WO2009109001A1 - Procédé de prévention et/ou de traitement d’une maladie, d’une condition ou d’un état associés à une fonction réduite des neurones dopaminergiques - Google Patents

Procédé de prévention et/ou de traitement d’une maladie, d’une condition ou d’un état associés à une fonction réduite des neurones dopaminergiques Download PDF

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WO2009109001A1
WO2009109001A1 PCT/AU2009/000257 AU2009000257W WO2009109001A1 WO 2009109001 A1 WO2009109001 A1 WO 2009109001A1 AU 2009000257 W AU2009000257 W AU 2009000257W WO 2009109001 A1 WO2009109001 A1 WO 2009109001A1
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receptor antagonist
disease
substance
subject
condition
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PCT/AU2009/000257
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Robert Vink
Emma Thornton
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Adelaide Research & Innovation Pty Ltd
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Publication of WO2009109001A1 publication Critical patent/WO2009109001A1/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
    • A61K31/435—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, cocaine
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5355—Non-condensed oxazines 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to a method of preventing and/or treating a disease, condition or state associated with reduced dopaminergic neuron function.
  • Neurodegenerative diseases such as Parkinson's disease place a huge burden on society, both socially and economically. Many of these diseases have a significant impact on the affected individual and ultimately require medical intervention. Moreover, as the population ages and the average individual lives longer, the prevalence of neurodegenerative diseases is likely to increase.
  • Parkinson's disease involves the loss of dopaminergic neurons, which are neurons that release dopamine from its synapses. Such diseases may result not only in the loss of motor skills, but also in the development of a number of other non-motor symptoms, such as mood disturbances and cognitive disturbances.
  • Parkinson's disease is characterised by a loss of dopaminergic neurons from the substantia nigra. These dopaminergic neurons release dopamine within the striatum, the area of the brain that regulates smooth execution of movement. As such, motor symptoms such as resting tremor and bradykinesia, a slowness in movement, predominate as the disease progresses. Fortunately, the loss of dopaminergic neurons progresses slowly, and surviving neurons can compensate for this loss by increasing dopamine synthesis and release. This is reasonably effective until approximately 50% of neurons have been lost, at which point the clinical symptoms present.
  • levodopa can in itself cause significant side effects including drowsiness, dizziness, headache, loss of appetite, stomach upset, nausea, vision changes, or trembling of the hands.
  • metabolism of levodopa is not exclusive to the CNS and may also occur in peripheral tissues, further adverse side- effects may result.
  • Peripheral metabolism of levodopa and associated side effects may be minimized by treatment with carbidopa or benserazide, which inhibit the conversion of levodopa to dopamine and which are not able to cross the blood brain barrier. Nevertheless, despite the beneficial effects of carbidopa and benserazide, side effects are still commonly associated with levodopa administration.
  • levodopa can be beneficial in improving motor symptoms and quality of life, it is unable to stop the progression of the disease.
  • levodopa after prolonged use of levodopa almost all patients will develop additional motor complications such as dyskinesia and motor fluctuations, and also experience "wearing off effects or shorter periods in which levodopa gives a symptomatic response. They may also experience pain, nausea and hypotension. Depression is also seen in up to 40% of patients, as well as stress and anxiety, speech and swallowing difficulties, sexual dysfunction and cognitive decline. Indeed, the levodopa-related effects are often more disabling than the initial motor symptoms associated with Parkinson's disease.
  • Other diseases or conditions associated with reduced dopaminergic neuron function include reverse schizophrenia and attention deficit hyperactivity disorder (ADHD). Treatment of these diseases and conditions can also involve the administration of levodopa to increase the dopamine levels in the CNS.
  • ADHD attention deficit hyperactivity disorder
  • the present invention relates to the use of substance P receptor antagonists to prevent and/or treat such diseases, conditions or states.
  • the present invention arises from studies into the association of substance P with diseases, conditions or states associated with reduced dopaminergic neuron function.
