperature in the range from -100 °C to 250 °C, more preferably from 0 °C to the reflux temperature for 1 minute to a day, more preferably from 20 minutes to 5 hours. Alternatively, the hydroxy group of the compound of formula 1-1 may be converted to the sulfonate group using a sulfonating agent in the presence of, or absence of a base. Examples of such sulfonating agents include: p-toluenesulfonyl chloride, p- toluenesulfonic anhydride, methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, or the like in the presence or absence of a reaction- inert solvent. Examples of such bases include: an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, halide or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, potassium fluoride, sodium hydride or potassium hydride, or an amine such as triethylamine, tributylamine, diisopropylethylamine, pyridine or dimethylaminopyridine in the presence or absence of a reaction-inert solvent. Examples of suitable solvents include: aliphatic hydrocarbons, such as hexane, heptane and petroleum ether; aromatic hydrocarbons, such as benzene, toluene, o- dichlorobenzene, nitrobenzene, pyridine, and xylene; halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride and 1 ,2-dichloroethane; and ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and 1 ,4-dioxane; N,N- dimethylformamide, and dimethylsulfoxide. This reaction may be carried out at a temperature in the range from -50 °C to 100 °C, more preferably from -10 °C to 50 °C for 1 minute to a day, more preferably from 20 minutes to 5 hours. Step 1 B In this step, a compound of formula 1-4 can be prepared by the alkylation of a compound of formula 1 -3 with the alkylating agent 1-2 in the presence of a base in a reaction-inert solvent. Examples of suitable solvents include: tetrahydrofuran, N,N- dimethylformamide, dimethylsulfoxide, diethylether, toluene, ethylene glycol dimethylether generally or 1 ,4-dioxane. Examples of suitable bases include: alkyl lithiums, such as n-butyllithium, seo-butyllithium or tert-butyllithium; aryllithiums, such as phenyllithium or lithium naphtilide; methalamide such as sodium amide or lithium diisopropylamide; and alkali metal, such as potassium hydride or sodium hydride. This reaction may be carried out at a temperature in the range from -50 °C to 200 °C, usually from -10 °C to 100 °C for 5 minutes to 72 hours, usually 30 minutes to 36 hours. Step l C In this step, a compound of formula 1-6 can be prepared by the aldol condensation of a compound of formula 1-3 with an aldehyde compound 1 -5 in the presence of a base in a reaction-inert solvent. Examples of suitable solvents include: tetrahydrofuran, N,N- dimethylformamide, dimethylsulfoxide, ether, toluene, ethylene glycol dimethylether or 1 ,4-dioxane. Examples of suitable bases include: lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, thallium(l) carbonate, sodium ethoxide, potassium terf-butoxide, potassium acetate, cesium fluoride, tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium iodide, pyridine, picoline, 4- (Λ/,Λ/-dimethylamino)pyridine, triethylamine, tributylamine, diisopropylethylamine, N- methylmorphorine and Λ/-methylpiperidine. This reaction may be carried out at a temperature in the range from -50 °C to 250 °C, usually from -10 °C to 150 °C for 5 minutes to 72 hours, usually 30 minutes to 24 hours. Step 1 D In this step, the compound of formula 1 -4 can be prepared by the reduction of the olefin compound of formula 1-6 with a reducing agent in an inert solvent. Examples of suitable solvents include: methanol, ethanol, ethyl acetate, tetrahydrofuran (THF) or mixtures thereof. The reduction may be carried out under known hydrogenation conditions in the presence of a metal catalyst, e.g. nickel catalysts such as Raney nickel, palladium catalysts such as Pd-C, platinum catalysts such as Ptθ2, or ruthenium catalysts such as RuCl2 ( h3P)3 under hydrogen atmosphere or in the presence of hydrogen sources such as hydrazine or formic acid. If desired, the reaction is carried out under acidic conditions, e.g. in the presence of hydrochloric acid or acetic acid. This reaction may be carried out at a temperature in the range from -50 °C to 200 °C, usually from -10 °C to 100 °C for 5 minutes to 72 hours, usually 30 minutes to 36 hours. Step 1 E In this step, a compound of formula 1-7 can be prepared by Horner-Emmons reaction of the compound of formula 1 -4 with formaldehyde or paraformaldehyde in the presence of a base in a reaction-inert solvent. Examples of suitable solvents include: tetrahydrofuran, Λ/,Λ/-dimethylformamide, dimethylsulfoxide, diethylether, toluene, ethylene glycol dimethylether, water or 1 ,4-dioxane. Examples of suitable bases include: lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, thallium(l) carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, potassium hydride or sodium hydride. This reaction may be carried out at a temperature in the range from 0 °C to 200 °C, usually from 50 °C to 150 °C for 5 minutes to 72 hours, usually 30 minutes to 50 hours. Step 1 F In this step, a compound of formula 1 -10 can be prepared by Michael reaction of a compound of formula 1 -8 with an enone compound of formula 1 -9 in the presence of a base in a reaction-inert solvent. Examples of suitable solvents include: acetonitrile, tetrahydrofuran, Λ/,Λ/-dimethylformamide, dimethylsulfoxide, ether, toluene, ethylene glycol dimethylether, water or 1 ,4-dioxane. Examples of suitable bases include: triethylamine, tributylamine, diisopropylethylamine, pyridine, picoline, N- methylmorphorine and Λ/-methylpiperidine, sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate. This reaction may be carried out at a temperature in the range from 0 °C to 200 °C, usually from 25 °C to 100 °C for 5 minutes to 60 hours, usually 30 minutes to 30 hours. Step l G In this step, a compound of formula 1 -11 can be prepared by the alkylation of a compound of formula 1-10 with the alkylating agent 1 -2 in the presence of a base in a reaction-inert solvent. Examples of suitable solvents include: tetrahydrofuran, diethylether, toluene, ethylene glycol dimethylether generally or 1 ,4-dioxane. Examples of suitable bases include: lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, methalamide such as sodium amide or lithium diisopropylamide; and alkali metal, such as potassium hydride or sodium hydride. If desired, this reaction may be carried out in the presence or absence of an additive such as Λ/,/V'-dimethylpropyleneurea (DMPU), hexamethylphosphoramide (HMPA), N,N,N',N'- tetramethylethylenediamine (TMEDA). This reaction may be carried out at a temperature in the range from -100 °C to 200 °C, usually from -80 °C to 100 °C for 5 minutes to 72 hours, usually 30 minutes to 36 hours. Step 1 H In this step, the compound of formula 1-11 can be prepared by Michael reaction of the compound of formula 1-8 with the enone compound of formula 1 -7 in the presence or absence of a base in a reaction-inert solvent. Examples of suitable solvents include: methanol, ethanol, tetrahydrofuran, Λ/,Λ/-dimethylformamide, dimethylsulfoxide, diethylether, toluene, ethylene glycol dimethylether, water or 1 ,4-dioxane. Examples of suitable bases include: triethylamine, tributylamine, diisopropylethylamine, pyridine, picoline, Λ/-methylmorphorine and Λ/-methylpiperidine. This reaction may be carried out at a temperature in the range from 0 °C to 200 °C, usually from 25 °C to 100 °C for 1 hour to 2 weeks, usually 5 hours to 10 days. Step 11 In this step, an acid compound of formula 1-12 may be prepared by hydrolysis of the ester compound of formula 1-11 in a solvent. The hydrolysis may be carried out by conventional procedures. In a typical procedure, the hydrolysis carried out under the basic condition, e.g. in the presence of sodium hydroxide, potassium hydroxide or lithium hydroxide. Suitable solvents include, for example, alcohols such as methanol, ethanol, propanol, butanol, 2-methoxyethanol, and ethylene glycol; ethers such as tetrahydrofuran (THF), 1 ,2-dimethoxyethane (DME), and 1 ,4-dioxane; amides such as Λ/,Λ/-dimethylformamide (DMF) and hexamethylphospholictriamide; and sulfoxides such as dimethyl sulfoxide (DMSO). This reaction may be carried out at a temperature in the range from -20 °C to 100 °C, usually from 20 °C to 75 °C for 30 minutes to 48 hours, usually 60 minutes to 30 hours. The hydrolysis may also be carried out under the acidic condition, e.g. in the presence of hydrogen halides, such as hydrogen chloride and hydrogen bromide; sulfonic acids, such as p-toluenesulfonic acid and benzenesulfonic acid; pyridium p- toluenesulfonate; and carboxylic acid, such as acetic acid and trifluoroacetic acid. Suitable solvents include, for example, alcohols such as methanol, ethanol, propanol, butanol, 2-methoxyethanol, and ethylene glycol; ethers such as tetrahydrofuran (THF), 1 ,2-dimethoxyethane (DME), and 1 ,4-dioxane; halogenated hydrocarbons, such as dichloromethane, 1 ,2-dichloroethane, amides such as Λ/,Λ/-dimethylformamide (DMF) and hexamethylphospholictriamide; and sulfoxides such as dimethyl sulfoxide (DMSO). This reaction may be carried out at a temperature in the range from -20 °C to 100 °C, usually from 0 °C to 65 °C for 30 minutes to 24 hours, usually 60 minutes to 10 hours. Step 1J In this step, which only applies to the preparation of a compound of formula (la), an amide compound of formula (la) may be prepared by the coupling reaction of an amine compound of formula 1 -13 with the acid compound of formula 1-12 in the presence or absence of a coupling reagent in an inert solvent. If desired, this reaction may be carried out in the presence or absence of an additive such as 1 -hydoroxybenzotriazole (HOBt) or 1 -hydroxyazabenzotriazole. Examples of suitable solvents include: acetone, nitromethane, Λ/,Λ/-dimethylformamide (DMF), sulfolane, dimethyl sulfoxide (DMSO), 1- methyl-2-pirrolidinone (NMP), 2-butanone, acetonitrile; halogenated hydrocarbons, such as dichloromethane, 1 ,2-dichloroethane, chloroform; and ethers, such as tetrahydrofuran and 1 ,4-dioxane. This reaction may be carried out at a temperature in the range from - 20 C to 100 °C, more preferably from about 0 C to 60 °C for 5 minutes to 1 week, more preferably 30 minutes to 24 hours, will usually suffice. Suitable coupling reagents are those typically used in peptide synthesis including, for example, diimides (e.g., dicyclohexylcarbodiimide (DCC), water soluble carbodiimide (WSC)), O-benzotriazol-1 - yl-Λ/, /,Λ/',Λ/'-tetramethyluronium hexafluorophosphate (HBTU), 2-ethoxy-Λ/- ethoxycarbonyl-1 ,2-dihydroquinoline, 2-bromo-1 -ethylpyridinium tetrafluoroborate (BEP), 2-chloro-1 ,3-dimethylimidazolinium chloride, benzotriazol-1 -yloxy- tris(dimethylamino)phosphonium hexafluorophosphate (BOP), diethyl azodicarboxylate- triphenylphosphine, diethylcyanophosphate, diethylphosphorylazide, 2-chloro-1 - methylpyridinium iodide, N, Λ/'-carnbonyldiimidazole , benzotriazole-1 -yl diethyl phosphate, ethyl chloroformate or isobutyl chloroformate. If desired, the reaction may be carried out in the presence of a base such as, Λ/,Λ/-diisopropylethylamine, N- methylmorpholine, 4-(dimethylamino)pyridine and triethylamine. The amide compound of formula (I) may be formed via an acylhalide, which may be obtained by the reaction with halogenating agents such as oxalylchloride, phosphorus oxychloride and thionyl chloride. The resulting acylhalide may be converted to the corresponding amide compound by treating with the amine compound of formula 1-13 under the similar conditions as described in this step.
