WO2007113243A2 - Utilisation des inhibiteurs de la pde 5 pour le traitement de la vessie hyperactive - Google Patents

Utilisation des inhibiteurs de la pde 5 pour le traitement de la vessie hyperactive Download PDF

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WO2007113243A2
WO2007113243A2 PCT/EP2007/053090 EP2007053090W WO2007113243A2 WO 2007113243 A2 WO2007113243 A2 WO 2007113243A2 EP 2007053090 W EP2007053090 W EP 2007053090W WO 2007113243 A2 WO2007113243 A2 WO 2007113243A2
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alkyl
pde
group
inhibitor
cycloalkyl
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PCT/EP2007/053090
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WO2007113243A3 (fr
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Iñigo SÁENZ DE TEJADA GORMAN
Javier Angulo Frutos
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Investigación Y Clínica Andrológicas S.L.
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Publication of WO2007113243A3 publication Critical patent/WO2007113243A3/fr

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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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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 to the use of an inhibitor of cyclic guanosine 3', 5'- monophosphate-specific phosphodiesterase type 5 (PDE 5) activity or of an inhibitor of PDE 5 expression for the manufacture of a medicament for the treatment and/or prophylaxis of overactive bladder disease.
  • PDE 5 cyclic guanosine 3', 5'- monophosphate-specific phosphodiesterase type 5
  • Overactive bladder is a medical condition referring to the symptoms of urinary urgency and frequency, with or without urge urinary incontinence (Urology, 55 (supp. 5A): 1-2 (2000)). It can occur idiopathically, in the absence of local pathological, neurological or metabolic factors that would account for these symptoms. It can also occur as the result of neurological disease (for example, spinal cord injury, cerebrovascular disease, Parkinsonism or multiple sclerosis) or bladder outlet obstruction. The latter is most common in men with benign prostatic hyperplasia, and is sometimes referred to as lower urinary tract symptoms (LUTS).
  • the following three symptomatic groups are included in overactive bladder: (1) increased urinary frequency and urinary urgency alone, (2) increased urinary frequency, urinary urgency and urinary incontinence, and (3) mixed-type urinary incontinence.
  • the normal bladder fills at a physiological rate dictated by the function of the kidneys.
  • the bladder can accommodate large volumes of urine due to the physical properties of the bladder as well as a neural inhibitory system.
  • the inhibitory mechanism is believed to involve inhibition of parasympathetic activity and, possibly, an increase in sympathetic tone to produce detrusor relaxation and allow filling to occur.
  • the bladder neck and urethra are contracted, preventing leakage.
  • Voiding, or micturition is characterized by a relaxation of the outlet neck and the urethra followed by contraction of the detrusor muscle. When micturition is complete, the detrusor muscle relaxes and the bladder neck and urethra contract to seal off the bladder and allow bladder filling.
  • UUI urge urinary incontinence
  • Muscarinic-cholinergic receptor antagonists e.g. oxybutin hydrochloride, tolterodine tartrate, trospium chloride, darifenacin succinate, solifenacin
  • oxybutin hydrochloride tolterodine tartrate
  • trospium chloride darifenacin succinate
  • solifenacin solifenacin
  • Estrogen and progesterone therapy has been studied and is believed to partially alleviate incontinence in some women.
  • Other studies suggest alpha-adrenergic agonists, beta-adrenergic-receptor activating agents, cholinergic receptor-blocking compounds and cholinergic receptor-stimulating drugs may be beneficial.
  • PDE 5 cyclic guanosine 3',5'-monophosphate-specific phosphodiesterase type 5
  • OBD overactive bladder disease
  • the inhibitors used in the invention allow treating OBD by inhibiting upstream targets in one or more biochemical pathways that modulate PDE 5 activity.
  • the expression of PDE 5 is inhibited at one or more transcriptional, translational, or post-translational levels.
  • the PDE 5 inhibitor used in the present invention is selective with respect to the inhibition of other PDE's (e.g., PDE 1, PDE 2, PDE 3, PDE 4, PDE 6, PDE 7, PDE 8,
  • PDE 9, PDE 10, and PDE 11 in the target tissue(s) or organs(s). More particularly, PDE 5 inhibitor is at least 2 to 5 times more effective in inhibiting PDE 5 activity than inhibiting any other PDE activity in those target tissues or organs.
  • the inhibitor of PDE 5 activity is a compound of formula (I):
  • R 0 is selected from the group consisting of hydro, halo and C 1-6 alkyl
  • R 1 is selected from the group consisting of hydro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo Ci-6 alkyl, C 3- S cycloalkyl, C 3- S cycloalkyl Ci -3 alkylene, and aryl-Ci -3 alkylene, wherein aryl is phenyl or phenyl substituted with one to three substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkoxy, methylenedioxy, and heteroaryl Ci -3 alkylene, wherein heteroaryl is thienyl, furyl, or pyridyl, each optionally substituted with one to three substituents independently selected from the group consisting of halo, C 1-6 alkyl, and C 1-6 alkoxy;
  • R 2 is an optionally substituted monocyclic aromatic aromatic compound
  • fused ring A is a 5- or 6-membered ring, saturated or partially or fully unsaturated, and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulfur, and nitrogen;
  • R 3 represents hydro or Ci -3 alkyl, or R 1 and R 3 together represent a 3- or 4-membered alkyl or alkenyl chain component of a 5- or 6-membered ring; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
  • the inhibitor of PDE 5 activity is a compound of formula (II):
  • R 4 , R 5 , and R 6 are independently selected from the group consisting of hydro, Ci-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo Ci -6 alkyl, C 3- S cycloalkyl, and C 3- S cycloalkyl Ci -3 alkylene; and
  • R 7 and R 8 are independently selected from the group consisting of hydro, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo Ci -6 alkyl, C 3- s cycloalkyl, and C 3- s cycloalkyl Ci -3 alkylene or together represent a 5 or 6 membered cycloalkyl or heterocycloalkyl.
  • the inhibitor of PDE 5 activity is a compound of formula (III):
  • R 9 , R 10 , and R 11 are independently selected from the group consisting of hydro, Ci-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo Ci -6 alkyl, C 3- s cycloalkyl, and C 3- s cycloalkyl Ci -3 alkylene; and R 12 and R 13 are independently selected from the group consisting of hydro, C 1-6 alkyl, C 2- O alkenyl, C 2-6 alkynyl, halo C 1-6 alkyl, C 3- S cycloalkyl, and C 3- S cycloalkyl Ci -3 alkylene or together represent a 5 or 6 membered cycloalkyl or heterocycloalkyl.
  • the inhibitor of PDE 5 activity is a compound of formula (IV):
  • R 14 , R 15 , R 16 , R 17 , and R 18 are independently selected from the group consisting of hydro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo C 1-6 alkyl, C 3- s cycloalkyl, C 3- s cycloalkyl Ci -3 alkylene, C 3- s cycloheteroalkyl, and C 3- s cyclo he tero alkyl Ci -3 alkylene.
