Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D233/24—Radicals substituted by nitrogen atoms not forming part of a nitro radical
• • 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
• • 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
  • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• This invention relates to an imidazolinylmethyl aryl sulfonamide which is an alpha- IA adrenergic partial agonist, associated pharmaceutical compositions, and methods for use as a therapeutic agent.
• Alpha- 1 adrenergic receptors are G-protein coupled transmembrane receptors that mediate various actions of the sympathetic nervous system through the binding of the catecholamines, epinephrine and norepinephrine (NE).
• alpha-1 A previously known as alpha-lC
• alpha-IB alpha-IB
• alpha-ID alpha-1 adrenoceptor for prazosin
• the alpha-1 adrenoceptor plays a part in the sympathetic maintenance of smooth muscle tone and alpha-1 adrenergic agonists are known to increase muscle tone in the lower urinary tract necessary for urine storage and urine emptying thus making adrenergic receptors important targets for drug development in urinary dysfunction (Testa, Eur.J.Pharmacol., 1993, 249, 307- 315.
• Urinary incontinence is a condition defined as the involuntary loss of urine to such an extent as to become a hygienic or social concern to the patient.
• Stress urinary incontinence occurs when the internal sphincter does not close completely.
• the primary symptom is minor leakage from activities, such as coughing, sneezing, laughing, running, lifting, or even standing, that apply pressure to a full bladder. Leakage stops when the activity stops.
• SUI is most common in women between the ages of 25 and 50, and many regularly exercising women have some degree of SUI.
• SUI SUI
• Treatment with pharmaceuticals is limited to the use of non-selective adrenergic agonists. Only a limited number of pharmaceutical agents have been employed, with varying success, to treat stress incontinence.
• Phenylpropanolamine, pseudoephrine and midodrine are considered first-line therapy for mild to moderate stress incontinence (Wein, supra; Lundberg (editor), JAMA 1989, 261(18):2685-2690). These agents are believed to work both by direct activation of alpha- 1 adrenoceptors and in- directly by displacement of endogenous norepinephrine from sympathetic neurons following uptake into the nerve terminal (Andersson and Sjogren, Progress in Neurobiology, 1982, 71-89).
• alpha- 1 adrenoceptors located on the smooth muscle cells of the proximal urethra and bladder neck (Sourander, Gerontology 1990, 36:19-26; Wein, supra) evokes contraction and an increase in urethral closure pressure.
• phenylpropanolamine, pseudoephrine, and midodrine is limited by a lack of selectivity among the alpha- 1 adrenoceptor subtypes and by the indirect action of these agents (i.e. activation of alpha- 1, alpha-2, and beta-adrenoceptors in the central nervous system and periphery).
• any desired therapeutic effect of these agents may be accompanied by undesirable side effects such as an increase in blood pressure.
• the increase in blood pressure is dose-dependent and therefore limits the ability to achieve therapeutically effective circulating concentrations of these agents (Andersson and Sjogren, supra).
• these agents produce insomnia, anxiety and dizziness as a result of their central nervous system stimulant actions (Andersson and Sjogren, supra, Wein, supra).
• alpha- IA/ IL agonists are known to be useful in treating various disease states including urinary incontinence, nasal congestion, sexual dysfunction such as ejaculation disorders and priapism, and CNS disorders such as depression, anxiety, dementia, senility, Alzheimer's, deficiencies in attentiveness and cognition, and eating disorders such as obesity, bulimia, and anorexia. See e.g. US Patent Nos. 5,952,362, 6,756,395, 6,852,726, and 6,979,696 which disclose a variety of 2-imidazolinylmethyl aryl and heteroaryl derivatives as alpha-lA/L agonists.
• Full agonists of the alpha 1A/1L adrenoceptor subtype while potentially effective at treating urinary incontinence, can be limited by undesirable cardiovascular and central nervous system side effects.
• Selective alpha 1A/1L receptor modulators with reduced intrinsic efficacy i.e., "partial agonists” can reduce such side effects while maintaining the contractile effects on urethral smooth muscle needed for treating incontinence.