Scheme 2 (only for compounds of formula (la))
Figure imgf000018_0001
2-4 2-5
Figure imgf000018_0002
In the above formula, Ra and L1 are defined above. Step 2A In this step, a compound of formula 2-2 may be prepared by Michael reaction of the compound of formula 1-8 with an enone compound of formula 2-1. This reaction is essentially the same as and may be carried out in the same manner as and using the same reagents and reaction conditions as Step 1 H in Scheme 1. Step 2B In this step, an acid compound of formula 2-3 may be prepared by hydrolysis of the compound of formula 2-2. This reaction is essentially the same as and may be carried out in the same manner as and using the same reagents and reaction conditions as Step 11 in Scheme 1. Step 2C In this step, an amide compound of formula 2-4 may be prepared by coupling of the amine compound of formula 1 -13 with the acid compound of formula 2-3. This reaction is essentially the same as and may be carried out in the same manner as and using the same reagents and reaction conditions as Step 1 J in Scheme 1. Step 2D In this step, the compound of formula 2-4 may be converted to a compound with a leaving group L1 of formula 2-5 under conditions known to those skilled in the art. This reaction is essentially the same as and may be carried out in the same manner as and using the same reagents and reaction conditions as Step 1 A in Scheme 1. Step 2E In this step, the compound of formula (I) can be prepared by replacement of the leaving group of the compound of formula 2-5 with a compound of formula R5H in the presence of a base in a reaction-inert solvent. Examples of suitable solvents include: acetonitrile, tetrahydrofuran, /,Λ/-dimethylformamide, dimethylsulfoxide, ether, toluene, ethylene glycol dimethylether or 1 ,4-dioxane. Examples of suitable bases include: lithium hydroxide, sodium hydroxide, potassium hydroxide, barium- hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, thallium(l) carbonate, sodium ethoxide, potassium tert-butoxide, potassium acetate, cesium fluoride, tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium iodide, pyridine, picoline, 4-(Λ/,/V-dimethylamino)pyridine, triethylamine, tributylamine, diisopropylethylamine, Λ/-methylmorphorine and N- methylpiperidine. This reaction may be carried out at a temperature in the range from 0 °C to 250 °C, usually from -10 °C to 150 °C for 5 minutes to 72 hours, usually 30 minutes to 36 hours.
Scheme 3
Figure imgf000020_0001
In the above formula, Ra and L1 are defined above. Step 3A In this step, the compound of formula 2-2 may be converted to a compound with a leaving group L1 of formula 3-1 under conditions known to those skilled in the art. This reaction is essentially the same as and may be carried out in the same manner as and using the same reagents and reaction conditions as Step 2D in Scheme 2. Step 3B In this step, a compound of formula 3-2 can be prepared by replacement of the leaving group of the compound of formula 3-1 with the compound of formula R5H. This reaction is essentially the same as and may be carried out in the same manner as and using the same reagents and reaction conditions as Step 2E in Scheme 2. Step 3C In this step, a compound of formula 3-3 may be prepared by hydrolysis of the compound of formula 3-2. This reaction is essentially the same as and may be carried out in the same manner as and using the same reagents and reaction conditions as Step 11 in Scheme 1. Step 3D In this step, which applies only to the preparation of compounds of formula (la), the compound of formula (la) may be prepared by coupling of the amine compound of formula 1 -13 with the acid compound of formula 3-3. This reaction is essentially the same as and may be carried out in the same manner as and using the same reagents and reaction conditions as Step 1 J in Scheme 1. In the above Schemes from 1 to 3, examples of suitable solvents include a mixture of any two or more of those solvents described in each step. The starting materials in the aforementioned general syntheses are commercially available or may be obtained by conventional methods known to those skilled in the art. The compounds of formula (I), and the intermediates above-mentioned preparation methods can be isolated and purified by conventional procedures, such as recrystallization or chromatographic purification. The various general methods described above may be useful for the introduction of the desired groups at any stage in the stepwise formation of the required compound, and it will be appreciated that these general methods can be combined in different ways in such multi-stage processes. The sequence of the reactions in multi-stage processes should of course be chosen so that the reaction conditions used do not affect groups in the molecule which are desired in the final product.
Suitable nociceptin receptor antagonists also include compounds of formula (II) as claimed in WO 03/064425:
Figure imgf000021_0001
(II) or a pharmaceutically acceptable salt or solvate thereof, wherein
R a through R12a are independently selected from the group consisting of hydrogen; halo; hydroxy; cyano; (CrC6)alkyl; (CrC6)alkyl substituted with one to five halo which may be same or different; (d-C6)alkyl substituted with one to five substituents independently selected from the group consisting of hydroxy, amino, [(d-C6)alkyl]NH-, [(d-C6)alkyl]2N, H2NC(=O)-, [(Cι-Cβ)alkyl]NHC(=0)-, [(Cι-C6)alkyl]2NC(=O)-, (d-C6)alkoxy and a fully saturated five to six membered heterocyclyl containing one to two hetero atoms independently selected from nitrogen and oxygen; (d-C6)alkoxy; (d-C6)alkoxy substituted with one to five halo which may be same or different; (d-C6)alkoxy substituted with one to five substituents independently selected from the group consisting of hydroxy, amino, [(d-C6)alkyl]NH-, [(Cι-C6)alkyl]2N-, H2NC(=O)-, [(d- C6)alkyl]NHC(=O)- and [(d-C6)alkyl]2NC(=O)-; amino; [(d-C6)alkyl]NH-; [(d-C6)alkyl]2N; carboxy; [(C C6)alkoxy]C(=O)-; H2NC(=O)-; [(C C6)alkyl]NHC(=O)-; [(d- C6)alkyl]NHC(=O)- wherein said (Cι-C6)alkyl is substituted with one hydroxy; [(d- C6)alkyl]2NC(=O)-; [(Cι-C6)alkyl]2NC(=O)-wherein either or both of (d-C6)alkyl is substituted with one hydroxy; aryl selected from phenyl and naphthyl; and four- to eight- membered heterocyclyl containing one to four hetero atoms in the ring independently selected from nitrogen, oxygen and sulfur; or two of R1a, R2a, R3a and R a groups taken together form -CH2- or -(CH2)2- and the remaining two groups are defined as above; X1a and X2a are independently selected from CH2; CH-hydroxy; O; NH; S; C(=O); SO2; and [(d-C6)alkyl]N, or X a and X2a taken together form CH=CH; R13a is selected from the group consisting of hydrogen; hydroxy; (d-C6)alkyl; (d-C6)alkyl substituted with one to five halo which may be same or different; and (d-C6)alkyl substituted with one to five substituents independently selected from the group consisting of hydroxy, amino, [(d-C6)alkyl]NH-, [(d-C6)alkyl]2N-, H2NC(=O)-, [(C C6)alkyl]NHC(=O)-, [(d-C6)alkyl]2NC(=O)-, (d- C6)alkoxy and a fully saturated five to six membered heterocyclyl containing one to two hetero atoms independently selected from nitrogen and oxygen; or
R12a and R13a taken together with the three ring atoms of the dihydro- or tetrahydroquinoline ring separating said substituents form a five to seven membered ring which is partially or fully unsaturated, wherein the ring atom not shared with the dihydro- or tetrahydroquinoline ring and adjacent to the nitrogen atom in the dihydro- or tetrahydroquinoline ring is a carbon atom; the remaining one to three ring atoms not shared with the dihydro- or tetrahydroquinoline ring are carbon atoms, one of said carbon atoms being optionally replaced with a nitrogen, oxygen or sulfur atom; and one or two of the carbon and nitrogen atoms not shared with the dihydro- or tetrahydro- quinoline ring are optionally substituted with substituents independently selected from oxo; hydroxy; (d-C6)alkyl; (C C6)alkyl substituted with one to five halo which may be same or different; (d-C6)alkyl substituted with one to five substituents independently selected from the group consisting of hydroxy, amino, [(d-C6)alkyl]NH-, [(d-C6)alkyl]2N, H2NC(=O)-, [(d-C6)alkyl]NHC(=O)-, [(d-C6)alkyl]2NC(=O)-, (d-C6)alkoxy and a fully saturated five to six membered heterocyclyl containing one to two hetero atoms independently selected from nitrogen and oxygen; (d-C6)alkoxy; (d-C6)alkoxy substituted with one to five halo which may be same or different; (d-C6)alkoxy substituted with one to five substituents independently selected from the group consisting of hydroxy, amino, [(C C6)alkyl]NH-, [(Cι-C6)alkyl]2N-, H2NC(=O)-, [(d- C6)alkyl]NHC(=O)- and [(d-C6)alkyl]2NC(=O)-; amino; [(d-C6)alkyl]NH-; and [(C C6)alkyl]2N-; both R 4a and R15a are hydrogen or taken together form oxo; and the dotted line represents a single or double bond.