  • the inhibitor of PDE 5 activity is a compound of formula (V):
  • R 0 is selected from the group consisting of hydro, halo, and C 1-6 alkyl
  • R 1 is selected from the group consisting of hydro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo Ci-6 alkyl, C 3- s cycloalkyl, C 3- s cycloalkyl Ci -3 alkylene, and aryl Ci -3 alkylene, wherein aryl is phenyl or phenyl substituted with one to three substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkoxy, methylenedioxy, and heteroaryl Ci -3 alkylene, wherein heteroaryl is thienyl, furyl, or pyridyl, each optionally substituted with one to three substituents independently selected from the group consisting of halo, C 1-6 alkyl, and C 1-6 alkoxy
  • R 2 is an optionally substituted monocyclic aromatic ring
  • the inhibitor of PDE 5 activity is a compound of formula (VI):
  • R a is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, aryl, aryl Ci -3 alkyl, Ci -3 alkylenearyl, heteroaryl, heteroaryl Ci -3 alkyl, and Ci -3 alkyleneheteroaryl;
  • R b is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3- s cycloalkyl,
  • B is aryl or heteroaryl and is selected from the group consisting of optionally substituted 5- or 6-membered aromatic rings and optionally substituted fused bicyclic aromatic ring systems, either carbocyclic or containing at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur;
  • Het represents a 5- or 6-membered heterocyclic ring, saturated or partially or fully unsaturated, containing at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur, and optionally substituted with Ci -4 alkyl or
  • the inhibitor of PDE 5 activity is a compound of formula (VII):
  • R 20 is hydrogen, or R 19 and R 20 are taken together to form a 3- or 4- membered alkyl ene or alkenylene chain component of a 5- or 6-membered ring, optionally containing at least one heteroatom;
  • R a is selected from the group consisting of hydrogen, Ci -6 alkyl, C 3-6 cycloalkyl, aryl, aryl Ci -3 alkyl, Ci -3 alkylenearyl, heteroaryl, heteroaryl Ci -3 alkyl, and Ci -3 alkyleneheteroaryl;
  • R b is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3- scycloalkyl, Ci- 3 alkyleneN(R a ) 2 , aryl, aryl Ci -3 alkyl, Ci -3 alkylenearyl, and heteroaryl;
  • R d is a 5- or 6-membered ring or a bicyclic fused ring system, saturated or partially or fully unsaturated, comprising carbon atoms and optionally one to three heteroatoms selected from oxygen, sulfur, and nitrogen, and optionally substituted with one or more R 19 ;
  • n is 0 or 1
  • q is 0, 1, 2, 3, or 4
  • t is 1, 2, 3, or 4;
  • m is 1, 2, 3 or 4; and pharmaceutically acceptable salt, solvate, hydrate, isomer and prodrugs thereof.
  • the inhibitor of PDE 5 expression is an antisense oligonucleotide which negatively regulates PDE 5 expression.
  • the inhibitor of PDE 5 expression is a ribozyme inhibitor.
  • the inhibitor of PDE 5 expression is a doble- stranded RNA wherein one strand is complementary to a target region in PDE 5- encoding polynucleotide.
  • the inhibitor of PDE 5 expression is a circular lasso RNA which inhibits the PDE 5-encoding polynucleotide.
  • Another object of the present invention refers to a pharmaceutical composition
  • a pharmaceutical composition comprising at least of the PDE 5 activity inhibitors defined above, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
  • Another object of the invention relates to a method of preventing and/or treating overactive bladder disease comprising administering to a patient in need thereof a therapeutically effective amount of a PDE inhibitor as the ones defined above.
  • Figure 1 outlines a generic experimental protocol for the assessment of tadalafil (a PDE 5 inhibitor) in treating experimental OAB.
  • Figure 2 shows the effects of tadalafil (0.5 mg/kg; intravenously) on micturition frequency during infusion of 0.9% NaCl containing 0.3% acetic acid (CH 3 COOH) at a rate of 5 mL/hr for 20 min in male rats. Data are expressed as the mean ⁇ SEM of the number of micturition reflexes observed within the period of infusion, and n indicates the number of animals used.
  • Figure 3 shows the effects of tadalafil (0.5 mg/kg; i.v.) on micturition volume during infusion of 0.9% NaCl containing 0.3% acetic acid (CH 3 COOH) at a rate of 5 mL/hr for 20 min in male rats. Data are expressed as the mean ⁇ SEM, and n indicates the number of animals used.
  • Figure 4 shows the effects of tadalafil (0.5 mg/kg; i.v.) on intravesical pressure increases during micturition reflexes induced by infusion of 0.9% NaCl containing 0.3% acetic acid (CH 3 COOH) at a rate of 5 mL/hr rate for 20 min in male rats. Data are expressed as the mean ⁇ SEM, and n indicates the number of animals used.
  • Figure 5 compares the effects of tadalafil (0.5 mg/kg; i.v.) and vehicle on micturition frequency during infusion of 0.9% NaCl containing 0.3% acetic acid (CH 3 COOH) at a rate of 5 mL/hr for 20 min in male rats. Data are expressed as the mean ⁇ SEM of the percentage of the number of micturition reflexes observed in the previous exposure to
  • Figure 6 compares the effects of tadalafil (0.5 mg/kg; i.v.) and vehicle on micturition volume during infusion of 0.9% NaCl containing 0.3% acetic acid (CH 3 COOH) at a rate of 5 mL/hr for 20 min in male rats. Data are expressed as the mean ⁇ SEM of the percentage of micturition volume observed in the previous exposure to CH 3 COOH, before vehicle or tadalafil administration. Number of animals used is in parentheses. The difference between tadalafil and vehicle (control) was significant (p ⁇ 0.01 by unpaired Student's t-test).
  • Figure 7 compares the effects of tadalafil (0.5 mg/kg; i.v.) and vehicle on intravesical pressure (IVP) increases during micturition reflexes induced by infusion of 0.9% NaCl containing 0.3% acetic acid (CH 3 COOH) at a rate pf 5 mL/hr for 20 min in male rats. Data are expressed as the mean ⁇ SEM of the percentage of IVP increases observed in the previous exposure to CH 3 COOH, before vehicle or tadalafil administration. Number of animals used is in parentheses. The difference between tadalafil and vehicle (control) was not significant.
  • Figure 8 shows the lack of effect of vehicle on micturition frequency, mean volume for micturition, and IVP increase during infusion of 0.9% NaCl containing 0.3% acetic acid (CH 3 COOH) at a rate of 5 ml/hr for 20 min in male rats.
  • Figure 9 shows the effect of the anticholinergic oxybutynin under the same experimental conditions as used for obtaining data in Figure 8.
  • Figure 10 shows the effect of the PDE 5 inhibitor tadalafil under the same experimental conditions as used for obtaining data in Figure 8.
  • An object of the present invention refers to the use of an inhibitor of PDE 5 activity or of an inhibitor of PDE 5 expression for the manufacture of a medicament for the treatment and/or prophylaxis of overactive bladder disease (OBD).
  • Inhibiting of PDE 5 activity can be either direct or indirect and selective or non-selective.
  • Direct inhibition of PDE 5 activity refers to inhibiting PDE 5 activity through an interaction between PDE 5 and an inhibitor.
  • Indirect inhibition of PDE 5 activity refers to inhibiting PDE 5 activity through inhibiting PDE 5 expression at one or more transcriptional, translational, or post-translational levels.
  • “Selectively inhibiting” PDE 5 activity refers to inhibiting the activity of PDE 5, either directly or indirectly, more effectively than inhibiting at least one other member of the PDE family.
  • Non-selectively inhibiting PDE 5 refers to inhibiting the activity of PDE 5, either directly or indirectly, while simultaneously inhibiting the activity of one or more other members of the PDE family at a comparable level.
  • Ci-6 alkyl refers to a straight or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing no insaturation, having one to six carbon atoms, and which is attached to the rest of the molecule by a single bond, e. g., methyl, ethyl, n-propyl, /-propyl, n-butyl, t-butyl, n-pentyl, etc.
  • An alkyl group can be unsubstituted or substituted with one or two suitable substituents.