• a compound having the desired alpha- IA adrenergic partial agonist profile is desirable.
• the application provides a compound of formula I:
• the compound of Formula I N-[2,3-Dibromo-4-(4,5-dihydro-lH-imidazol-2-ylmethyl)-5- fluoro-phenylj-methanesulfonamide (nomenclature used in this Application is based on AUTONOMTM v.4.0), has been found to exhibit unexpectedly enhanced selectivity, for enhancement of intraurethral pressure (IUP) over blood pressure (MAP), as a partial agonist of alpha- IA adrenoceptors.
• IUP intraurethral pressure
• MAP blood pressure
• the combination of the dibromo substituents on the 2- and 3-positions with the fluoro substituent at the 5-position of the phenyl ring provide unexpected advantages over the general class of imidazolinylmethyl aryl sulfonamides in that it has both a favorable intrinsic activity, or efficacy, as a partial agonist, which is ideally between 0.35 to 0.60, of 0.38 and an affinity, or pEC50 value, of 6.7.
• the combination of high affinity and partial agonist behavior is critical for optimization of urethral activity benefits associated with effective modulation of alpha-1 A adrenoceptors coupled with minimization of diastolic blood pressure related side effects.
• the compound of Formula I in comparison to analogue compounds, exhibits improved durability of IUP response over time which is necessary for effective treatment of incontinence.
• the application provides the compound of formula I, wherein the pharmaceutically acceptable salt is hydrochloride. In one embodiment, the application provides a composition comprising the compound of formula 1 and further comprising a pharmaceutically acceptable carrier.
• the application provides the above composition, wherein the composition is suitable for administration to a subject having a disease state which is alleviated by treatment with an alpha- 1 A receptor partial agonist.
• the application provides a method for preventing, alleviating, or treating a disorder modulated by alpha- IA adrenoceptors, said method comprising administering to a subject in need thereof an effective amount of the compound of formula 1.
• the application provides the above method, wherein the disorder is selected from urge incontinence, stress incontinence, overflow incontinence, and functional incontinence.
• the application provides a method for preventing, alleviating, or treating a disorder modulated by alpha- IA adrenoceptors, wherein the disorder is stress incontinence.
• the application provides a method for preventing, alleviating, or treating a disorder modulated by alpha- IA adrenoceptors, wherein the disorder is urge incontinence.
• the application provides a method for preventing, alleviating, or treating a disorder modulated by alpha- IA adrenoceptors, wherein the disorder is overflow incontinence.
• the application provides a method for preventing, alleviating, or treating a disorder modulated by alpha- IA adrenoceptors, wherein the disorder is functional incontinence.
• the application provides a method for preventing, alleviating, or treating a disorder modulated by alpha- IA adrenoceptors, said method comprising administering to a subject in need thereof an effective amount of the compound of formula 1 in combination with a second modulator of alpha- IA adrenoceptors.
• the application provides a method of treating or preventing a disease state characterized by urinary incontinence comprising administering to a subject in need thereof an effective amount of a compound of formula 1.
• IUP intraurethral pressure and is measured as the 2 minute mean from the first peak of the urethral response.
• MAP means mean arterial blood pressure and is measured as the average blood pressure during the 2 minute section where IUP is measured.
• durability of IUP response over time means the slope of the IUP response in mmHg/min and is calculated immediately after the 2 minute IUP response for 5 minutes (2-7 minutes post the first peak) for the top 3 doses.
• Aryl means the monovalent cyclic aromatic hydrocarbon radical consisting of one or more fused rings in which at least one ring is aromatic in nature, which can optionally be substituted with hydroxy, cyano, lower alkyl, lower alkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, dialkylamino, amino carbonyl, carbonylamino, aminosulf- onyl, sulfonylamino, nitro, and/or alkylsulphonyl, unless otherwise indicated.
• aryl radicals include, but are not limited to, phenyl, naphthyl, biphenyl, indanyl, anthraquinolyl, and the like.
• Arylsulfonyl means a radical -S(O) 2 R where R is an aryl group as defined herein.
