US20140296513A1 - Novel therapeutic use of p75 receptor antagonists - Google Patents

Novel therapeutic use of p75 receptor antagonists Download PDF

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US20140296513A1
US20140296513A1 US14/306,882 US201414306882A US2014296513A1 US 20140296513 A1 US20140296513 A1 US 20140296513A1 US 201414306882 A US201414306882 A US 201414306882A US 2014296513 A1 US2014296513 A1 US 2014296513A1
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alkyl
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Roberta Avallone
Marco Baroni
Tiziano Croci
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Sanofi SA
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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
    • A61K31/495—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
    • A61K31/4995—Pyrazines or piperazines forming part of bridged 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
    • A61K31/435—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
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, ***e
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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

  • the subject of the present invention is the use of p75 receptor antagonists for the preparation of medicaments for use in the treatment and/or prevention of overactive bladder and other urinary disorders.
  • Overactive bladder syndrome (sometimes called an ‘irritable’ bladder or ‘detrusor instability’) is a common condition characterized by repeated and uncontrolled bladder contractions. Symptoms include urgency, frequency, nocturia and urge incontinence. Their causes are not fully understood although they are partially due to the defective behaviour of the detrusor. Bladder training is usually the main treatment, and medication (including antimuscarinic agents) does generally not alleviate all symptoms.
  • Urinary disorders may include, but are not limited to, incontinence (inability to control urine flow), interstitial cystitis (IC), bladder pain syndrome (BPS), benign prostate hyperplasia (PBH), cancers of the urinary tract; some of them can have serious, even life-threatening, complications.
  • the compounds according to the present invention have an affinity for the p75 neurotrophin receptor.
  • Neurotrophins belong to a family of proteins of which the biological effect is in particular survival, development and function of neurons.
  • the p75 receptor which is the receptor for all neurotrophins, is a transmembrane glycoprotein of the tumoral necrosis factor (TNF) receptor family (W. J. Friedman and L. A. Greene, Exp. Cell. Res., (1999), 253, 131-142).
  • TNF tumoral necrosis factor
  • the p75 receptor is expressed in several cell types, and several biological functions have been attributed to said receptor: firstly, modulation of the affinity of neurotrophins for receptor tyrosine kinases (trk); secondly, in the absence of trk, induction of a signal for cell death by apoptosis.
  • the neurotrophin precursors, proneurotrophins are capable of binding to p75 with a high affinity, and are considered to be powerful inducers of p75 dependent apoptosis in neurons and certain cell lines.
  • the p75 receptor is a key component in the process of cell survival/proliferation or death, not only in the central nervous system but also in a number of peripheral tissues like nerves, liver, bladder muscles and prostate.
  • This pleiotropic receptor has multiple and even opposite functions, which likely depend on the cell and tissue type, as well as on the physio-pathological status of the organism.
  • mice selectively over expressing bladder Nerve Growth Factor exhibited: increased bladder wall innervation, decreased bladder capacity, more frequent micturition, increased non-voiding bladder contractions; all consistent with an overactive bladder (OAB) phenotype (Girard B M and al “Neurotrophin/receptor expression in urinary bladder of mice with overexpression of NGF in urothelium” Am J Physiol Renal Physiol. 300: F345F355, (2011)).
  • OAB overactive bladder
  • p75 receptors and Trks receptors are expressed throughout the rat urinary bladder and are present in nerve fibers of the detrusor smooth muscle, the suburothelial nerve plexus, urothelial cells, and nerve fibers associated with the suburothelial bladder vasculature (Klinger M B and al “p75NTR Expression in Rat Urinary Bladder Sensory Neurons and Spinal Cord with Cyclophosphamide-Induced Cystitis” J. Comp. Neurol. 507: 1379-1392, (2008)).
  • the present invention provides for the use of a p75 receptor antagonist in the preparation of medicaments for use in the treatment and/or prevention of overactive bladder and other urinary disorders.