  • the present invention provides a method of preventing and/or treating a disease, condition or state associated with reduced dopaminergic neuron function in a subject, the method including administering to the subject an effective amount of a substance P receptor antagonist.
  • the present invention also provides use of a substance P receptor antagonist in the preparation of a medicament for preventing and/or treating a disease, condition or state associated with reduced dopaminergic neuron function in a subject.
  • the present invention also provides a pharmaceutical composition when used to treat a disease, condition or state associated with reduced dopaminergic function, the composition including a substance P receptor antagonist.
  • the present invention also provides a pharmaceutical composition including a substance P receptor antagonist and a dopaminergic agent.
  • the present invention also provides a combination product including the following components: a substance P receptor antagonist; and a dopaminergic agent; wherein the components are provided in a form for separate administration to a subject, or in a form for co-administration to a subject.
  • the present invention also provides a method of alleviating one or more complications in a subject associated with administration of a dopaminergic agent, the method including administering to the subject an effective amount of a substance P receptor antagonist.
  • the present invention also provides use of a substance P receptor antagonist in the preparation of a medicament for alleviating one or more complications in a subject associated with administration of a dopaminergic agent.
  • the present invention also provides a method of inhibiting progression of a disease, condition or state associated with reduced dopaminergic neuron function in a subject, the method including administering to the subject an effective amount of a substance P receptor antagonist.
  • the present invention also provides use of a substance P receptor antagonist in the preparation of a medicament for inhibiting progression of a disease, condition or state associated with reduced dopaminergic neuron function in a subject.
  • dopaminergic neuron is a neuron that releases dopamine from its synapses.
  • dopaminergic neurons include dopaminergic neurons present in the ventral tegmental area of the midbrain, substantia nigra pars compacta, and arcuate nucleus of the hypothalamus.
  • Dopaminergic neuron function as used throughout the specification is to be understood to mean one or more activities of a dopaminergic neuron.
  • Dopaminergic neuron function includes, for example, the stimulation of a dopaminergic neuron, the transmission of an electrical impulse along a dopaminergic neuron, release of dopamine as a result of the electrical impulse, binding of released dopamine to dopamine receptors, and dopamine receptor signalling.
  • a disease condition or state associated with reduced dopaminergic function is a disease, condition or state associated with one or more of a loss of dopaminergic neuron function, a loss of dopaminergic neurons, and dopaminergic neuron dysfunction.
  • dopaminergic agent as used throughout the specification is to be understood to mean an agent that increases one or more of the level and/or activity of dopamine, an agent that increases dopaminergic neuron function, an agent that binds to and activates a dopamine receptor, and an agent that increases the responsiveness of the central nervous system to dopamine.
  • substance P receptor antagonist as used throughout the specification is to be understood to mean an agent that directly or indirectly inhibits the binding of substance P to one of its receptors.
  • a substance P receptor antagonist includes a derivative, a variant, an analogue, a pharmaceutically acceptable salt, a tautomer or a pro-drug of a substance P receptor antagonist.
  • substance P is an excitatory neurotransmitter and is a peptide having the structure RPKPEEFFGLM-NH 2 .
  • Methods for determining the ability of an agent to act as a substance P receptor antagonist are known in the art.
  • variant as used throughout the specification is to be understood to mean an amino acid sequence of a polypeptide or protein that is altered by one or more amino acids.
  • the variant may have "conservative” changes, wherein a substituted amino acid has similar structural or chemical properties to the replaced amino acid (e.g., replacement of leucine with isoleucine).
  • a variant may also have "non-conservative” changes (e.g., replacement of a glycine with a tryptophan) or a deletion and/or insertion of one or more amino acids.
  • the term also includes within its scope any insertions/deletions of amino acids for a particular polypeptide or protein.
  • a "functional variant” will be understood to mean a variant that retains the functional capacity of a reference protein or polypeptide.