• 2-Imidazolinylmethyl means the moiety designated by the structure It is to be understood that the double bond in 2-imidazoline and 2-imidazolinylmethyl may assume other resonance forms.
• 2-imidazoline 2-imidazolinylmethyl include all such resonance forms.
• “Isomerism” means compounds that have identical molecular formulae but that differ in the nature or the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereoisomers”, and stereoisomers that are non-superimposable mirror images are termed “enantiomers”, or sometimes optical isomers. A carbon atom bonded to four nonidentical substituents is termed a "chiral center".
• Chiral compound means a compound with one or more chiral center. It has two enantiomeric forms of opposite chirality and may exist either as an individual enantiomer or as a mixture of enantiomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a "racemic mixture”. A compound that has more than one chiral center has 2 n ⁇ l enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center may exist as either an individual diastereomer or as a mixture of diastereomers, termed a "diastereomeric mixture”.
• the stereoisomers may be characterized by the absolute configuration (R or S ) of the chiral centers.
• Absolute conf ⁇ gure- tion refers to the arrangement in space of the substituents attached to a chiral center.
• the sub- stituents attached to a chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al. Angew. Chem. Inter., 1966, Edit., 5, 385; errata 511; Cahn et al. Angew. Chem., 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. (London), 1951, 612; Cahn et al., Experientia, 1956, 12, 81; Cahn, J., Chem.Educ, 1964, 41, 116).
• Tautomers refers to compounds whose structures differ markedly in arrangement of atoms, but which exist in easy and rapid equilibrium. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of the invention, and the naming of the compounds does not exclude any tautomer form.
• “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical compo- sition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
• “Pharmaceutically acceptable salts” of a compound means salts that are pharmaceutically acceptable, as defined herein, and that possess the desired pharmacological activity of the parent compound. Such salts include:
• acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydro xynaphtoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and the like; or
• Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like.
• Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
• the preferred pharmaceutically acceptable salts are the salts formed from acetic acid, hydrochloric acid, sulphuric acid, methanesulfonic acid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium, potassium, calcium, zinc, and magnesium.
• Solidvates means solvent additions forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H 2 O, such combination being able to form one or more hydrate.
• Subject means mammals and non-mammals. Mammals means any member of the Mammalia class including, but not limited to, humans; non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and the like. The term "subject” does not denote a particular age or sex.
• “Therapeutically effective amount” means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state.
• the “therapeutically effective amount” will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors.
• “Pharmacological effect” as used herein encompasses effects produced in the subject that achieve the intended purpose of a therapy.
• a pharmacological effect would be one that results in the prevention, alleviation or reduction of urinary incontinence in a treated subject.
• Disease state means any disease, condition, symptom, or indication.
• Treating" or “treatment” of a disease state includes:
• X 1 -adrenergic receptors " ⁇ iA-adrenergic receptors" (previously known as “ ⁇ ic-adrenergic receptors"), “ ⁇ iL-adrenergic receptors”, or “ ⁇ iA/iL-adrenergic receptors”, which may be used inter- changeably with " ⁇ i-adrenoceptors", “ ⁇ iA-adrenoceptors” (previously known as “ ⁇ ic-adrenocep- tors receptors”), “ ⁇ iL-adrenoceptors” or “ ⁇ iA/iL-adrenoceptors” respectively, refers to a molecule conforming to the seven membrane-spanning G-protein receptors, which under physiologic conditions mediate various actions, e.g., in the central and/or peripheral sympathetic nervous system through the binding of the catecholamines, epinephrine and norepinephrine.
• "Agonist” or “full agonist” means
• Partial agonist means activates a receptor, but only produces a partial physiological response compared to a full agonist.
• Urinary Incontinence is a condition characterized by the involuntary loss of urine, which is objectively demonstrable. It is both a social and hygienic problem. Stated simply, incontinence results from the failure of the bladder and/or the urethra to work properly, or when the coordination of their functions is defective. While the prevalence of incontinence is two-fold higher in females, with the greatest incidence in postmenopausal women, it also affects males.