  • the present invention provides for the use of a p75 receptor antagonist of the following general formula (I):
  • R3 (I) and R4 (I) located on any one of the available positions, independently represent a hydrogen atom, a halogen atom, a (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy group, a trifluoromethyl or trifluoromethoxy radical, a cyano, or a COOH, COO(C 1 -C 4 )alkyl, CONH 2 , CONR6 (I) R7 (I) or NHCOR (I) group;
  • the compounds of Formula (I) may contain one or more asymmetrical carbon atoms. They may therefore exist in the form of enantiomers or of diastereoisomers. These enantiomers and diastereoisomers, and also mixtures thereof, including racemic mixtures, are part of the invention.
  • the compounds of Formula (I) may exist in the form of bases or addition salts with acids. Such addition salts are part of the invention.
  • salts may be prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for purifying or isolating the compounds of Formula (I) are also part of the invention.
  • a halogen atom is intended to mean: a fluorine, a chlorine, a bromine or an iodine;
  • an alkyl group is intended to mean: a linear or branched, saturated aliphatic group.
  • a C 1 -C 4 alkyl group may represent a methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl;
  • a fluoroalkyl group is intended to mean: an alkyl group of which one or more of the hydrogen atoms has (have) been substituted with a fluorine atom;
  • a perfluoroalkyl group is intended to mean: an alkyl group of which all the hydrogen atoms have been substituted with a fluorine atom, for example trifluoroalkyl;
  • an alkoxy group is intended to mean: an —O-alkyl radical where the alkyl group is as defined above.
  • the present invention provides for the use of a p75 receptor antagonist of the following general formula (II):
  • R4 (II) and R5 (II) which may be identical or different, are located on any available positions and are independently a hydrogen or halogen atom, a hydroxyl, a (C 1 -C 4 )alkyl, (C 1 -C 4 )fluoroalkyl, (C 1 -C 2 )perfluoroalkyl or (C 1 -C 4 )alkoxy group, a trifluoromethoxy group, a cyano group, or a COOH, COO(C 1 -C 4 )alkyl, CONH 2 , CONR6 (III) R7 (III) or NHCOR (III) group;
  • the compounds of formula (II) may comprise one or more asymmetrical carbon atoms. They may therefore exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers and also mixtures thereof, including racemic mixtures, form part of the invention.
  • the compounds of formula (II) may exist in the form of bases or of addition salts with acids. Such addition salts form part of the invention.
  • salts may be prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for purifying or isolating the compounds of formula (II) also form part of the invention.
  • a halogen atom is intended to mean: a fluorine, a chlorine, a bromine or an iodine;
  • an alkyl group is intended to mean: a linear or branched, saturated aliphatic group.
  • a C 1 -C 4 alkyl group which may represent a methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl;
  • a fluoroalkyl group is intended to mean: an alkyl group of which one or more hydrogen atoms have been substituted with a fluorine atom;
  • a perfluoroalkyl group is intended to mean: an alkyl group of which all the hydrogen atoms have been substituted with a fluorine atom;
  • an alkoxy group is intended to mean: an —O-alkyl group where the alkyl group is as defined above.
  • the present invention provides for the use of a p75 receptor antagonist of the following general formula (III):
  • the compounds of formula (III) may comprise one or more asymmetrical carbon atoms. They may therefore exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers, and also mixtures thereof, including racemic mixtures, form part of the invention.
  • the compounds of formula (III) may exist in the form of bases or of addition salts with acids. Such addition salts form part of the invention.
  • salts may be prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for purifying or isolating the compounds of formula (III) also form part of the invention.
  • a halogen atom is intended to mean: a fluorine, a chlorine, a bromine or an iodine;
  • an alkyl group is intended to mean: a linear, branched or cyclic, saturated aliphatic group.