  • Conservative substitutions typically include substitutions within the following groups: glycine and alanine; valine, isoleucine, and leucine; aspartic acid and glutamic acid; asparagine and glutamine; serine and threonine; lysine and arginine; and phenylalanine and tyrosine. Under some circumstances, substitutions within the aliphatic group alanine, valine, leucine and isoleucine are also considered as conservative. Sometimes substitution of glycine for one of these can also be considered conservative.
  • prevent as used throughout the specification is to be understood to mean an intervention that prevents or delays the onset of a disease, condition or state in a subject.
  • treat as used throughout the specification is to be understood to mean an intervention that improves the prognosis and/or state of a subject with respect to a disease, condition or state.
  • subject as used throughout the specification is to be understood to mean a human or animal subject.
  • the present invention also includes within its scope veterinary applications.
  • the animal subject may be a mammal, a primate, a livestock animal (eg. a horse, a cow, a sheep, a pig, or a goat), a companion animal (eg. a dog, a cat), a laboratory test animal (eg. a mouse, a rat, a guinea pig, a bird, a rabbit), an animal of veterinary significance, or an animal of economic significance.
  • Figure 1 shows immunohistology using an anti-substance P receptor antibody of sections of human substantia nigra from a normal subject (left panel), a subject with early stage Parkinson's disease (centre panel) and a subject with late stage Parkinson's disease (right panel).
  • Figure 2 shows Rotarod results for rodents with 6-OHDA-induced Parkinson's disease (closed squares), rodents with 6-OHDA-induced Parkinson's disease and treated with substance P (open bold triangles), rodents with 6-OHDA-induced Parkinson's disease and treated with a substance P receptor antagonist (N-acetyl-L-tryptophan) (open triangles) and control rodents (open squares).
  • Decreased time on the Rotarod is indicative of the induction of Parkinson's disease and increased motor deficits.
  • FIG 3 shows Rotarod results for rodents with 6-OHDA-induced Parkinson's disease (closed triangles), rodents with 6-OHDA-induced Parkinson's disease and treated with an alternative substance P receptor antagonist (L,733-060) (closed squares) and control rodents (open squares). Decreased time on the Rotarod is indicative of the induction of Parkinson's disease and increased motor deficits.
  • Figure 4 shows day 7 and day 14 Rotameter results for rodents with 6-OHDA-induced Parkinson's disease, rodents with 6-OHDA-induced Parkinson's disease and treated with substance P, rodents with 6-OHDA-induced Parkinson's disease and treated with a substance P receptor antagonist (N-acetyl-L-tryptophan) and control rodents. Increased ipsilateral turns per minute are indicative of increased lesion size in experimental Parkinson's disease.
  • a substance P receptor antagonist N-acetyl-L-tryptophan
  • Figure 5 shows the amount of dopaminergic cell loss in the substantia nigra in normal rodents (column 1), rodents with 6-OHDA-induced Parkinson's disease (column 2), rodents with 6-OHDA-induced Parkinson's disease and treated with substance P (column 3), rodents with 6-OHDA-induced Parkinson's disease and treated with a substance P receptor antagonist (N-acetyl-L-tryptophan; column 4) and rodents with 6- OHDA-induced Parkinson's disease and treated with an alternative substance P receptor antagonist (L,733-060; column 5). Decreased cell death is indicative of an attenuation of Parkinson's disease.
  • the present invention provides a method of preventing and/or treating a disease, condition or state associated with reduced dopaminergic neuron function in a subject, the method including administering to the subject an effective amount of a substance P receptor antagonist.
  • This embodiment of the present invention is directed to preventing and/or treating a disease, condition or state associated with reduced dopaminergic neuron function by administering to a subject one or more substance P receptor antagonists.
  • Dopaminergic neuron function may be reduced for a variety of reasons, including for example a loss of dopaminergic neurons and/or a dysfunction of dopaminergic neurons.
  • a reduction in dopaminergic neuron function in a subject may be associated, for example, with either or both of a reduction in dopaminergic function over time as measured within the one subject, or may be a reduction in dopaminergic function of one subject in relation to the average dopaminergic function in a population.