• Urinary incontinence can be classified into four basic types: urge, stress, overflow and functional, and as used herein the term “urinary incontinence” encompasses all four types.
• Urge incontinence is the involuntary loss of urine associated with a strong urge to void. This type of incontinence is the result of either an overactive or hypersensitive detrusor muscle. The patient with detrusor overactivity experiences inappropriate detrusor contractions and increases in intravesical pressure during bladder filling. Detrusor instability resulting from a hypersensitive detrusor (detrusor hyperreflexia) is most often associated with a neurological disorder.
• Genuine stress incontinence is the involuntary loss of urine occurring when increases in intra-abdominal pressure cause a rise in intravesical pressure which exceeds the resistance offered by urethral closure mechanisms.
• Stress incontinent episodes can result from normal activities such as laughing, coughing, sneezing, exercise, or, in severe stress incontinent patients, standing or walking.
• stress incontinence is often character- rized by a descensus of the bladder neck and funneling of the bladder outlet. This type of incontinence is most common in multiparous women, as pregnancy and vaginal delivery can cause loss of the vesicourethral angle and damage to the external sphincter. Hormonal changes associated with menopause may exacerbate this condition.
• Overflow incontinence is an involuntary loss of urine resulting from a weak detrusor or from the failure of the detrusor to transmit appropriate signals (sensory) when the bladder is full.
• Overflow incontinent episodes are characterized by frequent or continuous dribbling of urine and incomplete or unsuccessful voiding.
• Functional incontinence in contrast to the types of incontinence described above, is not defined by an underlying physiological dysfunction in the bladder or urethra. This type of incontinence includes the involuntary loss of urine resulting from such factors as decreased mobility, medications (e.g., diuretics, muscarinic agents, or alpha-1 adrenoceptor antagonists), or psychiatric problems such as depression or cognitive impairment.
• medications e.g., diuretics, muscarinic agents, or alpha-1 adrenoceptor antagonists
• psychiatric problems such as depression or cognitive impairment.
• a method of treating or preventing incontinence refers to the prevention of or relief from the symptoms of incontinence including involuntary voiding of feces or urine, and dribbling or leakage of feces or urine which may be due to one or more causes including, but not limited to, pathology altering sphincter control, loss of cognitive function, overdistention of the bladder, hyper- reflexia and/or involuntary urethral relaxation, weakness of the muscles associated with the bladder, or neurologic abnormalities.
• the compound of the present invention may be made by the methods depicted in the illustrative synthetic reaction schemes shown and described below.
• the starting materials and reagents used in preparing Formula I generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in standard references. Where necessary, conventional protecting group techniques were used as described by Greene et al, Protecting Groups in Organic Synthesis, 3rd Ed., Wiley Interscience, 1999.
• the following synthetic re- action schemes are merely illustrative of some methods by which the compound of the present invention may be synthesized, and various modifications to these synthetic reaction schemes may be made and will be suggested to one skilled in the art having referred to the disclosure contained in this Application.
• the starting materials and the intermediates of the synthetic reaction schemes may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
• the reactions described herein preferably take place at atom- spheric pressure over a temperature range from about -78°C to about 150 0 C, more preferably from about 0 0 C to about 125°C, and most preferably and conveniently at about room (or ambient) temperature (RT), e.g., about 20 0 C.
• RT room (or ambient) temperature
• the resulting orange semisolid (33.6Ig) was filtered through a thick plug of silica gel in dichloro- methane to remove a large amount of colored impurity.
• the resulting light yellow oil (32.6g) ran as a single spot on tic (1 :9 ethyl acetate - hexane) but nmr analysis revealed it to be a mixture of the title compound mixed with other components. No further purification was carried out at this point.
• the major less polar component was heated in vacuo with stirring at 150° C for about an hour after which time, the bubbling had stopped.
• the crude material was purified by chromatography on silica gel (hexane - ethyl acetate) to afford 24g of an oil which contained the title compound as a major component. No further purification was attempted at this point.