Preferred nociceptin receptor antagonists are compounds of formula (II) wherein both R14a and R15a are hydrogen. Other preferred nociceptin receptor antagonists are compounds wherein R14a and R15a taken together form oxo.
Further preferred nociceptin receptor antagonists are compounds of formula (II) wherein X1a and X2a are independently selected from the group consisting of CH2, O, NH and [(d-C6)alkyl]N or taken together form CH=CH.
Further preferred nociceptin receptor antagonists are compounds of formula (II) wherein R a, R a, R3a and R4a are all hydrogen.
Further preferred nociceptin receptor antagonists are compounds of formula (II) wherein R5a, R6a, R7a and R8a are all hydrogen.
Further preferred nociceptin receptor antagonists are compounds of formula (II) wherein R9a, R10a and R11a are independently selected from the group consisting of hydrogen; halo; hydroxy; cyano; (d-C6)alkyl; (Cι-C6)alkyl substituted with one to five halo which may be same or different; (d-C6)alkyl substituted with one to five substituents independently selected from the group consisting of hydroxy, amino, [(Cι-C6)alkyl]NH-, [(d-C6)alkyl]2N, H2NC(=C)-, [(Cι-C6)alkyl]NHC(=O)-, [(d-C6)alkyl]2NC(=O)-, (C,- C6)alkoxy and a fully saturated five to six membered heterocyclyl containing one to two hetero atoms independently selected from nitrogen and oxygen; H2NC(=O)-; [(d- C6)alkyl]NHC(=O)- and [(d-C6)alkyl]2NC(=O)-.
Further preferred nociceptin receptor antagonists are compounds of formula (II) wherein R12a is selected from the group consisting of hydrogen; halo; hydroxy; cyano; (d- C6)alkyl; (d-C6)alkyl substituted with one to five halo which may be same or different; (d-C6)alkyl substituted with one to five substituents independently selected from the group consisting of hydroxy, amino, [(d-C6)alkyl]NH-, [(d-CeJalkyl^N-, H2NC(=O)-, [(C C6)alkyl]NHC(=O)-, [(d-C6)alkyl]2NC(=O)-, (Cι-C6)alkoxy and a fully saturated five to six membered heterocyclyl containing one to two hetero atoms independently selected from nitrogen and oxygen; H2NC(=O)-; [(d-C6)alkyl]NHC(=O)- and [(d-C6)alkyl]2NC(=O)-.
Further preferred nociceptin receptor antagonists are compounds of formula (II) wherein
R 313a is selected from a group consisting of hydrogen; hydroxy; (d-C6)alkyl; (C C6)alkyl substituted with one to five halo which may be same or different; and (d-C6)alkyl substituted with one to five substituents independently selected from the group consisting of hydroxy, amino, [(CrC6)alkyl]NH-, [(d-C6)alkyl]2N-, H2NC(=O)-, [(d- C6)alkyl]NHC(=O)-, [(d-C6)alkyl]2NC(=O)-, (C C6)alkoxy and a fully saturated five to six membered heterocyclyl containing one to two hetero atoms independently selected from nitrogen and oxygen.
Further preferred individual nociceptin receptor antagonists of formula (II) are selected from: 2,3-dihydro-1 '-[(2-oxo-1 ,2,3,4-tetrahydro-3-quinolinyl)methyl]spiro[1 H-indene-1 ,4'- piperidine];
3-(2,3-dihydro-1 Η-spiro[indene-1 ,4'piperidin]- -ylmethyl)-8-methoxy-3,4-dihydroquinolin-
2(1 H)-one;
8-hydroxy-3-[(1 -methyl-1 ,2-dihydro-1 'H-spiro[indole-3,4'-piperidin]-1 '-yl)methyl]-3,4- dihydroquinolin-2(1 H)-one;
8-hydroxy-3-(1 'H,3H-spiro[2-benzofuran-l,4'-piperidin]-1 '-ylmethyl)-3,4-dihydroquinolin-
2(1 H)-one;
3-(2,3-dihydro-1 Η-spiro[indene-1 ,4'-piperidin]-1 '-ylmethyl)-8-(hydroxymethyl)-3,4- dihydroquinolin-2(1 H)-one; 8-chloro-3-(2,3-dihydro-1 Η-spiro[indene-1 ,4'-piperidin]-1 '-ylmethyl)-3,4-dihydroquinolin-
2(1 H)-one;
5-chloro-3-(2,3-dihydro-1 Η-spiro[indene-1 ,4'-piperidin]-1 '-ylmethyl)-3,4-dihydroquinolin-
2(1 H)-one;
8-(aminomethyl)-3-(2,3-dihydro-1 'H-spiro[indene-1 ,4'-piperidin]-1 '-ylmethyl)-3,4- dihydroquinolin-2(1 H)-one;
6-(2,3-dihydro-1 'H-spiro[indene-1 ,4'piperidin]-1 '-ylmethyl)-6,7-dihydro-5H-
[1 ,4]oxazino[2,3,4-ij]quinolin-3(2H)-one;
6-(2,3-dihydro-1 'H-spiro[indene-1 ,4'-piperidin]-1 '-ylmethyl)-1 ,2,6,7-tetrahydro-3H,5H- pyrido[3,2,1 -ij]quinazolin-3-one and and pharmaceutically acceptable salts and solvates thereof.
Another aspect of the invention is the use of a compound of formula (III), which are described in WO 05/016913:
Figure imgf000025_0001
or a pharmaceutically acceptable ester or amide of such compound, or a pharmaceutically acceptable salt thereof, wherein
X1b represents an oxygen atom; or N-R12b wherein R12b is selected from the group consisting of a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkanoyl group having 1 to 6 carbon atoms, an alkylaminocarbonyl group having 1 to 6 carbon atoms in the alkyl group, an aryl group as defined below, an arylalkyl group having 1 to 6 carbon atoms in the alkyl part and the aryl part as defined below, a heteroaryl group as defined below and a heteroarylalkyl group having 1 to 6 carbon atoms in the alkyl part and heteroaryl part as defined below;
R 1 and R2 each independently represent a hydrogen atom; an alkyl group having 1 to 6 carbon atoms; an alkoxy group having 1 to 6 carbon atoms; an alkanoyl group having 1 to 6 carbon atoms; an alkylcarbonylamino group having 1 to 6 carbon atoms in the alkyl part; an alkylaminocarbonyl group having 1 to 6 carbon atoms in the alkyl part; a mono-hydroxyalkyl group having 1 to 6 carbon atoms; a mono-aminoalkyl having 1 to 6 carbon atoms; or an alkoxyalkyl group having 1 to 6 carbon atoms in the alkoxy group and 1 to 6 carbon atoms in the alkyl part; or R1b and R2b taken together form oxo;
R3b, R45, R5b and R6b each independently represent a hydrogen atom; a halogen atom; a hydroxy group; an alkyl group having 1 to 6 carbon atoms; an alkoxy group having 1 to 6 carbon atoms; an alkanoyl group having 1 to 6 carbon atoms; a mono-hydroxyalkyl group having 1 to 6 carbon atoms; a mono-aminoalkyl group having 1 to 6 carbon atoms; an alkylcarbonylamino group having 1 to 6 carbon atoms in the alkyl part; an alkylaminocarbonyl group having 1 to 6 carbon atoms in the alkyl part; an alkylaminosulfonyl group having 1 to 6 carbon atoms in the alkyl part; an aryl group as defined below which is linked directly to the benzene ring or is attached via a spacer group to the benzene ring, and the spacer group is defined as below; or a heteroaryl group as defined below which is linked directly to the benzene ring or is attached via a spacer group to the benzene ring, and the spacer group is defined as below; provided that at least one of R3b through R6b must represent a hydrogen atom.