  • C 2- O alkenyl refers to a straight or branched chain alkenyl moiety consisting of carbon and hydrogen atoms, having two to six carbon atoms and at least one double bond of either E or Z stereochemistry where applicable, e.g., vinyl, allyl, 1- and 2-butenyl, and 2-methyl-2-propenyl.
  • An alkenyl group can be unsubstituted or substituted with one or two suitable substituents.
  • C 2- O alkynyl refers to a straight or branched chain alkynyl moiety consisting of carbon and hydrogen atoms, having two to six carbon atoms and at least one triple bond.
  • the triple bond of an alkynyl group can be unconjugated or conjugated to another unsaturated group.
  • Suitable alkynyl groups include, but are not limited to alkynyl groups such as ethynyl, propynyl, butynyl and pentynyl
  • An alkynyl group can be unsubstituted or substituted with one or two suitable substituents.
  • C3-8 cycloalkyl refers to an alicyclic group consisting of carbon and hydrogen atoms, having three to eight carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • a cycloalkyl group can be unsubstituted or substituted with one or two suitable substituents
  • heterocycloalkyl refers to a stable 3-to 15 membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the heterocycle may be a monocyclic, bicyclic or tricyclic ring system, which may include fused ring systems.
  • heterocycles include, but are not limited to, azepines, benzimidazole, benzothiazole, furan, isothiazole, imidazole, indole, piperidine, piperazine, purine, quinoline, thiadiazole, tetrahydrofuran.
  • aryl refers to a phenyl or phenyl substituted with one to three substituents independently selected from halo, C 1-6 alkyl, C 1-6 alkoxy and methylenedioxy.
  • heteroaryl refers to thienyl, furyl or pyridyl, each optionally substituted with one to three substituents independently selected form halo, C i-6 alkyl, and C 1-6 alkoxy.
  • C 1 -C 6 alkoxy refers to a radical of the formula -ORa, wherein R a is an alkyl radical as defined above, e. g., methoxy, ethoxy, propoxy, etc.
  • C 3- S cycloalkyl Ci -3 alkylene refers to a cycloalkyl group as defined above linked to a Ci -3 alkyl group. Preferred examples include methylcyclopentyl and methylcyclohexyl.
  • aryl Ci -3 alkylene refers to an aryl group linked to a Ci -3 alkyl group. Preferred example is benzyl.
  • heteroaryl Ci -3 alkylene refers to a heteroaryl group as defined above linked to a Ci -3 alkyl group.
  • halo refers to fluorine, chlorine, bromine or iodine.
  • the relative efficacies of inhibiting enzyme activity can be established by determining a decrease in the activity or expression of one PDE, e.g., PDE 5, and comparing the results to inhibition of another, e.g., non-PDE 5, PDE. Determination of the selectivity can be via the comparison of the enzyme activity of PDE 5 in a biochemical assay, level of mRNA transcription or level of protein expression. Such determinations are performed using conventional means, such as through measurement of IC50. In general, an IC50 can be determined by measuring the activity of a given enzyme in the presence of a range of concentrations of an inhibitor under study. The experimentally obtained values of enzyme activity then are plotted against the inhibitor concentrations used.
  • the concentration at which 50% enzyme activity is inhibited is taken as the IC50 value.
  • other inhibitory concentrations can be defined through appropriate determinations of activity. For example, in some settings it can be desirable to establish a 90% inhibitory concentration, i.e., IC 9 0, etc. It will be appreciated that determining an IC50 value is generally associated with direct inhibition of an enzyme, but that inhibition of an enzyme through indirect means also provides the same measurable endpoint, i.e., a decrease in enzyme activity. Thus, IC comparisons are contemplated for determining a degree of selective inhibition whether by direct or indirect mechanisms. In a particular embodiment, PDE 5 activity is selectively inhibited at least about
  • PDE 1 5-fold, at least about 10-fold, at least about 15-fold, at least about 20-fold, at least about 25-fold, at least about 30-fold, at least about 35-fold, at least about 40-fold, at least about 45-fold, or at least about 50-fold more than any one or more members of the PDE family (e.g., PDE 1, PDE 2, PDE 3, PDE 4, PDE 6, PDE 7, PDE 8, PDE 9, PDE 10, and PDE 11).
  • PDE 5 activity is selectively inhibited at least about 50-fold, at least about 60-fold, at least about 70-fold, at least about 80-fold, at least about 90-fold, at least about 100-fold, at least about 200-fold, at least about 250- fold, at least about 300-fold, at least about 350-fold, at least about 400-fold, at least about 450-fold, or at least about 500-fold, more than any one or more members of the PDE family selectively inhibits PDE 5.
  • the inhibitor of PDE 5 activity used in the present invention is a compound of formula (I):
  • R 0 is selected from the group consisting of hydro, halo and C 1-6 alkyl
  • R 1 is selected from the group consisting of hydro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo Ci-6 alkyl, C 3- S cycloalkyl, C 3- S cycloalkyl Ci -3 alkylene, and aryl-Ci -3 alkylene, wherein aryl is phenyl or phenyl substituted with one to three substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkoxy, methylenedioxy, and heteroaryl Ci -3 alkylene, wherein heteroaryl is thienyl, furyl, or pyridyl, each optionally substituted with one to three substituents independently selected from the group consisting of halo, C 1-6 alkyl, and C 1-6 alkoxy;
  • R 2 is an optionally substituted monocyclic aromatic ring selected from the group consisting of phenyl, thiophenyl, furyl, and pyridinyl, or an optionally substituted bicyclic ring:
  • fused ring A is a 5- or 6-membered ring, saturated or partially or fully unsaturated, and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulfur, and nitrogen;
  • R 3 represents hydro or Ci -3 alkyl, or R 1 and R 3 together represent a 3- or 4-membered alkyl or alkenyl chain component of a 5- or 6-membered ring; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
  • beta-carboline compounds and derivatives thereof are described in U.S. Patents 5,859,006; 5,981,527; 6,825,197; 6,838,456; 6,858,620; 6,872,721; 6,878,711; 6,903,099; 6,911,542; 6,960,587; 6,962,918; 6,984,641; 6,001,847; 6,143,757; 6,043,252; 6,117,881; 6,306,870; 6,462,047; 6,992,192; and 7,022,856 as well as in U.S. Patent Applications Nos. 2003/0207867; 2004/0162291; 2004/0152705; 2004/0116458; and 2004/0147542, each of which is incorporated by reference herein in its entirety.