• the compound of the present invention have selective alpha-1 A adrenergic selective activity and as such are expected to be useful in the treatment of various disease states, such as urinary incontinence; nasal congestion; sexual dysfunction, such as ejaculation disorders and priapism; CNS disorders such as depression, anxiety, dementia, senility, Alzheimer's, deficiencies in attentiveness and cognition, and eating disorders such as obesity, bulimia, and anorexia.
• various disease states such as urinary incontinence; nasal congestion; sexual dysfunction, such as ejaculation disorders and priapism
• CNS disorders such as depression, anxiety, dementia, senility, Alzheimer's, deficiencies in attentiveness and cognition
• eating disorders such as obesity, bulimia, and anorexia.
• Urinary incontinence is a condition defined as the involuntary loss of urine to such an extent as to become a hygienic or social concern to the patient. Involuntary loss of urine occurs when pressure inside the bladder exceeds retentive pressure of the urethral sphincters (intraurethral pressure).
• Intraurethral pressure retentive pressure of the urethral sphincters
• Stress urinary incontinence is the involuntary loss of urine during coughing, sneezing, laughing, or other physical activities.
• the present methods to treat SUI include physiotherapy and surgery. Treatment with pharmaceutical agents is limited to the use of non selective- adrenergic agonists like phenylproanolamine and midodrine.
• the rationale for the use of adrenergic agonists for the treatment of SUI is based on physiological data indicating an abundant noradrenergic input to smooth muscle of the urethra.
• Urge incontinence (detrusor instability) is the involuntary loss of urine associated with a strong urge to void.
• Overflow incontinence is an involuntary loss of urine resulting from a weak detrusor or from the failure of the detrusor to transmit appropriate signals (sensory) when the bladder is full.
• Overflow incontinent episodes are characterized by frequent or continuous dribbling of urine and in- complete or unsuccessful voiding.
• Functional incontinence in contrast to the types of incontinence described above, is not defined by an underlying physiological dysfunction in the bladder or urethra.
• This type of incontinence includes the involuntary loss of urine resulting from such factors as decreased mobility, medications (e.g., diuretics, muscarinic agents, or alpha-1 adrenoceptor antagonists), or psychiatric problems such as depression or cognitive impairment.
• medications e.g., diuretics, muscarinic agents, or alpha-1 adrenoceptor antagonists
• psychiatric problems such as depression or cognitive impairment.
• the compound of this invention are also particularly useful for the treatment of nasal congestion associated with allergies, colds, and other nasal disorders, as well as the sequelae of congestion of the mucous membranes (e.g., sinusitis and otitis media), with less or no undesired side effects.
• IUP is the intraurethral pressure and is measured as the 2 minute mean from the first peak of the urethral response ( Figure 1).
• MAP is the mean arterial blood pressure and is measured as the average blood pressure during the 2 minute section where IUP is measured.
• the durability is the slope of the IUP response in mmHg/min and is calculated immediately after the 2 minute IUP response for 5 minutes (2-7 minutes post the first peak) for the top 3 doses.
• Surgical Instrumentation Female Yucatan Micro-swine were instrumented with a telemetry device with both pressure and ECG monitoring capabilities (Data Sciences International St Paul MN). In addition, a Bardport low profile titanium VAP was placed subcutanteously for blood sampling. All devices were implanted by the surgical veterinarian at Roche Palo Alto. Briefly, the telemetry probe body was placed subcutaneously in the cervical region. The intra-arterial pressure catheter was advanced via the superficial cervical artery into the subclavian artery for blood pressure measurement. The ECG leads were placed intra-muscularly: one in the intercostal muscle between the T8-T10 regions on the left side, and the other in the intercostal muscles between the T1-T3 regions on the right side. The VAP was placed subcutaneously in the neck region, with the catheter advanced into the jugular vein. Swine were allowed to fully recover from the surgery (typically 10 days).
• Placement of the catheter was confirmed via urethral prof ⁇ lometry (the third most distal transducer was placed at the high pressure zone of the urethra).