  • Parkinson's disease and related movement disorders include Parkinson's disease and related movement disorders, attention-deficit hyperactivity disorder (ADHD), Lesch-Nyhan syndrome and negative schizophrenia.
  • Parkinson's disease is normally classified as a disease associated with loss of dopaminergic neurons from the substantia nigra. There is currently no blood or laboratory test that is accurate for the diagnosis of Parkinson's disease and as such a number of clinical criteria are usually evaluated before a diagnosis is made.
  • the Unified Parkinson's Disease Rating Scale (Fahn S, et al. (1987), Recent Developments in Parkinson's Disease, VoI 2. Florham Park, NJ. Macmillan Health Care Information, pp 15 3-163, 293-304) is commonly used to assess a number of parameters to provide an indication of the presence and severity of Parkinson's disease in a subject.
  • Nuclear medical imaging including Positron Emission Tomography (PET) may also be used to assess the presence and severity of Parkinson's disease.
  • PET Positron Emission Tomography
  • Methods of assessing Parkinson's disease in a subject using PET include for example Sossi et al. (1998) /. Nucl. Med. 39: 1714-1719 and Suzuki et al. (2006) Parkinsonism and Related Disorders. 12: S90.
  • ADHD Attention-deficit hyperactivity disorder
  • DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders
  • LNS Lesch-Nyhan syndrome
  • HPRT hypoxanthine-guanine phosphoribosyltransferase
  • HRPT hypoxanthine-guanine phosphoribosyltransferase
  • the result is a build-up of uric acid in all body fluids, and development of symptoms such as severe gout, poor muscle control, and moderate retardation, which appear in the first year of life.
  • Neurological symptoms include facial grimacing, involuntary writhing, and repetitive movements of the arms and legs.
  • a striking feature of LNS is self-mutilating behaviors - characterized by lip and finger biting - that begin in the second year of life. Assaying levels of HPRT enzyme in red blood cells or cultured fibroblasts is used to make the definitive diagnosis.
  • Negative schizophrenia, or type II schizophrenia typically manifests in patients as social withdrawal and psychomotor retardation, including lack of emotional response, poverty of speech, and absence of volition or will. Symptoms and methods of diagnosing negative schizophrenia are provided, for example, by American Psychiatric Association (2000) Diagnostic and Statistical Manual of Mental Disorders (DSM-IV- TR), 4 th Ed. American Psychiatric Publishing Inc, Arlington, VA 22209.
  • the disease, condition or state associated with reduced dopaminergic neuron function is Parkinson's disease.
  • the substance P receptor antagonist in the various embodiments of the present invention is an agent that directly or indirectly inhibits the binding of substance P to one of its receptors.
  • the substance P receptor antagonist also includes a derivative, a variant, an analogue, a pharmaceutically acceptable salt, tautomer or pro-drug of a substance P receptor antagonist.
  • substance P is an excitatory neurotransmitter and is peptide a having the structure RPKPEEFFGLM-NH2.
  • Substance P binds to a number of receptors including the NKl receptor (neurokinin 1 receptor), the NK2 receptor and the NK3 receptor.
  • Substance P antagonists inhibit the binding of substance P to any one of its receptors.
  • the term "substance P" includes within its scope various variants, truncated forms or analogues of the peptide, for example as described in US patent 4,481,139.
  • the identification of a substance as a substance P receptor antagonist may be 10 determined by a method known in the art, for example as described in US patents 5,990,125, 6,482,829; and 5,972,938; and US patent application 20030083345.
  • Spantide III L-Norleucinamide, N6-(3-pyridinylcarbonyl)-D-lysyl-L-prolyl-3-(3-py ⁇ dinyl)-L-alanyl-L-prolyl-3,4-dichioro-D-phenylalanyl- L-asparaginyl-D-tryptophyl-L-phenylalanyl-3-(3-pyridinyl)-D-alanyl-L-leucyl-
  • substance P receptor antagonists are as described in US patents 4,481,139 and 5,977,104.