R7b and R8b both represent hydrogen atoms or taken together form oxo;
R9b, R10 and R11b each independently represent a hydrogen atom, a halogen atom or an alkyl group having 1 to 6 carbon atoms;
X2 , X3b and X4 each independently represent methylene, an oxygen atom, NR13b, where R 3b is defined as a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, or carbonyl, provided that at least one of X2b, X3b and X4 must represent methylene or carbonyl; or
X4b represents a bond and X2 and X3b each independently represent methylene, an oxygen atom, NR13b, where R13b is defined as a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, carbonyl, provided that at least one of X2b and X3b must be methylene or carbonyl;
Wherein the methylene in the definitions of X2b, X3b and X is each independently unsubstituted or substituted by at least one alkyl groups having 1 to 6 carbon atoms;
X5b represents a -CR14b or a nitrogen atom wherein R14b represents a hydrogen atom, a halogen atom or an alkyl group having 1 to 6 carbon atoms; Said amino parts of the alkylcarbonylamino groups and alkylaminocarbonyl groups in the definitions of R1b through R6 and R12b are unsubstituted or substituted by an alkyl group having 1 to 6 carbon atoms;
Said aryl groups and aryl parts of aralkyl groups referred to in the definitions of R1 through R6b and R12b are aromatic hydrocarbon groups having 5 to 14 carbon atoms; Said heteroaryl groups and heteroaryl parts of the heteroarylalkyl groups referred to in tthhee ddeeffiinniittiioonnss ooff RR33bb tthhrroouugghh RR66bb aanndd RR11 aarree 55-- ttoo 77--ιmembered heteroaryl groups containing 1 to 3 oxygen, sulfur and/or nitrogen atoms; and SSaaiidd ssppaacceerr ggrroouuppss rreeffeerrrreedd ttoo iinn tthhee ddeeffiinniittiioonnss ooff RR11bb aamnd R2 are each independently selected from the groups consisting of an oxygen atom, sulfonyl and carbonyl
Suitable compounds of formula (III) are selected from:
1 '-(1 ,2,3,4-tetrahydroisoquinolin-3-ylmethyl)-2,3-dihydrospiro[indene-1 ,4'-piperidine];
1 '-[(2-acetyl-1 ,2,3,4-tetrahydroisoquinolin-3-yl)methyl]-2,3-dihydrospiro[indene-1 ,4'- piperidine];
1 '-[(2-methyl-1 ,2,3,4-tetrahydroisoquinolin-3-yl)methyl]-2,3-dihydrospiro[indene-1 ,4'- piperidine];
1 '-[(3S)-1 ,2,3,4-tetrahydroisoquinolin-3-ylmethyl]-2,3-dihydrospiro[indene-1 ,4'- piperidine]; (3R)-3-(2,3-dihydro-1 Η-spiro[indene-1 ,4'-piperidin]-1 '-ylmethyl)-1 ,2,3,4- tetrahydroisoquinolin-7-ol;
3-(2,3-dihydro-1 Η-spiro[indene-1 ,4'-piperidin]-1 '-ylmethyl)-1 ,2,3,4-tetrahydroisoquinolin-
6-ol;
5-bromo-3-(2,3-dihydro-1 Η-spiro[indene-1 ,4'-piperidin]-1 '-ylmethyl)-1 ,2,3,4- tetrahydroisoquinolin-8-ol;
3-(2,3-dihydro-1 Η-spiro[indene-1 ,4'-piperidin]-1 '-ylmethyl)-2-methyl-1 ,2,3,4- tetrahydroisoquinolin-8-ol;
3-(2,3-dihydro-1 Η-spiro[indene-1 ,4'-piperidin]-1 '-ylmethyl)-1 ,2,3,4-tetrahydroisoquinolin-
8-ol; 3-(2,3-dihydro-1 Η-spiro[indene-1 ,4'-piperidin]-1 '-ylmethyl)-5-fluoro-1 ,2,3,4- tetrahydroisoquinolin-8-ol;
5-fluoro-3-[(1 -methyl-1 ,2-dihydro-1 'H-spiro[indole-3,4'-piperidin]-1 '-yl)methyl]-1 ,2,3,4- tetrahydroisoquinolin-8-ol;
5-chloro-3-(2,3-dihydro-1 Η-spiro[indene-1 ,4'-piperidin]-1 '-ylmethyl)-1 ,2,3,4- tetrahydroisoquinolin-8-ol;
5-chloro-3-(1 Η,3H-spiro[2-benzofuran-1 ,4'-piperidin]-1 '-ylmethyl)-1 ,2,3,4- tetrahydroisoquinolin-8-ol; 5-chloro-3-[(1 -methyl-1 ,2-dihydro-1 Η-spiro[indole-3,4'-piperidin]-1 '-yl)methyl]-1 ,2,3,4- tetrahydroisoquinolin-8-ol;
1 '-{[(3S)-1 -methyl-1 ,2,3,4-tetrahydroisoquinolin-3-yl]methyl}-2,3-dihydrospiro[indene-1 ,4'- piperidine]; 3-[(3,3-dimethyl-1 Η,3H-spiro[2-benzofuran-1 ,4'-piperidin]-1 '-yl)methyl]-1 ,2,3,4- tetrahydroisoquinolin-8-ol;
3-[(1 '-methyl-1 ',2'-dihydro-1 H-spiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1 -yl)methyl]-
1 ,2,3,4-tetrahydroisoquinolin-8-ol;
3-[(6-fluoro-1 'H,3H-spiro[2-benzofuran-1 ,4'-piperidine]-1 '-yl)methyl]-1 ,2,3,4- tetrahydroisoquinolin-8-ol;
3-[(5-fluoro-1 -methyl-1 ,2-dihydro-1 Η-spiro[indole-3,4'-piperidin]-1 '-yl)methyl]-1 ,2,3,4- tetrahydroisoquinolin-8-ol;
1 '-[(8-hydroxy-1 ,2,3,4-tetrahydroisoquinolin-3-yl)methyl]-1 -methylspiro[indole-3,4'- piperidin]-2(1 H)-one; 1 '-[5-chloro-8-hydroxy-1 ,2,3,4-tetrahydroisoquinolin-3-yl)methyl]-1 -methylspiro[indole-
3,4'-piperidin]-2(1 H)-one;
1 '-[(5-fluoro-8-hydroxy-1 ,2,3,4-tetrahydroisoquinolin-3-yl)methyl]-1 -methylspiro[indole-
3,4'-piperidin]-2(1 H)-one;
5-fluoro-3-[(6-fluoro-1 Η,3H-spiro[2-benzofuran-1 ,4'-piperidin]-1 '-yl)methyl]-1 ,2,3,4- tetrahydroisoquinolin-8-ol;
5-chloro-3-[(6-fluoro-1 Η,3H-spiro[2-benzofuran-1 ,4'-piperidin]-1 '-yl)methyl]-1 ,2,3,4- tetrahydroisoquinolin-8-ol;
5-chloro-3-[(5-fluoro-1 -methyl-1 ,2-dihydro-1 Η-spiro[indole-3,4'-piperidin]-1 '-yl)methyl]-
1 ,2,3,4-tetrahydroisoquinolin-8-ol; 5-fluoro-3-[(5-fluoro-1 -methyl-1 ,2-dihydro-1 Η-spiro[indole-3,4'-piperidin]-1 '-yl)methyl]-
1 ,2,3,4-tetrahydroisoquinolin-8-ol;
1 '-[(5-chloro-8-hydroxy-1 ,2,3,4-tetrahydroisoquinolin-3-yl)methyl]-5-fluoro-1 - methylspiro[indole-3,4'-piperidin]-2(1 H)-one;
1 '-[(5-chloro-1 ,2,3,4-tetrahydroisoquinolin-3-yl)methyl]-1 -methyl-1 ,2-dihydrospiro[indole- 3,4'-piperidine]; or
5-chloro-3-(2,3-dihydro-1 'H-spiro[indene-1 ,4'-piperidin]-1 '-ylmethyl)-3,4- dihydroisoquinolin-1 (2H)-one; or a pharmaceutically acceptable salt thereof.
3-[(5-fluoro-1 -methyl-1 ,2-dihydro-1 Η-spiro[indole-3,4'-piperidin]-1 '-yl)methyl]-8-hydroxy-
3,4-dihydro-1 H-isochromen-1 -one; 3-(2,3-dihydro-1 'H-spiro[indene-1 ,4'-piperidin]-1 '-ylmethyl)-3,4-dihydro-1 H-isochromen-8- ol or a pharmaceutically acceptable salt thereof. Further nociceptin receptor antagonists are included in patent application WO 03/000677, preferably the compounds exemplified in WO 03/000677, or a pharmaceutically acceptable salt or solvate thereof.