• the catheter was anchored into place by sutures placed in the skin surrounding the vulva and attached to tape fixed to the catheter.
• a huber needle with tubing assembly was placed in the VAP for serial blood sampling. Propofol infusion was ceased and the swine was allowed to wake up.
• the device when activated, transmits its signal to a receiver which forwards this signal to the data exchange matrix.
• the data exchange matrix then sends its signal stream to the Data-Quest ART Gold version 4.0 which processes and generates cardiovascular data.
• IUP was monitored by a solid state catheter connected to a TA6000 Polygraph (Data Sciences International, St. Paul, MN).
• An analogue signal from the TA6000 was sent to either a Gould Acquisition Interface or Power Lab data acquisition system and this data was processed by either the Ponema software version 3.2 (Data Sciences International, St. Paul, MN) or Power Lab Chart version 5.0.2 (ADInstruments, Colorado Springs, CO).
• Baseline included a two-minute sampling period just prior to infusion for IUP, MAP, and HR.
• Post-dose time points included two-minute sampling periods at approximately 5, 15, 30, 45, 60, 75, 90, 105, and 120 minutes post-infusion initialization for IUP, MAP, and HR.
• post-dose time points were sampled for two minutes leading up to the blood sample (e.g. 58-60 min post dose). If pig activity caused aberrant data points (typically a marked increase in HR) the two minute sampling period was moved either a few minutes before or after active period.
• the compound of Formula I has been found to exhibit unexpectedly enhanced selectivity, for enhancement of intraurethral pressure (IUP) over blood pressure (MAP), as a partial agonist of alpha-1 A adrenoceptors.
• IUP intraurethral pressure
• MAP blood pressure
• the combination of the dibromo substituents on the 2- and 3-positions with the fluoro substituent at the 5-position of the phenyl ring provide unexpected advantages over the general class of imidazolinylmethyl aryl sulfonamides in that it has both a favorable intrinsic activity, or efficacy, as a partial agonist, which is ideally between 0.35 to 0.60, of 0.38 and an affinity, or pEC50 value, of 6.7.
• the combination of high affinity and partial agonist behavior is critical for optimization of urethral activity benefits associated with effective modulation of alpha-1 A adrenoceptors coupled with minimization of diastolic blood pressure related side effects.
• the compound of Formula I in comparison to analogue compounds, ex- hibits improved durability of IUP response over time which is necessary for effective treatment of incontinence.
• the compound of formula I tested in the conscious pig model exhibited unexpectedly increased durability of IUP response over time ( Figure Ib) compared to an analogue compound, differing from the compound of formula I with the absence of the 3-bromo and 5-flouro substituents and substitution of a 2-chloro for the 2-bromo on the phenyl ring ( Figure Ic). Additionally, the compound of formula I has selectivity for enhancement of intraurethral pressure (IUP) over blood pressure (MAP). The compound of formula I also has a correspondingly low maximum arterial blood pressure effect.
• IUP intraurethral pressure
• MAP blood pressure
• the compound of formula I also has a correspondingly low maximum arterial blood pressure effect.
• the present invention includes pharmaceutical compositions comprising the compound of the present invention, or an individual isomer, racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof, together with at least one pharmaceutically acceptable carrier, and optionally other therapeutic and/or prophylactic ingredients.
• the compound of the present invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Suitable dosage ranges are typically 1-500 mg daily, preferably 1-100 mg daily, and most preferably 1-30 mg, depending upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved.
• One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this Application, to ascertain a therapeutically effective amount of the compound of the present invention for a given disease.
• the compound of the present invention will be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
• oral including buccal and sub-lingual
• parenteral including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous
• administration is generally oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.
• the compound of the present invention together with one or more conventional adjuvants, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages.
• the pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
• compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use.
• Formulations containing about one (1) milligram of active ingredient or, more broadly, about 0.01 to about one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.
• the compound of the present invention may be formulated in a wide variety of oral administration dosage forms.
• the pharmaceutical compositions and dosage forms may comprise the compound the present invention or pharmaceutically acceptable salts thereof as the active component.