  • NKl receptor antagonists are as described in US patent 5,990,125.
  • Tachykinin antagonists may also be used as substance P antagonists.
  • substance P receptor antagonists include piperdine and morpholine derivatives (as described in US 4,985,896), piperazino (as described in US 5,981,52), piperidinyl compounds as NKl or NK2 antagonists (as
  • the substance P receptor antagonist is one or more of a NKl receptor antagonist, a NK2 receptor antagonist, and a NK3 receptor antagonist.
  • the NKl receptor antagonist is selected from one or more of the group consisting of CGP49823, CP-96,345, CP99,994, CP-122,721, FK88, GR203040, GR205171, GR82334, GR94800, HSP-117, L-703,606 oxalate, L-732,138 (N-acetyl-L- tryptophan), L-733060, L-742,694, L-745,030, L-668,169, LY-303241, LY-303870, LY306740, MEN-11149, MK-869, PD-154075, R-544, RP-67580, RPR100893, Sendide, Spantide II, Spantide III, SR140333, WIN-41,7098, WIN-62,577, or a derivative, a variant, an analogue, a pharmaceutically acceptable salt, tautomer or prodrug thereof.
  • the NK2 receptor antagonist is selected from one or more of the group consisting of SR-48968, L-659877, GR103537, MGN-10627, SR144190 and GR94800, or a derivative, a variant, an analogue, a pharmaceutically acceptable salt, tautomer or pro-drug thereof.
  • the NK3 receptor antagonist is selected from one or more of the group consisting of SR-143,801, R820, R486, SB222200, L758,298 and NKP608, or a derivative, a variant, an analogue, a pharmaceutically acceptable salt, tautomer or prodrug thereof.
  • the substance P receptor antagonist is L-732,138, namely N-acetyl- L-tryptophan, or a derivative, analogue, pharmaceutically acceptable salt, tautomer or pro-drug thereof.
  • examples include lipid soluble analogues, N-acetyl-L-tryptophan 3,5- bis(trifluoromethyl)benzyl ester and N-acetyl tryptophan methyl ester.
  • One or more substance P receptor antagonists may also be used in the preparation of a medicament for preventing and/or treating a disease, condition or state associated with reduced dopaminergic function.
  • the present invention provides use of a substance P receptor antagonist in the preparation of a medicament for preventing and/or treating a disease, condition or state associated with reduced dopaminergic function.
  • One or more substance P receptor antagonists may also be used in a pharmaceutical composition, to prevent and/or treat a disease, condition or state associated with reduced dopaminergic function.
  • the present invention provides a pharmaceutical composition when used to prevent and/or treat a disease, condition or state associated with reduced dopaminergic function, the composition including a substance P receptor antagonist.
  • the administration of one or more substance P receptor antagonists may also be used to inhibit progression of the disease, condition or state associated with reduced dopaminergic neuron in the subject.
  • the present invention provides a method of inhibiting progression of a disease, condition or state associated with reduced dopaminergic neuron in a subject, the method including administering to the subject an effective amount of a substance P receptor antagonist.
  • the effective amount of a substance P receptor antagonist to be delivered in the various embodiments of the present invention is not particularly limited, so long as it is within such an amount and in such a form that generally exhibits a useful or therapeutic effect.
  • the term "effective amount” is the quantity which when delivered, improves the prognosis of the subject.
  • the amount to be delivered will depend on the particular characteristics of the condition being treated, the mode of delivery, and the characteristics of the subject, such as general health, other diseases, age, sex, genotype, body weight and tolerance to drugs.
  • a suitable dosage of the substance P receptor antagonist for delivery to the desired site of action in the various embodiments of the present invention may be selected.
  • the dosage of the substance P receptor antagonist administered to a subject in the various embodiments of the present is in the range from 0.1 mg/kg to 100 mg/kg.
  • the substance P receptor antagonist is administered to the subject at a dose of 0.25 mg/kg to 25 mg/kg.
  • a suitable dose of N-acetyl- tryptophan is 2.5 mg/kg.