  • the compound of formula (I) is a compound of formula (Ia):
  • the inhibitor of PDE 5 activity used in the present invention is a compound of formula (II):
  • R 4 , R 5 , and R 6 are independently selected from the group consisting of hydro, Ci-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo Ci -6 alkyl, C 3- S cycloalkyl, and C 3- S cycloalkyl Ci -3 alkylene; and
  • R 7 and R 8 are independently selected from the group consisting of hydro, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo Ci -6 alkyl, C 3- s cycloalkyl, and C 3- s cycloalkyl Ci -3 alkylene or together represent a 5 or 6 membered cycloalkyl or heterocycloalkyl; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
  • the compound of formula (II) is a compound of formula (Ha):
  • the inhibitor of PDE 5 activity used in the present invention is a compound of formula (III): R 13 (III) wherein R 9 , R 10 , and R 11 are independently selected from the group consisting of hydro, Ci-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo Ci -6 alkyl, C 3- S cycloalkyl, and C 3- S cycloalkyl Ci -3 alkylene; and
  • R 12 and R 13 are independently selected from the group consisting of hydro, Ci -6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, halo Ci -6 alkyl, C 3- s cycloalkyl, and C 3- s cycloalkyl Ci -3 alkylene or together represent a 5 or 6 membered cycloalkyl or heterocycloalkyl; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
  • Compounds of formula (III) are generally disclosed in US patents 6,362,178 and
  • the compound of formula (III) is a compound of formula (Ilia):
  • the inhibitor of PDE 5 activity used in the present invention is a compound of formula (IV):
  • R 14 , R 15 , R 16 , R 17 , and R 18 are independently selected from the group consisting of hydro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo C 1-6 alkyl, C 3- S cycloalkyl, C 3- S cycloalkyl Ci -3 alkylene, C 3- s cycloheteroalkyl, and C 3- s cyclo he tero alkyl Ci -3 alkylene; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
  • the compound of formula (IV) is a compound of formula (IVa):
  • udenafil which is interchangeably referred to throughout this disclosure as udenafil, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
  • the inhibitor of PDE 5 activity used in the present invention is a compound of formula (V):
  • R 0 is selected from the group consisting of hydro, halo, and C 1-6 alkyl
  • R 1 is selected from the group consisting of hydro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo Ci-6 alkyl, C 3- S cycloalkyl, C 3- S cycloalkyl Ci -3 alkylene, and aryl Ci -3 alkylene, wherein aryl is phenyl or phenyl substituted with one to three substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkoxy, methylenedioxy, and heteroaryl Ci -3 alkylene, wherein heteroaryl is thienyl, furyl, or pyridyl, each optionally substituted with one to three substituents independently selected from the group consisting of halo, C 1-6 alkyl, and C 1-6 alkoxy;
  • R 2 is an optionally substituted monocyclic aromatic ring selected from the group consisting of phenyl, thiophenyl, furyl, and pyridinyl, or an optionally substituted bicyclic ring
  • the inhibitor of PDE 5 activity used in the present invention is a compound of formula (VI):
  • R a is selected from the group consisting of hydrogen, Ci -6 alkyl, C 3-6 cycloalkyl, aryl, aryl Ci -3 alkyl, Ci -3 alkylenearyl, heteroaryl, heteroaryl Ci -3 alkyl, and Ci -3 alkyleneheteroaryl;
  • R b is selected from the group consisting of hydrogen, Ci -6 alkyl, C 3- s cycloalkyl, Ci -3 alkyleneN(R a ) 2 , aryl, aryl Ci -3 alkyl, Ci -3 alkylenearyl, and heteroaryl;
  • B is aryl or heteroaryl and is selected from the group consisting of optionally substituted 5- or 6-membered aromatic rings and optionally substituted fused bicyclic aromatic ring systems, either carbocyclic or containing at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur;
  • m is 1, 2, 3 or 4; or a pharmaceutically acceptable salt, solvate, hydrate, isomer or prodrug
  • the inhibitor of PDE 5 activity used in the present invention is a compound of formula (VII):
  • R 0 is selected from the group consisting of hydro, halo, and Ci_6alkyl
  • R 20 is hydrogen, or R 19 and R 20 are taken together to form a 3- or 4- membered alkylene or alkenylene chain component of a 5- or 6-membered ring, optionally containing at least one heteroatom;
  • R a is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, aryl, aryl Ci -3 alkyl, Ci -3 alkylenearyl, heteroaryl, heteroaryl Ci -3 alkyl, and Ci -3 alkyleneheteroaryl;
  • R b is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3- scycloalkyl, Ci- 3 alkyleneN(R a ) 2 , aryl, aryl Ci -3 alkyl, Ci -3 alkylenearyl, and heteroaryl;
  • R d is a 5- or 6-membered ring or a bicyclic fused ring system, saturated or partially or fully unsaturated, comprising carbon atoms and optionally one to three heteroatoms selected from oxygen, sulfur, and nitrogen, and optionally substituted with one or more R 19 ;
  • Het represents a 5- or 6-membered heterocyclic ring, saturated or partially or fully unsaturated, containing at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur, and optionally substituted with Ci -4 alkyl or
  • Inhibitors used in the invention embrace the compounds disclosed herein, compounds having similar inhibitory profiles, and compounds that compete with a disclosed inhibitor compound for binding to PDE 5, and in each case, conjugates and derivatives thereof.
  • the compounds used in the invention are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon or 15 N-enriched nitrogen are within the scope of this invention.
  • pharmaceutically acceptable salts refers to any pharmaceutically acceptable salt which, upon administration to the recipient is capable of providing (directly or indirectly) a compound as described herein.
  • non-pharmaceutically acceptable salts also fall within the scope of the invention since those may be useful in the preparation of pharmaceutically acceptable salts.
  • salts of compounds used in the invention are synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts are, for example, prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two.
  • nonaqueous media like ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
  • acid addition salts include mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulphonate and p-toluenesulphonate.
  • mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate
  • organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulphonate and p-toluenesulphonate.
  • alkali addition salts examples include inorganic salts such as, for example, sodium, potassium, calcium, ammonium, magnesium, aluminium and lithium salts, and organic alkali salts such as, for example, ethylenediamine, ethanolamine, N,N-dialkylenethanolamine, triethanolamine, glucamine and basic aminoacids salts.
  • inorganic salts such as, for example, sodium, potassium, calcium, ammonium, magnesium, aluminium and lithium salts
  • organic alkali salts such as, for example, ethylenediamine, ethanolamine, N,N-dialkylenethanolamine, triethanolamine, glucamine and basic aminoacids salts.
  • the preparation of salts and derivatives can be carried out by methods known in the art.
  • solvate means a compound or a pharmaceutically acceptable salt of a compound, wherein molecules of a suitable solvent are incorporated in the crystal lattice.
  • a suitable solvent is physiologically tolerable at the dosage administered. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a "hydrate”.
  • prodrug is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, depending on the functional groups present in the molecule and without limitation, the following derivatives of the present compounds: esters, amino acid esters, phosphate esters, metal salts sulfonate esters, carbamates, and amides. Prodrug design is discussed generally in Hardma et al. (Eds.), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed., pp. 11-16 (1996). A thorough discussion is provided in Higuchi et al., Prodrugs as Novel Delivery Systems, Vol. 14, ASCD Symposium Series, and in Roche (ed.), Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987).
  • prodrugs can be converted into a pharmacologically active form through hydrolysis of, for example, an ester or amide linkage, thereby introducing or exposing a functional group on the resultant product.
  • the prodrugs can be designed to react with an endogenous compound to form a water-soluble conjugate that further enhances the pharmacological properties of the compound, for example, increased circulatory half-life.
  • prodrugs can be designed to undergo covalent modification on a functional group with, for example, glucuronic acid, sulfate, glutathione, amino acids, or acetate.
  • the resulting conjugate can be inactivated and excreted in the urine, or rendered more potent than the parent compound.
  • High molecular weight conjugates also can be excreted into the bile, subjected to enzymatic cleavage, and released back into the circulation, thereby effectively increasing the biological half-life of the originally administered compound.
  • Particularly favoured derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.
  • the compounds used in the present invention may be in crystalline form either as free compounds or as solvates (e.g. hydrates).
  • the compounds of formula (I) to (VII) or their salts or solvates used in the invention are preferably in pharmaceutically acceptable or substantially pure form.
  • pharmaceutically acceptable form is meant, “inter alia”, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
  • Purity levels for the drug substance are preferably above 50%, more preferably above 70%, most preferably above 90%. In a preferred embodiment it is above 95% of the compounds of formula (I) to (VII), or of its salts, solvates or prodrugs.