• the pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
• a solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubi- lizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
• the carrier In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component.
• the active component In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and com- pacted in the shape and size desired.
• the powders and tablets preferably contain from about one (1) to about seventy (70) percent of the active compound.
• Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
• preparation is intended to include the formulation of the active compound with encapsulating material as carrier, providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is in association with it.
• carrier which is in association with it.
• cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges may be as solid forms suitable for oral administration.
• liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations.
• Emulsions may be prepared in solutions, e.g., in aqueous propylene glycol solutions or may contain emulsifying agents, e.g., such as lecithin, sorbitan monooleate, or acacia.
• Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents.
• Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.
• Solid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
• the compound of the present invention may be formulated for parenteral administration (e.g., by injection, e.g. bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
• the composition may take such form as a suspension, solution, or emulsion in oily or aqueous vehicles, e.g. a solution in aqueous polyethylene glycol.
• oily or non- aqueous carriers, diluents, solvents or vehicles examples include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents.
• the active ingredient may be in powder form, obtained by a- septic isolation of sterile solid or by lyophilisation from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen- free water.
• the compound of the present invention may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch.
• Ointments and creams may, e.g., be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
• Lotions may be formulated with an aqueous or oily base and will in general also containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
• Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
• the compound of the present invention may be formulated for administration as suppositories.
• a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, e.g., by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.
• the compound of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
• the compound of the present invention may be formulated for nasal administration.
• the solutions or suspensions are applied directly to the nasal cavity by conventional means, e.g., with a dropper, pipette or spray.
• the formulations may be provided in a single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved e.g. by means of a metering atomizing spray pump.
• the compound of the present invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration.
• the compound will generally have a small particle size e.g. of the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, e.g. by micronization.
• the active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluoro carbon (CFC), e.g., dichlorodi- fluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas.
• CFC chlorofluoro carbon
• the aerosol may conveniently also contain a surfactant such as lecithin.
• the dose of drug may be controlled by a metered valve.
• the active ingredients may be pro- vided in a form of a dry powder, e.g. a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinyl- pyrrolidine (PVP).
• the powder carrier will form a gel in the nasal cavity.
• the powder composition may be presented in unit dose form e.g. in capsules or cartridges of e.g., gelatin or blister packs from which the powder may be administered by means of an inhaler.
• formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient.
• the compound of the present invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with a treatment regimen is crucial.
• Compounds in transdermal delivery systems are frequently attached to an skin-adhesive solid support.
• the compound of interest can also be combined with a penetration enhancer, e.g., Azone (1-dodecylaza-cyclo- heptan-2-one).
• Sustained release delivery systems are inserted subcutaneous Iy into to the sub- dermal layer by surgery or injection.
• the subdermal implants encapsulate the compound in a lipid soluble membrane, e.g., silicone rubber, or a biodegradable polymer, e.g., polyactic acid.
• the pharmaceutical preparations are preferably in unit dosage forms.
• the preparation is subdivided into unit doses containing appropriate quantities of the active component.
• the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
• the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

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• 2009
  • 2009-01-26 JP JP2010545429A patent/JP2011511025A/ja active Pending
  • 2009-01-26 BR BRPI0906640A patent/BRPI0906640A2/pt not_active Application Discontinuation
  • 2009-01-26 MX MX2010007928A patent/MX2010007928A/es unknown
  • 2009-01-26 EP EP09708318A patent/EP2238114A1/en not_active Withdrawn
  • 2009-01-26 CN CN2009801029593A patent/CN101925580A/zh active Pending
  • 2009-01-26 AU AU2009211505A patent/AU2009211505A1/en not_active Abandoned
  • 2009-01-26 WO PCT/EP2009/050839 patent/WO2009098135A1/en active Application Filing
  • 2009-01-26 KR KR1020107016640A patent/KR20100096261A/ko not_active Application Discontinuation
  • 2009-01-26 CA CA2711726A patent/CA2711726A1/en not_active Abandoned
• 2010
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