Further suitable nociceptin receptor antagonists can be found in WO 03/095432, especially the preferred compounds listed in WO 03/095432, such as:
5-chloro-6-[4-ethyl-2-methylpiperazin-1 -yl]-2-[(1 ,4-trans)-4-methoxycarbonylamino-1 - methylcyclohexylcarbonyl]benzimidazole;
6-[4-ethyl-2-methylpiperazin-1 -yl]-2-[(1 ,4-trans)-4-methoxycarbonylamino-1 - methylcyclohexylcarbonyl]-5-methylbenzimidazole;
5-chloro-6-[4-(2-hydroxyethyl)-2-methylpiperazin-1 -yl]-2-[(1 ,4-trans)-4- methoxycarbonylamino-1 -methylcyclohexylcarbonyl]benzimidazole;
6-[4-(2-hydroxyethyl)-2-methylpiperazin-1 -yl]-2-[(1 ,4-trans)-4-methoxycarbonylamino-1 - methylcyclohexylcarbonyl]-5-methylbenzimidazole; 5-chloro-2-[(1 ,4-trans)-1 -ethyl-4-(methoxycarbonylamino)-cyclohexylcarbonyl]-6-[4-ethyl-
2-methylpiperazin-1-yl]benzimidazole;
2-[(1 ,4-trans)-1-ethyl-4-(methoxycarbonylamino)cyclohexylcarbonyl]-6-[4-ethyl-2- methylpiperazin-1-yl]-5-methyl-benzimidazole;
5-chloro-6-[4-ethyl-2-methylpiperazin-1 -yl]-2-[(1 ,4-trans)-4-hydroxy-1 - methylcyclohexylcarbony!]benzimidazole;
2-(1-acetyl-4-methylpiperidinyl-4-carbonyl)-6-[4-ethyl-2-methylpiperazin-1-yl]-5- methylbenzimidazole;
6-[4-ethyl-2-methylpiperazin-1-yl]-5-methyl-2-(4-methyltetrahydropyranyl-4- carbonyl)benzimidazole; 6-(4-ethyl-2-methylpiperazin-1 -yl)-7-fluoro-2-[(1 ,4-trans)-4-methoxycarbonylamino-1 - methylcyclohexylcarbonyl]-5-methylbenzimidazole;
5-chloro-2-[(1 ,4-trans)-1 ,4-dimethyl-4-hydroxycycIohexylcarbonyl]-6-(4-ethylpiperazin-1 - yl)benzimidazole;
5-chloro-6-(4-ethylpiperazin-1 -yl)-2-[(1 ,4-trans)-4-methoxycarbonylamino-1 - methoxymethylcyclohexylcarbonyl]benzimidazole;
6-[(S)-1 ,4-diazabicyclo[4.3.0]nonan-4-yf]-2-[(1 ,4-trans)-4-hydroxy-1 -methoxymethyl-4- methylcyclohexylcarbonyl]-5-methylbenzimidazole;
6-(4-ethylpiperazin-1 -yl)-2-[(1 ,4-trans)-4-hydroxy-1 -methoxymethyl-4- methylcyclohexylcarbonyl]-5-methylbenzimidazole. Suitable nociceptin receptor antagonists can also be found in patent applications WO 98/54168, US 6,258,825, WO 99/29696, WO 00/31061 , WO 00/34280, WO 01/012195, WO 01/32178, WO 01/036418, WO 01/83454, WO 02/40019, WO 02/088089, WO 02/26714, WO 02/090317, WO 02/090330, WO 03/008371 , WO 03/095427, WO 04/022558, WO 04/058248, WO 05/001693, WO 05/005411 , EP 963985, EP 963987, EP 970957, JP 2000-169476.
Yet a further aspect of the invention is a method of screening for compounds useful for treating urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder, urgency, urge incontinence, frequency, nocturia and/or mixed urinary incontinence, comprising screening compounds for antagonist activity against the nociceptin receptor, and selecting compounds with an IC50 of less than 100nM, preferably with an IC50 of less than 10nM, even more preferably with an IC50 of less than 1 nM.
Another aspect of the invention is a process for providing a medicament for the treatment of urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder, urgency, urge incontinence, frequency, nocturia and/or mixed urinary incontinence, comprising the following steps:
(a) testing compounds in a ligand binding assay against the nociceptin receptor;
(b) selecting a compound with an IC50 of less than 100 nM; (c) formulating a compound with the same structure as that selected in step (b), or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier or excipient; the process may also comprise the additional steps of:
(d) packaging the formulation of step (c); and
(e) making the package of step (d) available to a patient suffering from a urinary condition mentioned above.
Preferably, the compound selected in step (b) will have an IC50 of less than 10nM, even more preferably it will have an IC50 of less than 1 nM.
Yet another aspect of the invention is a process for providing a medicament for the treatment of urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder, urgency, urge incontinence, frequency, nocturia and/or mixed urinary incontinence, comprising the following steps:
(a) testing compounds in an assay, measuring the inhibition of the agonist- stimulated second messenger response of the nociceptin receptor; (b) selecting a compound with an IC50 of less than 10OnM;
(c) formulating a compound with the same structure as that selected in step (b), or a pharmaceutically acceptable carrier or excipient; the process may also comprise the additional steps of:
(d) packaging the formulation of step (c); and (e) making the package of step (d) available to a patient suffering from a urinary condition mentioned above.
Preferably, the assay in step (a) measures the inhibition of the nociceptin receptor agonist-mediated inhibition of forskolin-stimulated cAMP responses. Even more preferably, the assay in step (a) measures the inhibition of agonist-stimulated GTPγS binding. Preferably, the compound selected in step (b) will have an IC50 of less than 10 nM, even more preferably it will have an IC50 of less than 1 nM.
Another aspect of the invention is a process for preparing a medicament for the treatment of urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder, urgency, urge incontinence, frequency, nocturia and/or mixed urinary incontinence, comprising the steps of (a) testing compounds in a ligand binding assay against nociceptin receptor or testing compounds in an assay, measuring inhibition of the agonist stimulated second messenger response of the nociceptin receptor; (b) identifying one or more compounds capable of antagonising the nociceptin receptor with an IC5o of less than 100nM; and (c) preparing a quantity of those one or more identified compounds. Preferably, the compound(s) selected in step (b) will have an IC50 of less than 10 nM, even more preferably it/they will have an IC50 of less than 1 nM.
Another aspect of the invention is a method of preparing a composition for treating a urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder, urgency, urge incontinence, frequency, nocturia and/or mixed urinary incontinence, which comprises: (a) identifying a compound which specifically binds to the nociceptin receptor by a method which comprises contacting cells expressing the nociceptin receptor or membranes prepared from such cells with a radiolabelled nociceptin receptor ligand in the presence or absence of a test compound, measuring the radioactivity bound to the cells or membranes, comparing the radioactivity bound to the cells or membranes in the presence and absence of test compound, whereby a compound which causes a reduction in the radioactivity bound is a compound specifically binding to the nociceptin receptor; and (b) admixing said compound with a carrier.
Yet another aspect of the invention is a method of preparing a composition for treating urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder, urgency, urge incontinence, frequency, nocturia and/or mixed urinary incontinence, which comprises: (a) identifying a compound which specifically binds to and inhibits the activation of the nociceptin receptor by a method which comprises separately contacting cells expressing the nociceptin receptor on their surface and producing a second messenger response in response to a nociceptin receptor agonist, e.g. nociceptin, or a membrane preparation of such cells, with both the compound and an agonist of nociceptin receptor, and with only the agonist, under conditions suitable for activation of the nociceptin receptor, and measuring the second messenger response in the presence of only the agonist for the nociceptin receptor and in the presence of the agonist and the compound, a smaller change in the second messenger response in the presence of both agonist and compound than in the presence of the agonist only indicating that the compound inhibits the activation of the nociceptin receptor; and (b) admixing said compound with a carrier.
The invention relates to the use of a nociceptin receptor antagonist for the treatment of urinary conditions such as overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence and mixed urinary incontinence, in particular overactive bladder, urgency, urge incontinence, frequency, nocturia and/or mixed urinary incontinence alone, or in combination with one or more other agents such as
• Muscarinic acetylcholine receptor antagonist
• Alpha adrenergic receptor antagonist
• Alpha adrenergic receptor agonist or partial agonist • Serotonin and Noradrenalin reuptake inhibitor (SNRI)
• 5HT2C agonist (see WO 04/096196) • alpha2delta ligand, such as gabapentin or pregabalin.
Reference to a compound, an antagonist, an agonist or an inhibitor shall at all times be understood to include all active forms of such agents, including the free form thereof (e.g. the free and/or base form) and also all pharmaceutically acceptable salts, polymorphs, hydrates, silicates, stereo-isomers (e.g. diastereoisomers and enantiomers) and so forth. Active metabolites of any of the compounds, in any form, are also included.
Particular formulations of the compounds for either oral delivery or for topical application (creams, gels) are included in the invention. A formulation comprising a compound or combination of compounds as defined herein, preferably a formulation which is a creme or a gel, is also included in the invention.
The nociceptin receptor was first identified as an orphan G-protein coupled receptor with sequence homology to opioid receptors, and was named opioid receptor-like- 1 (ORL-1 ) (see Mollereau, C. et al (1994) FEBS Lett. 341 , 33-38). It was later identified as the receptor for nociceptin (Meunier, J-C et al (1995) Nature 377, 532-535; Reinscheid, R.K. et al (1995) Science 270, 792-794), and has also been called Orphanin FQ receptor. Its sequence can be found in SwissProt accession number P41146 for the human receptor; however, mammalian ORL-1 receptors may also be used in the methods of the invention, including rat, mouse (Nishi, M et al (1994) Biochem Biophys Res Comms 205, 1353-1357), guinea pig (SwissProt accession P47748), pig (Osinski, M et al (1999) Eur J Pharmacol 365, 281 -289; SwissProt accession P79292), and others.
As used herein, the term "amino acid sequence" is synonymous with the term "polypeptide" and/or the term "protein". In some instances, the term "amino acid sequence" is synonymous with the term "peptide". In some instances, the term "amino acid sequence" is synonymous with the term "protein".