  • compounds that selectively negatively regulate PDE 5 mRNA expression more effectively than they do other isozymes of the PDE family, and that possess acceptable pharmacological properties are also contemplated for their use in the present invention.
  • Representative polynucleotides encoding human PDE 5 are disclosed, for example, in Genbank Accession Nos. P16499, Pl 1541, NP 001074, NP_237223, NP_246273, and NP_236914, in each case the entire disclosures of which are incorporated herein by reference.
  • antisense oligonucleotides which negatively regulate PDE 5 expression via hybridization to messenger RNA (mRNA) encoding PDE 5 can also be used in the present invention. Modifications of PDE 5 expression can be achieved by designing complementary sequences or antisense molecules (DNA, RNA,
  • PNA PNA, or modified oligonucleotides
  • antisense oligonucleotides or larger polynucleotides can be designed from various locations along the coding or control regions of sequences encoding PDE 5. (See, e.g., Agrawal, S., ed.
  • antisense oligonucleotides at least 5 to about 50 nucleotides in length, including all lengths (measured in number of nucleotides) in between, which specifically hybridize to mRNA encoding PDE 5 and inhibit mRNA expression, and as a result PDE 5 protein expression, are contemplated for their use in the invention.
  • Antisense oligonucleotides include those comprising modified internucleotide linkages and/or those comprising modified nucleotides which are known in the art to improve stability of the oligonucleotide, i.e., make the oligonucleotide more resistant to nuclease degradation, particularly in vivo.
  • antisense oligonucleotides that are perfectly complementary to a region in the target polynucleotide possess the highest degree of specific inhibition antisense oligonucleotides that are not perfectly complementary, i.e., those which include a limited number of mismatches with respect to a region in the target polynucleotide, also retain high degrees of hybridization specificity and therefore also can inhibit expression of the target mRNA.
  • antisense oligonucleotides that are perfectly complementary to a target region in a polynucleotide encoding PDE 5, as well as antisense oligonucleotides that are not perfectly complementary (i.e., include mismatches) to a target region in the target polynucleotide to the extent that the mismatches do not preclude specific hybridization to the target region in the target polynucleotide, are also used in the present invention.
  • Preparation and use of antisense compounds is described, for example, in U.S. Patent No. 6,277,981, the entire disclosure of which is incorporated herein by reference (see also, Gibson (ed.), Antisense and Ribozyme Methodology, (1997), the entire disclosure of which is incorporated herein by reference).
  • ribozyme inhibitors which, as is known in the art, include a nucleotide region which specifically hybridizes to a target polynucleotide and an enzymatic moiety that digests the target polynucleotide. Specificity of ribozyme inhibition is related to the length of the antisense region and the degree of complementarity of the antisense region to the target region in the target polynucleotide.
  • ribozyme inhibitors comprising antisense regions from 5 to about 50 nucleotides in length, including all nucleotide lengths in between, that are perfectly complementary, as well as antisense regions that include mismatches to the extent that the mismatches do not preclude specific hybridization to the target region in the target PDE 5-encoding polynucleotide.
  • Ribozymes used in the present invention include those comprising modified internucleotide linkages and/or those comprising modified nucleotides which are known in the art to improve stability of the oligonucleotide, i.e., make the oligonucleotide more resistant to nuclease degradation, particularly in vivo, to the extent that the modifications do not alter the ability of the ribozyme to specifically hybridize to the target region or diminish enzymatic activity of the molecule. Because ribozymes are enzymatic, a single molecule is able to direct digestion of multiple target molecules thereby offering the advantage of being effective at lower concentrations than non-enzymatic antisense oligonucleotides. Preparation and use of ribozyme technology is described in U.S. Patent Nos. 6,696,250; 6,410,224; and 5,225,347, the entire disclosures of which are incorporated herein by reference.
  • RNAi technology is utilized for inhibiting PDE 5 expression.
  • double-stranded RNA dsRNA
  • dsRNA double-stranded RNA
  • siRNA short interfering RNA
  • complementarity of one strand in the dsRNA molecule can be a perfect match with the target region in the target polynucleotide, or may include mismatches to the extent that the mismatches do not preclude specific hybridization to the target region in the target PDE 5-encoding polynucleotide.
  • dsRNA molecules include those comprising modified internucleotide linkages and/or those comprising modified nucleotides which are known in the art to improve stability of the oligonucleotide, i.e., make the oligonucleotide more resistant to nuclease degradation, particularly in vivo.
  • RNAi compounds Preparation and use of RNAi compounds is described in U.S. Patent Publication No. 2004/0023390, the entire disclosure of which is incorporated herein by reference.
  • inhibition of PDE 5 expression is effected using RNA lasso technology.
  • Circular RNA lasso inhibitors are highly structured molecules that are inherently more resistant to degradation and therefore do not, in general, include or require modified internucleotide linkage or modified nucleotides.
  • the circular lasso structure includes a region that is capable of hybridizing to a target region in a target polynucleotide, the hybridizing region in the lasso being of a length typical for other RNA inhibiting technologies.
  • the hybridizing region in the lasso may be a perfect match with the target region in the target polynucleotide, or may include mismatches to the extent that the mismatches do not preclude specific hybridization to the target region in the target PDE 5-encoding polynucleotide.
  • RNA lassos are circular and form tight topological linkage with the target region, inhibitors of this type are generally not displaced by helicase action unlike typical antisense oligonucleotides, and therefore can be utilized as dosages lower than typical antisense oligonucleotides. Preparation and use of RNA lassos is described in U.S. Patent 6,369,038, the entire disclosure of which is incorporated herein by reference.
  • the inhibitors of PDE 5 activity and expression used in the present invention for the prevention and/or treatment of overactive bladder disease are formulated in a suitable pharmaceutical composition, in a therapeutically effective quantity.
  • Such pharmaceutical compositions may be for administration for injection, or for oral, nasal, transdermal or other forms of administration, including, e.g., by intravenous, intradermal, intramuscular, intravesical, intraurethral, intramammary, intraperitoneal, intrathecal, intraocular, retrobulbar, intrapulmonary (e.g., aerosolized drugs) or subcutaneous injection (including depot administration for long term release); by sublingual, anal, vaginal, or by surgical implantation, e.g., embedded under the splenic capsule, brain, or in the cornea.
  • the pharmaceutical composition is administered transdermally and intravesically.
  • the pharmaceutical composition may be administered in a single dose or a plurality of doses over a period of time.
  • compositions comprise effective amounts of the active compound together with pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants and/or carriers.
  • Such compositions include diluents of various buffer content (e.g., Tris-HCl, acetate, phosphate), pH and ionic strength; additives such as detergents and solubilizing agents (e.g., Tween 80, Polysorbate 80), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite), preservatives (e.g., Thimersol, benzyl alcohol) and bulking substances (e.g., lactose, mannitol); incorporation of the material into particulate preparations of polymeric compounds such as polylactic acid, polyglycolic acid, etc.
  • buffer content e.g., Tris-HCl, acetate, phosphate
  • solubilizers emulsifiers
  • compositions optionally may include still other pharmaceutically acceptable liquid, semisolid, or solid diluents that serve as pharmaceutical vehicles, excipients, or media, including but are not limited to, polyoxyethylene sorbitan monolaurate, magnesium stearate, methyl- and propylhydroxybenzoate, starches, sucrose, dextrose, gum acacia, calcium phosphate, mineral oil, cocoa butter, and oil of theobroma. Such compositions may influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the inhibitors.