  • a C1-C4 alkyl group which may represent a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl or cyclobutyl;
  • a fluoroalkyl group is intended to mean: an alkyl group of which one or more hydrogen atoms have been substituted with a fluorine atom;
  • a perfluoroalkyl group is intended to mean: an alkyl group of which all the hydrogen atoms have been substituted with a fluorine atom, for example a trifluoroalkyl group such as trifluoromethyl;
  • an alkoxy group is intended to mean: an —O-alkyl radical where the alkyl group is as defined above;
  • a perfluoroalkoxy group is intended to mean: an alkoxy group of which all the hydrogen atoms have been substituted with a fluorine atom, for example a trifluoroalkoxy group such as trifluoromethoxy;
  • a cycloalkyl group is intended to mean: a cyclic alkyl group.
  • a halogen atom is intended to mean: a fluorine, a chlorine, a bromine.
  • the present invention provides for the use of a p75 receptor antagonist of the following general formula (IV):
  • the fused heterocycle of formula Y (IV) may be attached to the rest of the molecule via any of the available carbon atoms, and in which:
  • nucleus or an aromatic or saturated 5-atom nucleus, containing a nitrogen, oxygen or sulfur atom, the nucleus possibly being substituted with one or two (C1-C4)alkyl groups;
  • the compounds of formula (IV) may comprise one or more asymmetric carbon atoms. They may thus exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers, and also mixtures thereof, including racemic mixtures, form part of the invention.
  • the compounds of formula (IV) may exist in the form of bases or of acid-addition salts. Such addition salts form part of the invention.
  • salts may be prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for purifying or isolating the compounds of formula (IV) also form part of the invention.
  • the present invention provides for the use of a p75 receptor antagonist selected from:
  • Said p75 receptor antagonists above, and the pharmaceutically acceptable salts thereof may be used at daily doses of 0.1 to 200 mg per kilo of body weight of the mammal to be treated, preferably at daily doses of from 0.5 to 100 mg/kg. In humans, the dose may vary preferably from 0.5 mg to 50 mg per day, in particular from 1 to 30 mg, depending on the age of the individual to be treated, the type of treatment, prophylactic or curative, and the seriousness of the disorder.
  • Said p75 receptor antagonists are generally administered as a dosage unit of 0.5 to 50 mg, preferably of 1 to 30 mg, of active principle, one to five times a day. Preferable unit dosage forms comprise 1 or 30 mg of p75 receptor antagonists.
  • Said dosage units are preferably formulated in pharmaceutical compositions in which the active principle is mixed with a pharmaceutical excipient.
  • compositions of the present invention use can me made for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, transdermal or rectal administration.
  • Said p75 receptor antagonists, and the pharmaceutically acceptable salts thereof may be administered in unit administration forms, mixed with conventional pharmaceutical supports, to animals and humans for treating the abovementioned disorders.
  • the unit administration forms which are suitable comprise oral forms such as tablets, gel capsules, powders, granules and oral solutions or suspensions, sublingual and buccal administration forms, subcutaneous, intramuscular or intravenous administration forms, local administration forms and rectal administration forms.
  • the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
  • a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
  • the tablets may be coated with sucrose or other suitable materials, or they may be treated such that they have sustained or delayed activity and that they release, in a continuous manner, a predetermined amount of active principle.
  • Usual excipients include lactose monohydrate, microcrystalline cellulose, povidone, sodium carboxymethylstarch, magnesium stearate, ethylcellulose, hypromellose, macrogol 400, titane dioxide.
  • a preparation of gel capsules is obtained by mixing the active ingredient with a diluent and pouring the mixture obtained into soft or hard gel capsules.
  • a preparation in the form of a syrup or elixir may contain the active ingredient together with a sweetener, preferably a calorie-free sweetener, methylparaben and propylparaben as antiseptics, and also a flavour enhancer and a suitable colorant.
  • a sweetener preferably a calorie-free sweetener, methylparaben and propylparaben as antiseptics, and also a flavour enhancer and a suitable colorant.
  • the water-dispersible powders or granules may contain the active ingredient mixed with dispersing agents or wetting agents, or suspending agents, such as polyvinylpyrrolidone, and also with sweeteners or flavour correctors.