In addition to the specific amino acid sequences mentioned herein, the present invention also encompasses the use of variants, homologues and derivatives thereof. In the present context, a homologous sequence is taken to include an amino acid sequence which may be at least 75, 85 or 90% identical to the amino acid sequence of the human nociceptin receptor sequence shown in Mollereau, C. et al ((1994) FEBS Lett. 341 , 33-38), preferably at least 95 or 98% identical. In particular, homology should typically be considered with respect to those regions of the sequence known to be essential for an activity. Although homology can also be considered in terms of similarity (i.e. amino acid residues having similar chemical properties/functions), in the context of the present invention it is preferred to express homology in terms of sequence identity. Such sequence homology/identity can be easily assessed by publicly or commercially available bioinformatics software, such as Blast2 (Altschul, S.F. et al (1997) Nucl. Acids Res. 25, 3389-3402), or programs included in the GCG software package (Devereux et al (1984) Nucl. Acids Res. 12, 387; Wisconsin Package Version 10, Genetics Computer Group (GCG, Madison, Wisconsin), such as Bestfit or Gap. In most cases, the default parameters offered by the software, e.g. Bestfit or Gap, for Gap Penalties etc. are suitable for this assessment.
"Potency" as used herein is a measure of how effective a compound is at producing the desired response and can be expressed in terms of the concentration of compound which produces a particular level of the response attainable. Affinity as used herein is a measure of how well a compound binds to or becomes associated with a receptor. The affinity of a compound can be determined in a binding assay as described in Example 2 herein, and affinity in this context will refer to the IC50 of the compound, i.e. to the concentration inhibiting 50% of the labelled compound from binding to the receptors, or to the Ki, which is the inhibition constant of the compound and can be calculated from the IC50, or can also refer to the KD, which is the dissociation constant of the compound. In the present context the potency of a compound is related to its affinity but can also be determined in a functional assay such as an assay measuring the ability of the test compound to antagonise agonist-induced inhibition of forskolin-stimulated cAMP production, or agonist induced GTPγS formation (Example 3 herein), both of which will provide a functional measure of antagonist affinity/potency. Potency could also, although not exclusively, be defined using an anaesthetised animal model to test the effect of compounds on bladder capacity as described in Example 1 herein. The potency/efficacy in this case could refer to the ED50 of the compound, i.e. the administered dose which shows 50% of the maximal response to that or another nociceptin receptor antagonist compound, or could refer to the dose of compound required to elicit a defined increase in bladder capacity or a defined change in any other measurable urological parameter.
"Selectivity" as used herein is a measure of the relative potency of a drug between two receptor subtypes for the same ligand. This can be determined in binding assays, e.g. as described in Example 2 herein, or in functional assays, e.g. as described in Example 3 herein.
For the avoidance of doubt, the term "compound" may refer to a chemical or biological agent, and includes, for example, antibodies, antibody fragments, other proteins, peptides, sugars, any organic or inorganic molecules. Compounds that may be used for screening include, but are not limited to, peptides such as, for example, soluble peptides, including but not limited to members of random peptide libraries; (see, e.g.,
Lam et al. (1991 ) Nature 354, 82-84; Houghten et al. (1991 ) Nature 354, 84-86), and combinatorial chemistry-derived molecular library made of D- and or L- configuration amino acids, phosphopeptides (including, but not limited to, members of random or partially degenerate, directed phosphopeptide libraries; see, e.g., Songyang et al. (1993)
Cell 72, 767-778), antibodies (including, but not limited to, polyclonal, monoclonal, humanized, anti-idiotypic, chimeric or single chain antibodies, and Fab, F(ab')2 and Fab expression library fragments, and epitope-binding fragments thereof), and small organic or inorganic molecules.
The skilled person will be well aware how to obtain antibodies or antibody fragments that recognise the nociceptin receptor and can then be screened by the methods of the invention for their potential to be suitable for use in the treatment of urinary conditions mentioned above. For the production of antibodies, various host animals may be immunized by injection with nociceptin receptor, a nociceptin receptor peptide (e.g. one corresponding to extracellular loops or the extracellular domain), truncated nociceptin receptor polypeptides (nociceptin receptor in which one or more domains, e.g. the transmembrane domain or cellular domain, has been deleted), functional equivalents of nociceptin receptor or mutants of nociceptin receptor. Such host animals may include but are not limited to rabbits, mice, hamsters, rats, goats, sheep, to name but a few. Various adjuvants may be used to increase the immunological response, depending on the host species, including but not limited to Freund's (complete and incomplete), mineral gels such as aluminum hydroxide, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanin, dinitrophenol, and potentially useful human adjuvants such as BCG (bacille Calmette-Guerin) and Corynebacterium patvum. Polyclonal antibodies are heterogeneous populations of antibody molecules derived from the sera of the immunized animals.
Monoclonal antibodies, which are homogeneous populations of antibodies to a particular antigen, may be obtained by any technique which provides for the production of antibody molecules by continuous cell lines in culture. These include, but are not limited to, the hybridoma technique of Kohler and Milstein, ((1975) Nature 256, 495-497 and U.S. Patent No. 4,376,110), the human B-cell hybridoma technique (Kosbor et al. (1983) Immunology Today 4, 72; Coie et al. (1983) Proc. Natl. Acad. Sci. USA 80, 2026-2030), and the EBV-hybridoma technique (Cole et al. (1985) Monoclonal Antibodies And Cancer Therapy, Alan R. Liss, Inc., pp. 77-96). Such antibodies may be of any immunoglobulin class including IgG, IgM, IgE, IgA, IgD and any subclass thereof. The hybridoma producing the mAb of this invention may be cultivated in vitro or in vivo. Production of high titers of mAbs in vivo makes this the presently preferred method of production.
In addition, techniques developed for the production of "chimeric antibodies" (Morrison et al. (1984) Proc. Natl. Acad. Sci., 81 , 6851-6855; Neuberger et al. (1984) Nature, 312, 604-608; Takeda et al. (1985) Nature, 314, 452-454) by splicing the genes from a mouse antibody molecule of appropriate antigen specificity together with genes from a human antibody molecule of appropriate biological activity can be used. A chimeric antibody is a molecule in which different portions are derived from different animal species, such as those having a variable region derived from a murine mAb and a human immunoglobulin constant region.
Alternatively, techniques described for the production of single chain antibodies (U.S. Patent 4,946,778; Bird (1988) Science 242, 423-426; Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85, 5879-5883; and Ward et al. (1989) Nature 334, 544-546) can be adapted to produce single chain antibodies against nociceptin receptor gene products. Single chain antibodies are formed by linking the heavy and light chain fragments of the Fv region via an amino acid bridge, resulting in a single chain polypeptide.
Antibody fragments which recognize specific epitopes may be generated by known techniques. For example, such fragments include but are not limited to: the F(ab')2 fragments which can be produced by pepsin digestion of the antibody molecule and the Fab fragments which can be generated by reducing the disulfide bridges of the F(ab')2 fragments or by papain digestion of antibody molecules. Alternatively, Fab expression libraries may be constructed (Huse et al. (1989) Science, 246, 1275-1281 ) to allow rapid and easy identification of monoclonal Fab fragments with the desired specificity.
Antibodies to nociceptin receptor may also be obtained by generating anti-idiotype antibodies against a nociceptin receptor ligand, e.g. nociceptin itself, using techniques well known to those skilled in the art (see, e.g. Greenspan & Bona (1993) FASEB J 7, 437-444; and Nissinoff (1991 ) J. Immunol. 147, 2429-2438).
The suitability of the nociceptin receptor antagonist can be readily determined by evaluation of their potency and selectivity using methods such as those disclosed herein, followed by evaluation of their toxicity, pharmacokinetics (absorption, metabolism, distribution and elimination), etc in accordance with standard pharmaceutical practice. Suitable compounds are those that are potent and selective, have no significant toxic effect at the therapeutic dose, and preferably are bioavailable following oral administration.
Oral bioavailablity refers to the proportion of an orally administered drug that reaches the systemic circulation. The factors that determine oral bioavailability of a drug are dissolution, membrane permeability and hepatic clearance. Typically, a screening cascade of firstly in vitro and then in vivo techniques is used to determine oral bioavailablity.
Dissolution, the solubilisation of the drug by the aqueous contents of the gastro-intestinal tract (GIT), can be predicted from in vitro solubility experiments conducted at appropriate pH to mimic the GIT. Preferably the nociceptin receptor antagonists have a minimum solubility of 50μg/ml. Solubility can be determined by standard procedures known in the art such as described in Lipinski CA et al.; Adv. Drug Deliv. Rev. 23(1-3), 3-25, 1997.
Membrane permeability refers to the passage of a compound through the cells of the
GIT. Lipophilicity is a key property in predicting this and is determined by in vitro Log
D74 measurements using organic solvents and buffer. Preferably the nociceptin receptor antagonists have a Log D74 of -2 to +4, more preferably -1 to +3. The Log D can be determined by standard procedures known in the art such as described in Stopher, D and McClean, S; J. Pharm. Pharmacol. 42(2), 144, 1990.
Cell monolayer assays such as those using the Caco-2 cell line add substantially to prediction of favourable membrane permeability in the presence of efflux transporters such as P-glycoprotein, so-called Caco-2 flux. Preferably, the nociceptin receptor antagonists have a Caco-2 flux of greater than 2x10"6cms'1, more preferably greater than 5x10'6cms"1. The Caco-2 flux value can be determined by standard procedures known in the art such as described in Artursson, P and Magnusson, C; J. Pharm. Sci, 79(7), 595-600, 1990.