  • compositions may be prepared in liquid form, or may be in dried powder, such as lyophilized form.
  • Implantable sustained release formulations are also contemplated, as are transdermal formulations.
  • Solid dosage forms include tablets, capsules, pills, troches or lozenges, cachets or pellets.
  • proteinoid encapsulation may be used (as, for example, proteinoid microspheres reported in U.S. Pat. No. 4,925,673), or liposomal encapsulation may be used, the liposomes optionally derivatized with various polymers (e.g., U.S. Pat. No. 5,013,556).
  • the formulation will include a preparation of the invention and inert ingredients which allow for protection against the stomach environment, and release of the biologically active material in the intestine.
  • the compounds used in the invention may be chemically modified so that oral delivery is efficacious.
  • the chemical modification contemplated is the attachment of at least one moiety to the compound molecule itself, where said moiety permits (a) inhibition of proteolysis; and (b) uptake into the blood stream from the stomach or intestine. Also desired is the increase in overall stability of the compound and increase in circulation time in the body.
  • moieties include polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone and polyproline (Abuchowski and Davis, Soluble Polymer-Enzyme Adducts, Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, NY, (1981), pp 367-383; Newmark, et al, J Appl. Biochem. 4:185-189 (1982)).
  • Other polymers that could be used are poly-l,3-dioxolane and poly-l,3,6-tioxocane.
  • a salt of a modified aliphatic amino acid such as sodium N-(8-[2-hydroxybenzoyl]amino) caprylate (SNAC)
  • SNAC sodium N-(8-[2-hydroxybenzoyl]amino) caprylate
  • compositions can be included in formulation as fine multiparticulates in the form of granules or pellets of particle size about, for example, one mm.
  • the formulation of the material for capsule administration can also be as a powder, lightly compressed plugs or even as tablets.
  • Compositions are optionally prepared by compression.
  • Colorants and flavoring agents may be included.
  • the preparation may be formulated (such as by liposome or microsphere encapsulation) and then further contained within an edible product, such as a refrigerated beverage containing colorants and flavoring agents.
  • compositions can be diluted or increased in the volume with an inert material.
  • exemplary diluents include carbohydrates, especially mannitol, ⁇ -lactose, anhydrous lactose, cellulose, sucrose, modified dextrans and starch.
  • Certain inorganic salts may also be used as fillers including calcium triphosphate, magnesium carbonate and sodium chloride.
  • Some commercially available diluents are Fast-Flo, Emdex, STA- Rx 1500, Emcompress and Avicell.
  • compositions including disintegrants are further contemplated in solid dosage form compositions.
  • Materials used as disintegrants include, but are not limited to, starch
  • disintegrant including the commercial disintegrant based on starch, Explotab
  • sodium starch glycolate Amberlite
  • sodium carboxymethylcellulose ultramylopectin
  • sodium alginate gelatin
  • orange peel acid carboxymethyl cellulose
  • natural sponge and bentonite Another form of disintegrant is an insoluble cationic exchange resin.
  • Powdered gums may also be used as disintegrants and as binders, and these can include powdered gums such as agar, Karaya or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants.
  • compositions including binders are further contemplated to hold the therapeutic agent together to form a hard tablet and exemplary binders include materials from natural products such as acacia, tragacanth, starch, and gelatin. Others include methyl cellulose (MC), ethyl cellulose (EC) and carboxymethyl cellulose (CMC). Polyvinyl pyrrolidone (PVP) and hydroxypropylmethyl cellulose (HPMC) could both be used in alcoholic solutions to granulate the therapeutic.
  • MC methyl cellulose
  • EC ethyl cellulose
  • CMC carboxymethyl cellulose
  • PVP polyvinyl pyrrolidone
  • HPMC hydroxypropylmethyl cellulose
  • Lubricants include, but are not limited to, stearic acid, including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes. Soluble lubricants may also be used such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights, Carbowax 4000 and 6000.
  • Glidants that might improve the flow properties of a pharmaceutical composition during formulation and to aid rearrangement during compression are also provided.
  • exemplary glidants include starch, talc, pyrogenic silica and hydrated silicoaluminate.
  • a surfactant as a wetting agent is contemplated.
  • exemplary surfactants include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfo succinate, and dioctyl sodium sulfonate.
  • Cationic detergents are contemplated, including for example and without limitation, benzalkonium chloride or benzethonium chloride.
  • compositions using as surfactants lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose are also contemplated. Compositions comprising these surfactants, either alone or as a mixture in different ratios, are therefore further provided.
  • additives are included in a pharmaceutical composition to enhance uptake of the compound, such additives including, for example and without limitation, fatty acids oleic acid, linoleic acid and linolenic acid.
  • controlled release formulations are also provided.
  • a preparation is incorporated into an inert matrix which permits release by either diffusion or leaching mechanisms e.g., gums.
  • Slowly degenerating matrices e.g., alginates, polysaccharides, may also be incorporated into the formulation.
  • Another form of a controlled release is by a method based on the Oros therapeutic system (Alza Corp.), i.e., the drug is enclosed in a semipermeable membrane which allows water to enter and push drug out through a single small opening due to osmotic effects. Some enteric coatings also have a delayed release effect.
  • compositions disclosed herein including for example, a variety of sugars which could be applied in a coating pan.
  • the compositions also include a film coated tablet and the materials used in this instance are divided into two groups.
  • the first includes the nonenteric materials, such as and without limitation methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, methylhydroxy- ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl-methyl cellulose, sodium carboxy- methyl cellulose, providone and the polyethylene glycols.
  • the second group consists of the enteric materials that are commonly esters of phthalic acid. A mix of materials is also contemplated to provide the optimum film coating.
  • Film coating may be carried out in a pan coater or in a fluidized bed or by compression coating.
  • pulmonary delivery of a preparation of the invention is also contemplated herein.
  • the compound is delivered to the lungs of a mammal while inhaling and traverses across the lung epithelial lining to the blood stream.
  • Pulmonary delivery is described in Adjei et al, Pharma. Res. (1990) 7: 565-9; Adjei et al. (1990), Internatl. J. Pharmaceutics 63: 135-44; Braquet et al. (1989), J Cardiovasc. Pharmacol. 13 (suppl.5): s.143-146; Hubbard et al. (1989), Annals Int. Med. 3: 206-12; Smith et al. (1989), J Clin. Invest.
  • nebulizers metered dose inhalers
  • powder inhalers all of which are familiar to those skilled in the art.
  • Specific examples of commercially available devices suitable for the practice of this invention are the Ultravent nebulizer, manufactured by
  • each formulation is specific to the type of device employed and may involve the use of an appropriate propellant material, in addition to diluents, adjuvants and/or carriers useful in therapy.
  • the composition is prepared in particulate form with an average particle size of less than 10 ⁇ m (or microns), preferably form 0.5 to 5 ⁇ m.
  • Formulations suitable for use with a nebulizer will typically comprise the compounds used in the invention dissolved in water at a concentration of about 0.1 to 25 mg per mL of solution.
  • the formulation may also include a buffer and a simple sugar (e.g., for protein stabilization and regulation of osmotic pressure).
  • the nebulizer formulation may also contain a surfactant, to reduce or prevent surface induced aggregation of the protein caused by atomization of the solution in forming the aerosol.
  • Formulations for use with a metered-dose inhaler device will generally comprise a finely divided powder containing the inventive compound suspended in a propellant with the aid of a surfactant.
  • the propellant may be any conventional material employed for this purpose, such as a chlorofluorocarbon, a hydrochlorofiuorocarbon, a hydro fluorocarbon, or a hydrocarbon, including trichlorofiuorome thane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1,1,1,2-tetrafiuoroethane, or combinations thereof.