  • the active principle is mixed into an excipient for preparing creams or ointments, or it is dissolved in a vehicle for intraocular administration, for example in the form of an eyewash.
  • suppositories prepared with binders which melt at rectal temperature, for example cocoa butter or polyethylene glycols.
  • aqueous suspensions, saline solutions or injectable sterile solutions which contain pharmacologically compatible dispersion agents and/or wetting agents, for example propylene glycol or butylene glycol, are used.
  • the active principle may also be formulated in the form of microcapsules, optionally with one or more supports or additives.
  • the present invention provides a method of treating and/or preventing overactive bladder or other urinary disorders in a patient which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of a p75 receptor antagonist.
  • the p75 receptor antagonist is selected from a compound of general formula (I), a compound of general formula (II), a compound of general formula (III), and a compound of the following general formula (IV).
  • the p75 receptor antagonist is selected from the group consisting of compound n° 1: 1-[4-(4-chloro-3-trifluoromethyl-phenyl)-3,6-dihydro-2 H-pyridin-1-yl]-2-[8-(5-fluoro-pyrimidin-2-yl)-3,8-diaza-bicyclo[3.2.1 ]oct-3-yl]ethanone; compound n° 2: 6- ⁇ (3S,5R)-3,5-Dimethyl-4-[2-oxo-2-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethyl]piperazin-1-yl ⁇ nicotinic acid hydrochloride; compound n° 3: 6- ⁇ (3S,5R)-4-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-ox
  • terapéuticaally effective amount is meant to describe an amount of a compound, composition, medicament or active ingredient effective in producing the desired therapeutic effect.
  • FIG. 1 is a cystometrogram (CMG) from a rat during the light phase in response to continuously-infused saline, in normal filling-voiding micturition cycle.
  • CMG cystometrogram
  • FIG. 2 shows the effect of the compounds on intercontraction intervals (ICI) in SHR male rats, characterized by overactive bladder (OAB).
  • FIG. 3 represents the positive activity of the compounds according to the invention on bladder capacity of SHR male rats.
  • FIG. 4 shows the dose response activity (3, 10, 30 mg/kg po) of compound 2 on intercontraction intervals in SHR male rats.
  • FIG. 5 represents the dose dependent activity of compound n° 2 on bladder capacity in SHR male rats.
  • FIG. 6 shows the effect of a one-week treatment with compound n° 2 on intercontraction intervals (ICI) in SHR male rats.
  • FIG. 7 shows the effect of a one-week treatment with compound n° 2 on bladder capacity in SHR male rats.
  • vehicle or compounds were administered orally at 2 ml/kg.
  • cystometrograms are analyzed using a specific software, SOF-552 cystometry data analysis.
  • Rats were removed from study, before any treatment when adverse events occurred that included: a reduction in body weight post-surgery, lethargy superior or equal to 20%, pain, or distress not relieved by sanofi's approved regimen of postoperative analgesics or hematuria.
  • the compounds increased the ICI and the bladder capacity in this pathophysiological model.
  • the compounds had no effect on micturition pressure parameters suggesting a specific response. These compounds can thus be useful for the treatment and/or prevention of overactive bladder.
  • the treatment started at least 5 days after surgery, and lasted 7 days.
  • the cystometry test was performed 24 h after the end of the last treatment.
  • the chronic treatment (one week) with a p75 antagonist, affects the micturition reflex in SHR rats, characterized by DO-OAB.
  • the compound n° 2 increased the ICI and the bladder capacity in this pathophysiological model.
  • the compound had no effect on micturition pressure parameters suggesting a specific response. This compound can thus be useful for the treatment and/or prevention of overactive bladder.
  • a unitary dosage form of a compound of the invention in the form of a tablet may comprise the following constituents:
  • p75 receptor antagonist 5.0 mg Lactose 122.0 mg Microcristalline cellulose 36.0 mg Sodium carboxymethylstarch 7.0 mg Polyvidone 9 mg Magnesium stearate 1.0 mg

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Citations (1)

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