Metabolic stability addresses the ability of the GIT to metabolise compounds during the absorption process or the liver to do so immediately post-absorption: the first pass effect. Assay systems such as microsomes, hepatocytes etc are predictive of metabolic lability. Preferably nociceptin receptor antagonists show metabolic stability in the assay system that is commensurate with an hepatic extraction of less then 0.5. Examples of assay systems and data manipulation are described in Obach, RS; Curr. Opin. Drug Disc. Devel. 4(1 ), 36-44, 2001 and Shibata, Y et al.; Drug Met. Disp. 28(12), 1518-1523, 2000.
Because of the interplay of the above processes, further support that a drug will be orally bioavailable in humans can be gained by in vivo experiments in animals. Absolute bioavailability is determined in these studies by administering the compound separately or in mixtures by the oral route. For absolute determinations (% orally bioavailable) the intravenous route is also employed. Examples of the assessment of oral bioavailability in animals can be found in Ward, KW et al.; Drug Met. Disp. 29(1), 82-87, 2001 ; Berman, J et al.; J. Med. Chem. 40(6), 827-829, 1997 and Han KS and Lee, MG; Drug Met. Disp. 27(2), 221-226, 1999.
The compounds of the invention can be administered alone but will generally be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
For example, the compounds of the invention can be administered orally, buccally or sublingually in the form of tablets, capsules, multi-particulates, gels, films, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications. The compounds of the invention may also be administered as fast-dispersing or fast- dissolving dosage forms or in the form of a high energy dispersion or as coated particles. Suitable formulations may be in coated or uncoated form, as desired.
Such solid pharmaceutical compositions, for example, tablets, may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably corn, potato or tapioca starch), disintegrants such as sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
The following formulation examples are illustrative only and are not intended to limit the scope of the invention. Active ingredient means a compound of the invention.
Formulation 1 :
A tablet is prepared using the following ingredients : Active ingredient (50mg) is blended with cellulose (microcrystalline), silicon dioxide, stearic acid (fumed) and the mixture is compressed to form tablets.
Formulation 2:
An intravenous formulation may be prepared by combining active ingredient (100mg) with isotonic saline (1000ml)
The tablets are manufactured by a standard process, for example, direct compression or a wet or dry granulation process. The tablet cores may be coated with appropriate overcoats.
Solid compositions of a similar type may also be employed as fillers in gelatin or HPMC capsules. Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the nociceptin receptor antagonists may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof. Modified release and pulsatile release dosage forms may contain excipients such as those detailed for immediate release dosage forms together with additional excipients that act as release rate modifiers, these being coated on and/or included in the body of the device. Release rate modifiers include, but are not exclusively limited to, hydroxypropylmethyl cellulose, methyl cellulose, sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate, polyethylene oxide, Xanthan gum, Carbomer, ammonio methacrylate copolymer, hydrogenated castor oil, camauba wax, paraffin wax, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, methacrylic acid copolymer and mixtures thereof. Modified release and pulsatile release dosage forms may contain one or a combination of release rate modifying excipients. Release rate modifying excipients may be present both within the dosage form i.e. within the matrix, and/or on the dosage form, i.e. upon the surface or coating.
Fast dispersing or dissolving dosage formulations (FDDFs) may contain the following ingredients: aspartame, acesulfame potassium, citric acid, croscarmellose sodium, crospovidone, diascorbic acid, ethyl acrylate, ethyl cellulose, gelatin, hydroxypropylmethyl cellulose, magnesium stearate, mannitol, methyl methacrylate, mint flavouring, polyethylene glycol, fumed silica, silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, sorbitol, xylitol. The terms dispersing or dissolving as used herein to describe FDDFs are dependent upon the solubility of the drug substance used i.e. where the drug substance is insoluble a fast dispersing dosage form can be prepared and where the drug substance is soluble a fast dissolving dosage form can be prepared.
The compounds of the invention can also be administered parenterally, for example, intracavernosaly, intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion or needleless injection techniques. For such parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art. The following dosage levels and other dosage levels herein are for the average human subject having a weight range of about 65 to 70kg. The skilled person will readily be able to determine the dosage levels required for a subject whose weight falls outside this range, such as children and the elderly.
The dosage of the combination of the invention in such formulations will depend on its potency, but can be expected to be in the range of from 1 to 500mg of nociceptin receptor antagonist for administration up to three times a day. A preferred dose is in the range 10 to 100mg (e.g. 10, 25, 50 and 100mg) of nociceptin receptor antagonist which can be administered once, twice or three times a day (preferably once). However the precise dose will be as determined by the prescribing physician and will depend on the age and weight of the subject and severity of the symptoms.
For oral and parenteral administration to human patients, the daily dosage level of a compound of the invention will usually be from to 5 to 500mg/kg (in single or divided doses).
Thus tablets or capsules may contain from 5mg to 250mg (for example 10 to 10Omg) of the compound of the invention for administration singly or two or more at a time, as appropriate. The physician in any event will determine the actual dosage which will be most suitable for any individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention. The skilled person will appreciate that the compounds of the invention may be taken as a single dose as needed or desired (i.e. prn). It is to be appreciated that all references herein to treatment include acute treatment (taken as required) and chronic treatment (longer term continuous treatment).
The compounds of the invention can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomiser or nebuliser, with or without the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1 ,1 ,1 ,2- tetrafluoroethane (HFA 134A [trade mark]) or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbon dioxide or other suitable gas. In the case of a pressurised aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurised container, pump, spray, atomiser or nebuliser may contain a solution or suspension of the active compound, e.g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of the compounds of the invention and a suitable powder base such as lactose or starch.
Aerosol or dry powder formulations are preferably arranged so that each metered dose or "puff" contains from 1 μg to 50mg of a compound of the invention for delivery to the patient. The overall daily dose with an aerosol will be in the range of from 1 μg to 50mg which may be administered in a single dose or, more usually, in divided doses throughout the day.
Alternatively, the compounds of the invention can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder. The compounds of the invention may also be dermally or transdermally administered, for example, by the use of a skin patch, depot or subcutaneous injection. They may also be administered by the pulmonary or rectal routes.
For application topically to the skin, the compounds of the invention can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
The compounds of the invention may also be used in combination with a cyclodextrin. Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Formation of a drug-cyclodextrin complex may modify the solubility, dissolution rate, bioavailability and/or stability property of a drug molecule. Drug- cyclodextrin complexes are generally useful for most dosage forms and administration routes. As an alternative to direct complexation with the drug the cyclodextrin may be used as an auxiliary additive, e.g. as a carrier, diluent or solubiliser. Alpha-, beta- and gamma-cyclodextrins are most commonly used and suitable examples are described in published international patent applications WO91/11172, WO94/02518 and WO98/55148.
Oral administration of the compounds of the invention is a preferred route, being the most convenient. In circumstances where the recipient suffers from a swallowing disorder or from impairment of drug absorption after oral administration, the drug may be administered parenterally, sublingually or buccally.
Examples
The examples below are carried out using standard techniques, which are well-known and routinely used by those skilled in the art; the examples illustrate but do not limit the invention.
Figure 1 demonstrates the effect of the nociceptin antagonist J-113397 on bladder capacity in anaesthetised spontaneously hypertensive rats (SHR's).
Figure 2 demonstrates the effect of a saline bolus on bladder capacity in anaesthetised SHR's.
Figure 3 shows the effect of SB-61211 1 on bladder capacity in anaesthetised female spontaneously hypertensive rats (SHRs).
Example 1 : Assay showing the beneficial effect of a nociceptin receptor antagonist in the treatment of urinary incontinence
Urethane anaesthetised rats were cannulated at the carotid artery for blood pressure measurements, and at the jugular vein for intravenous infusions. The bladder was catheterised, .and saline infused into the bladder at a rate of 45μl/min. After the bladder trace had stabilised the bladder infusion was turned off. Three separate measurements of bladder capacity were then made with the bladder being emptied after each void, a bladder infusion rate of 150μl/min was used. The mean of these three measurements was used as the baseline for all future measurements. A 0.5ml bolus of saline or J- 113397 was then infused intravenously over 5 minutes. This was followed by a continuous infusion at 17μl/min of saline or J-113397 to maintaine a plasma concentration of 500ng/ml or 10OOng/ml of J-1 13397.
Figure 1 demonstrates the effect of the nociceptin antagonist J-113397 on bladder capacity in anaesthetised SHR rats. The Y axis is percentage change from intitial control readings. The white bar is following saline infusion. The checked bar is following an infusion of J-1 13397 targeting plasma levels of J-113397 at 500ng/ml. The black bar is following an infusion of J-113397 targeting plasma levels of J-113397 at 1000ng/ml. Error bars are SE's. The results demonstrate that J-113397 shows a dose-dependent increase in bladder capacity in these animals. Figure 2 shows the result for time-matched control animals, receiving sequential infusions of saline instead of J-113397. Again, the Y axis is percentage change from initial control readings. The white bar is following the first saline infusion, the checked bar is following the second saline infusion, and the black bar is following the last saline infusion. Error bars are standard errors. Number of animals in each group was 5. The results demonstrate that the increase in bladder capacity in Figure 1 is not the result of the infusion of volume into the animals, but is clearly an effect of J-113397, the nociceptin receptor antagonist.