  • Suitable surfactants include sorbitan trioleate and soya lecithin. Oleic acid may also be useful as a surfactant.
  • Formulations for dispensing from a powder inhaler device will comprise a finely divided dry powder containing the compound used in the invention and may also include a bulking agent, such as lactose, sorbitol, sucrose, mannitol, trehalose, or xylitol in amounts which facilitate dispersal of the powder from the device, e.g., 50 to 90% by weight of the formulation.
  • a bulking agent such as lactose, sorbitol, sucrose, mannitol, trehalose, or xylitol in amounts which facilitate dispersal of the powder from the device, e.g., 50 to 90% by weight of the formulation.
  • Nasal delivery of preparations of the invention is also contemplated.
  • Nasal delivery allows the passage of the protein to the blood stream directly after administering the therapeutic product to the nose, without the necessity for deposition of the product in the lung.
  • Formulations for nasal delivery include those with dextran or cyclodextran. Delivery via transport across other mucous membranes is also contemplated.
  • Buccal delivery of the compound is also contemplated.
  • Buccal delivery formulations are known in the art for use with peptides.
  • Pharmaceutically acceptable carriers include carbohydrates such as trehalose, mannitol, xylitol, sucrose, lactose, and sorbitol.
  • Other ingredients for use in formulations may include DPPC, DOPE, DSPC and DOPC.
  • Natural or synthetic surfactants may be used. PEG may be used (even apart from its use in derivatizing a compound).
  • Dextrans such as cyclodextran, may be used.
  • Cyclodextrins may be used.
  • Bile salts and other related enhancers may be used.
  • Cellulose and cellulose derivatives may be used. Amino acids may be used, such as use in a buffer formulation.
  • a therapeutically effective amount is an amount of a PDE 5 inhibitor sufficient to treat or prevent the symptoms, progression, or onset of OAB.
  • the therapeutically effective amount will vary depending on the inhibitor, the state of the subject's OAB or its severity, and the age, weight, etc., of the subject to be treated. Dosage ranges contemplated are about 0.001 to about 20 mg/kg.
  • a selective inhibitor is administered in an amount to selectively inhibit PDE 5.
  • a therapeutically effective amount can vary, depending on any of a number of factors, including, e.g., the specific inhibitor, the route of administration, the condition of the subject, as well as other factors understood by those in the art.
  • Toxicity and therapeutic efficacy of inhibitors of PDE 5 activity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). Additionally, this information can be determined in cell cultures or experimental animals additionally treated with other therapies including but not limited to radiation, chemotherapeutic agents, photodynamic therapies, radio frequency ablation, anti-angiogenic agents, and combinations thereof.
  • dosage ranges are contemplated.
  • the dosage range contemplated is about 0.02 to about
  • This dosage may be administered in commercially available tablets of 5 mg,
  • tablet dosages contemplated include about 1, about 2, about 3, about 4, about 6, about 7, about 8, about 9, about 11, about 12, about 13, about
  • the dosage range contemplated is about 0.2 to about 1 mg/kg.
  • This dosage is, in various embodiments, administered using commercially available tablets of 25 mg, 50 mg, or 100 mg sildenafil citrate.
  • Other tablet dosages contemplated include about 5, about 10, about 15, about 20, about 30, about 35, about 40, about 45, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, and about 150 mg sildenafil citrate.
  • the dosage range contemplated is about 0.2 to about 0.4 mg/kg.
  • This dosage is, in various embodiments, administered using a commercially available tablets of 5 mg, 10 mg, or 20 mg vardenafil.
  • Other tablet dosages contemplated include about 1, about 2, about 3, about 4, about 6, about 7, about 8, about 9, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, and about 30 mg vardenafil.
  • the dosage range contemplated is about 1 to about 2 mg/kg. This dosage is administered, in certain embodiments, using available tablets of 100 mg or 200 mg udenafil.
  • Other tablet dosages contemplated include about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 205, about 210, about 215, about 220, about 225, about 230, about 235, about 240, about 245, about 250, about 255, about 260, about 265, about 270, about 275, about 280, about 285, about 290, about 295, and about 300 mg udenafil.
  • the compounds used in the present invention may also be administered with other therapeutic agents to provide a combination therapy.
  • the other therapeutic agents may form part of the same composition or be provided as a separate composition.
  • the other therapeutic agent can be administered simultaneously with the compound that inhibits PDE 5 or can be administered prior of after administration of the compound that inhibits PDE 5.
  • Contemplated therapeutic agents include, but are not limited to, estrogenic agents, progestational substances, alpha-adrenergic antagonists, beta-adrenergic receptor blocking agents, cholinergic-receptor blocking compounds, vasopressin analogs, 5-HT reuptake inhibitors, norepinephrine reuptake inhibitors, acetylcholine uptake inhibitors, botulinum toxins, calcitonin gene-related peptide receptor ligands, calcium channel blockers, cyclooxygenase-2 inhibitors, IL-I beta inhibitors, lipoxygenase inhibitors, and cholinergic-receptor-stimulating drugs.
  • the therapeutic agents are alpha adrenergic receptor agonists and/or beta-adrenergic receptor agonists.
  • therapeutic agents contemplated include, but are not limited to, amsulosin hydrochloride, tamsulosin hydrochloride, oxybutynin chloride, desmopressin acetate, duloxetine hydrochloride, tolterodine tartrate, darifenacin hydrobromide, botulinum toxin type A, cizolirtine citrate, temiverine hydrochloride hydrate, ajulemic acid, solifenacin succinate, imidafenacin, trospium chloride, solabegron hydrochloride, capeserod hydrochloride, fesoterodine, casopitant hydrochloride, (+)-(S,S)-reboxetine, and ATD-oxybutynin.
  • one aspect provides the use of an inhibitor of PDE 5 in the manufacture of a medicament for treating one or more correlated diseases or conditions in which OAB may arise.
  • diseases or conditions include drug side effects, heavy metal poisoning, nerve damage, neurological disease, fibromyalgia, diabetes, irritable bowel syndrome, stroke, bladder hyperfiexia, post-surgical denervation of the bladder, disorders associated with serotonin 5-hydroxytryptamine (5-HT) metabolism, and nocturnal enuresis.
  • Specific neurological diseases correlated with OAB include multiple sclerosis, Parkinson's disease, brain injury, and spinal cord injury.
  • Anxiety disorders such as depression, anxiety, and attention deficit disorders have all been associated with the onset of O AB.
  • the invention relates to a method of preventing and/or treating overactive bladder disease comprising administering to a patient in need thereof a therapeutically effective amount of a PDE inhibitor as the ones defined above.
  • the method disclosed herein may be used in conjunction with non- pharmaceutically based OAB therapies, including, but not limited to, bladder retraining and nerve stimulation therapy.
  • the catheter was connected to a pressure transducer and to the data acquisition system to register intravesical pressure.
  • the intravesical catheter is also connected to an infusion pump (Harvard Apparatus, Harvard, MA, USA). After a stabilization period, a continuous infusion of the bladder with physiological salt solution (0.9% NaCl; 5 mL/hr) is started and maintained for 20 minutes.
  • physiological salt solution (0.9% NaCl; 5 mL/hr
  • the micturition frequency, the infused volume required for each micturition (micturition volume) and the intravesical pressure increase produced in each micturition reflex were determined.
  • Figure 1 shows a pictorial representation of this experimental setup.