Figure 3 shows the effect of SB-612111 on bladder capacity in anaesthetised female spontaneously hypertensive rats. Note that after IV bolus dose administration of SB- 61211 1 the amount of saline required to be infused into the bladder in order to evoke a micturition response is greater than that required in the absence of SB-612111
Example 2: Ligand binding assay for identifying nociceptin receptor ligands
Materials: The cell membranes from human HEK-293 cells expressing human nociceptin (ORL-1 ) receptors (Batch 1634) were purchased from Receptor Biology Inc. [3H]Nociceptin (specific activity 150Ci/mmol) and WGA (wheatgerm agglutinin)-SPA beads were obtained from Amersham Pharmacia Biotech K.K. Nociceptin was from Peptide Institute Inc.
Nociceptin receptor binding assay: Competitive displacement analyses were performed in duplicate in a 96-well plate using a scintillation proximity assay (SPA). The membrane preparation (6.3 μg) was incubated for 45 min at 22°C with 0.4nM [3H]nociceptin, 1.0 mg of WGA-SPA beads and 10-fold six different concentrations (0.01 nM to 1000 nM) of compounds in a final volume of 200 /I containing 50mM HEPES buffer pH7.4, 10mM
MgCI2 and 1 mM EDTA. The plate was then centrifuged at 1000 rpm for 1 min. The radioactivity was measured by a 1450 MicroBetaTM(Wallac) Liquid Scintillation Counter.
Nociceptin was tested at three concentrations (0.1 ,1 ,10 nM) in order to validate this experiment. Non-specific binding was determined by the addition of 1μM unlabeled nociceptin. Under these conditions, 98% specific binding was obtained. Each IC50 value was calculated using a Excel CurveFit Macro program. Example 3: Functional assays for detecting nociceptin receptor activity:
(a) GTPγS binding assay:
Cell membranes are prepared from HEK-293 cells transfected with human nociceptin receptor cDNA using standard technology. The membranes are then incubated with 400 pM [35S]GTPγS, 10 or 50 nM nociceptin and various concentrations of test compounds in assay buffer (20mM HEPES, 100 mM NaCI, 5mM MgCI2, 1 mM EDTA, 5mM GDP, 1 mM DTT, pH 7.4), containing 1.5mg of wheat germ agglutinin-coated SPA beads for 60 to 90 minutes at 25°C in a final volume of 200μl.
Basal binding is assessed in the absence of nociceptin and non-specific binding is defined by the addition of unlabelled 10mM GTPγS. Membrane-bound radioactivity is detected by a Liquid Scintillation Counter.
(b) Reporter gene assay:
HEK293 CRE-βlac cells are transfected with human nociceptin receptor cDNA in pcDNA3.1 Zeo using standard technology. Following Zeocin selection, clones are screened for nociceptin agonist-mediated inhibition of forskolin-stimulated cAMP responses using a commercial cAMP assay kit (Amersham BIOTRAK cAMP).
The nociceptin receptor is a GHinked GPCR. Stimulation of HEK293 CRE β-lac nociceptin receptor cells with forskolin leads to increased cAMP levels and hence increased β-lactamase. A nociceptin receptor agonist (i.e. nociceptin) will inhibit this stimulation, thus reducing β-lactamase levels. However, in the presence of a nociceptin receptor antagonist compound, the effect of nociceptin on β-lactamase production will be blocked. This screen therefore aims to identify antagonists of the nociceptin receptor.
Example 4: Selectivity assay: μ-opioid receptor binding assay
Cell membranes prepared from CHO-K1 cells transfected to express the human μ-opioid receptor were incubated for 45 minutes at 22°C with 1.0 nM [3H]DAMGO, 1.0 mg of wheat germ agglutinin-coated SPA beads and various concentrations of test compounds in a final volume of 200μl of 50mM Tris-HCL buffer pH7.4, containing 5 mM MgCI2. Nonspecific binding was determined by the addition of 1 mM unlabelled DAMGO. After the reaction, the assay plate was centrifuged at 1 ,000rpm for 1 min and then the radioactivity was measured by a Liquid Scintillation Counter.
Each percent non-specific binding thus obtained is graphed as a function of compound concentration. A sigmoidal curve is used to determine 50% binding (i.e. IC50 values).
Nociceptin receptor antagonists demonstrating selectivity over μ-opioid receptor demonstrate higher binding affinity for nociceptin receptors than for μ-opioid receptors.
The skilled person will be able to adapt this assay for κ-opioid receptors, δ-opioid receptors, as well as other receptors over which selectivity of the nociceptin receptor antagonists is desired.

Claims

Claims
1. Use of a nociceptin receptor antagonist in the manufacture of a medicament for the treatment of overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence or mixed incontinence.
2. Use of claim 1 wherein the medicament is for the treatment of overactive bladder, urgency, urge incontinence, nocturia or mixed incontinence.
3. Use according to claim 1 or claim 2, wherein the nociceptin receptor antagonist is a compound of formula (lb):
Figure imgf000048_0001
(lb)
or a pharmaceutically acceptable ester of such a compound, or a pharmaceutically acceptable salt thereof, wherein
R1 and R2 independently represent a hydrogen atom, a halogen atom or an alkyl group having from 1 to 3 carbon atoms;
R5 represents a phenyl group or a heteroaryl group and said heteroaryl group is a 5- to 6-membered hetero aromatic group having either from 1 to 4 ring nitrogen heteroatoms or 1 or 2 nitrogen ring heteroatoms and 1 oxygen or 1 sulfur ring heteroatom; said phenyl group and heteroaryl group are optionally substituted by 1 to 3 groups selected from a halogen atom, a hydroxy group, an alkyl group having from 1 to 3 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, an alkoxyalkyl group having a total of from 2 to 6 carbon atoms, a hydroxyalkyl group having from 1 to 3 carbon atoms, an amino group, a mono-or di-alkylamino group each alkyl part having from 1 to 3 carbon atoms, an aminocarbonyl group, a mono- or di- alkylaminocarbonyl group having from 1 to 3 carbon atoms in each alkyl group, an alkanoylamino group having from 2 to 3 carbon atoms and an alkylsulfonylamino group having from 1 to 3 carbon atoms; -X-Y- represents a group of the formula -N(R7)C(=O)-, -C(=O)N(R7)-, -N(R7)CH2-, - CH2N(,R7)-, -N(R7)SO2-, -SO2N(R7)-, -CH2CH2-, -CH=CH-, -CH(CH2OH)CH2-, - CH2CH(CH2OH)- ,-CH2CH(OH)-, -CH(OH)CH2-, -C(R7)(R8)-O- or -O-C(R7)(R8)-; R7 represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms; R8 represents a hydrogen atom, an alkyl group having from 1 to 3 carbon atoms or a hydroxyalkyl group having from 1 to 3 carbon atoms; and n represents an integer 0, 1 or 2
4. Use according to claim 1 or claim 2, wherein the nociceptin receptor antagonist is selected from J-1 13397, JTC-801 , or SB-612111 , or a pharmaceutically acceptable salt thereof.
5. The use of any of claims 1 to 4 wherein the IC50 of the antagonist for the nociceptin receptor is less than 100nM.
6. The use of any of claims 1 to 5 wherein the antagonist for the nociceptin receptor is selective for the nociceptin receptor.
7. A method of screening for compounds useful for the treatment of overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence or mixed incontinence, comprising screening compounds for antagonist activity against nociceptin receptor, and selecting compounds with an IC50 of less than 100 nM.
8. Use of a compound in the manufacture of a medicament for the treatment of overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence or mixed incontinence, wherein said compound is identified by the method of claim 7.
9. A process for providing a medicament for the treatment of overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence or mixed incontinence, comprising the following steps: (a) testing compounds in a ligand binding assay against nociceptin receptor; (b) selecting a compound with an IC50 of less than 100 nM; (c) formulating a compound with the same structure as that selected in step (b), or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier or excipient.
10. A process for providing a medicament for the treatment of overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence or mixed incontinence, comprising the following steps: (a) testing compounds in an assay, measuring the inhibition of the agonist- stimulated second messenger response in cells expressing nociceptin receptor; (b) selecting a compound with an IC50 of less than 100 nM; (c) formulating a compound with the same structure as that selected in step (b), or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier or excipient.
11. The process of claim 9 or claim 10, additionally comprising the following steps (d) packaging the formulation of step (c); (e) making the package of step (d) available to a patient suffering from overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence, or mixed urinary incontinence.
12. A process for preparing a medicament for the treatment of overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence or mixed incontinence, comprising the steps of (a) testing compounds in a ligand binding assay against nociceptin receptor or testing compounds in an assay, measuring the inhibition of the agonist-stimulated .second messenger response of nociceptin receptor, (b) identifying one or more compounds capable of antagonising nociceptin receptor with an IC50 of less than 100nM; and (c) preparing a quantity of those one or more identified compounds.
13. Use of a nociceptin receptor antagonist for the manufacture of a medicament for increasing bladder capacity.
14. Method of treatment of overactive bladder, urgency, urge incontinence, frequency, nocturia, stress incontinence or mixed incontinence which comprises administering to a patient in need thereof a therapeutically effective amount of a nociceptin receptor antagonist.
PCT/IB2005/001529 2004-06-03 2005-05-23 Treatment of urinary conditions including incontinence WO2005117862A1 (en)

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GB0412416.0 2004-06-03
GB0412416A GB0412416D0 (en) 2004-06-03 2004-06-03 Treatment of incontinence
US58438504P 2004-06-30 2004-06-30
US60/584,385 2004-06-30

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