  • bladder overactivity was induced by intravesically infusing 0.9% NaCl containing 0.3% acetic acid (Kakizaki and de Groat. J Urol, 155(l):355-60 (1996); Woods et al. J Urol, 166(3): 1142-7 (2001)).
  • urodynamic parameters under bladder hyperactivity conditions were evaluated during 20 min of infusion.
  • Tadalafil was then intravenously administered and infusion of 0.9% NaCl containing 0.3% acetic acid was again started after 45 min.
  • Urodynamic parameters were again evaluated during a 20 min infusion period.
  • the number of micturition reflexes, the micturition volume and the IVP increase during micturition were measured for each animal during all three treatment periods (control, acetic acid induced OAB, and acetic acid induced OAB plus tadalafil treatment) were obtained (see Figures 2, 3, and 4).
  • tadalafil citrate 0.5 mg/kg; i.v.
  • IVP intravesical pressure
  • Data are expressed as the mean ⁇ SEM, and n indicates the number of animals used.
  • Tadalafil significantly reduced micturition frequency and increased micturition volume (* indicates p ⁇ 0.05 versus control, and the f indicates p ⁇ 0.05 versus CH 3 COOH by one-way ANOVA followed by Student-Newman-Keuls test).

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Urology & Nephrology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne l'utilisation d'un inhibiteur de l'activité de la phosphodiestérase spécifique de la guanosine 3', 5'-monophosphate cyclique de type 5 (PDE 5) ou d'un inhibiteur de l'expression de la PDE 5 pour la fabrication d'un médicament destiné au traitement et/ou à la prophylaxie de la vessie hyperactive. En outre, l'invention concerne des compositions pharmaceutiques contenant lesdits inhibiteurs de l'activité et de l'expression de PDE 5.
PCT/EP2007/053090 2006-03-31 2007-03-30 Utilisation des inhibiteurs de la pde 5 pour le traitement de la vessie hyperactive WO2007113243A2 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008100886A1 (fr) * 2007-02-12 2008-08-21 Auspex Pharmaceuticals, Inc. Modulateurs de la pde5 hautement sélectifs et à longue durée d'action
EP1961753A1 (fr) * 2005-11-17 2008-08-27 Topharman Shanghai Co., Ltd. Derives de la pirazolopyrimidinone, leur preparation et leur utilisation
WO2009056232A2 (fr) * 2007-10-30 2009-05-07 Bayer Schering Pharma Aktiengesellschaft Combinaisons d'inhibiteurs des pde5 avec des antagonistes des récepteurs muscariniques
EP2106792A1 (fr) 2008-04-02 2009-10-07 Pelvipharm Utilisation d'une combinaison d'udénafil et d'alfuzosine ou oxybutynine pour le traitement de la vessie hyperactive
EP2192903A2 (fr) * 2007-10-02 2010-06-09 Dong-A Pharm.Co., Ltd. Composition et méthode pour le traitement ou la prévention de l'hyperplasie bénigne de la prostate et des symptômes du tractus urinaire inférieur
CN104470522A (zh) * 2012-07-27 2015-03-25 韦尔斯利医药有限公司 用于缓解尿频的药物制剂及其使用方法
US9415048B2 (en) 2010-07-08 2016-08-16 Wellesley Pharmaceuticals, Llc Pharmaceutical formulation for reducing frequency of urination and method of use thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6143757A (en) * 1995-07-14 2000-11-07 Icos Corporation Chemical compounds
EP1317924A1 (fr) * 2001-12-06 2003-06-11 Pfizer Limited Kit pour la reduction des douleurs causees par l'administration des inhibiteurs du pde-v
WO2005049616A1 (fr) * 2003-11-24 2005-06-02 Pfizer Limited 5,7-diaminopyrazolo[4,3-d]pyrimidines a effet inhibiteur par rapport a la pde-5
WO2007039075A2 (fr) * 2005-09-29 2007-04-12 Bayer Healthcare Ag Inhibiteurs pde et combinaisons de ceux-ci pour traiter des troubles urinaires

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6143757A (en) * 1995-07-14 2000-11-07 Icos Corporation Chemical compounds
EP1317924A1 (fr) * 2001-12-06 2003-06-11 Pfizer Limited Kit pour la reduction des douleurs causees par l'administration des inhibiteurs du pde-v
WO2005049616A1 (fr) * 2003-11-24 2005-06-02 Pfizer Limited 5,7-diaminopyrazolo[4,3-d]pyrimidines a effet inhibiteur par rapport a la pde-5
WO2007039075A2 (fr) * 2005-09-29 2007-04-12 Bayer Healthcare Ag Inhibiteurs pde et combinaisons de ceux-ci pour traiter des troubles urinaires

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DAUGAN ALAIN ET AL: "The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 1: 5,6,11,11a-tetrahydro-1H-imidazo[1',5':1,6 ]pyrido[3,4-b ]indole-1,3(2H)-dione analogues" JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 46, no. 21, 9 October 2003 (2003-10-09), pages 4525-4532, XP002335512 ISSN: 0022-2623 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2253632A1 (fr) * 2005-11-17 2010-11-24 Topharman Shanghai Co., Ltd. Derives de la pirazolopyrimidinone, leur preparation et leur utilisation
EP1961753A1 (fr) * 2005-11-17 2008-08-27 Topharman Shanghai Co., Ltd. Derives de la pirazolopyrimidinone, leur preparation et leur utilisation
EP1961753A4 (fr) * 2005-11-17 2009-11-25 Topharman Shanghai Co Ltd Derives de la pirazolopyrimidinone, leur preparation et leur utilisation
WO2008100886A1 (fr) * 2007-02-12 2008-08-21 Auspex Pharmaceuticals, Inc. Modulateurs de la pde5 hautement sélectifs et à longue durée d'action
EP2192903A2 (fr) * 2007-10-02 2010-06-09 Dong-A Pharm.Co., Ltd. Composition et méthode pour le traitement ou la prévention de l'hyperplasie bénigne de la prostate et des symptômes du tractus urinaire inférieur
EP2192903A4 (fr) * 2007-10-02 2010-09-29 Dong A Pharm Co Ltd Composition et méthode pour le traitement ou la prévention de l'hyperplasie bénigne de la prostate et des symptômes du tractus urinaire inférieur
WO2009056232A2 (fr) * 2007-10-30 2009-05-07 Bayer Schering Pharma Aktiengesellschaft Combinaisons d'inhibiteurs des pde5 avec des antagonistes des récepteurs muscariniques
WO2009056232A3 (fr) * 2007-10-30 2009-11-12 Bayer Schering Pharma Aktiengesellschaft Combinaisons d'inhibiteurs des pde5 avec des antagonistes des récepteurs muscariniques
EP2106792A1 (fr) 2008-04-02 2009-10-07 Pelvipharm Utilisation d'une combinaison d'udénafil et d'alfuzosine ou oxybutynine pour le traitement de la vessie hyperactive
WO2009121929A1 (fr) * 2008-04-02 2009-10-08 Pelvipharm Utilisation d’une combinaison d’udénafil et d’alfuzosine ou d’oxybutynine dans le traitement d’une vessie hyperactive
US9415048B2 (en) 2010-07-08 2016-08-16 Wellesley Pharmaceuticals, Llc Pharmaceutical formulation for reducing frequency of urination and method of use thereof
CN104470522A (zh) * 2012-07-27 2015-03-25 韦尔斯利医药有限公司 用于缓解尿频的药物制剂及其使用方法
CN107335057A (zh) * 2012-07-27 2017-11-10 韦尔斯利医药有限公司 用于缓解尿频的药物制剂及其使用方法

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