  • the dosage of the substance P receptor antagonist in a pharmaceutical composition may be in the range from 10-5,000 mg per subject, and typically will be in the range of 50-2,000 mg per subject.
  • Suitable dosages are generally as described in US patents 4,990,125 and US 5,977,104.
  • the prevention and/or treatment of a disease, condition or state associated with reduced dopaminergic neuron function may further include administering to the subject one or more agents selected from the group consisting of a dopaminergic agent (eg levodopa), an anticholinergic, Amantadine, a monoamine oxidase (MAO) inhibitor, and a COMT inhibitor.
  • a dopaminergic agent eg levodopa
  • an anticholinergic eg.g levodopa
  • Amantadine e.g., a monoamine oxidase (MAO) inhibitor
  • MAO monoamine oxidase
  • COMT inhibitor e.g COMT inhibitor
  • the present invention also provides use of one or more of the above agents for preventing and/or treating a disease, condition or state associated with reduced dopaminergic function, the use of one or more of the above agents in the preparation of a medicament with a substance P receptor antagonist, and the use of one or more of the above
  • a suitable dose of one or more of the above agents may be selected.
  • the prevention and/or treatment of a disease, condition or state associated with reduced dopaminergic function further includes administration to the subject of a dopaminergic agent.
  • Dopaminergic agents include, for example, levodopa, phenylalanine, theanine, tyrosine, vitamin C, vitamin B6, amantadine, yohimbe (lV ⁇ -hydroxy-yohimban-l ⁇ -carboxylic acid methyl ester), monoamine oxidase inhibitors, buproprion and dopamine agonists.
  • Dopamine agonists include bromocriptine, cabergoline, pergolide, pramipexole, ropinirole and apomorphine.
  • the dopaminergic agent is levodopa.
  • Levodopa has a chemical formula of 3,4-dihydroxy-L-phenylalanine and is available commercially.
  • a suitable dose for administration to a subject may be chosen.
  • a subject being treated for Parkinson's disease may generally receive an initial levodopa dose of 100 mg to 1 g daily, usually in 250 mg increments four times a day.
  • the levodopa dose can be increased in increments of 100 to 750 mg/day at 3 to 7 day intervals, until a daily maintenance dose of 2.5 to 6 g/day is reached.
  • no more than 8 g/day levodopa is administered.
  • Levodopa is most commonly administered orally in tablet form, however other routes of administration may be used including intravenous, intraperitoneal, subcutaneous, intramuscular or topical routes or by direct injection. Under some circumstances, levodopa may be delivered by oral sustained release administration.
  • levodopa may also be administered with carbidopa or benserazide.
  • Carbidopa or benserazide inhibit the conversion of levodopa to dopamine, and like dopamine, neither is able to cross the blood brain barrier.
  • another embodiment includes the administration of carbidopa or benserazide in conjunction with levodopa.
  • administration of a substance P receptor antagonist delays and/or prevents the "wearing off effects of levodopa.
  • the effects of the levodopa in many patients begin to last for shorter periods of time, also known as “wearing off, forcing an increase in the dosage required. This can result in dyskinesia, which is an inability to control muscles.
  • the administration of the substance P receptor antagonist reduces the amount and/or frequency of the dopaminergic agent administered to the subject.
  • the administration of the substance P receptor antagonist reduces one or more complications (side-effects) in the subject associated with administration of the dopaminergic agent.
  • Such complications include drowsiness, dizziness, headache, loss of appetite, stomach upset, nausea, vision changes, trembling of the hands, dyskinesia, pain, nausea, hypotension, depression, stress and anxiety, speech and swallowing difficulties, sexual dysfunction and cognitive decline, seizures, vomiting or diarrhea, gastrointestinal bleeding, insomnia, confusion, nightmares, muscle twitches, loss of appetite, change in sense of taste, decreased attention span, memory loss, nervousness, weakness, increased sweating, fatigue, unusual or uncontrolled movements of the mouth, tongue, face, head, neck, arms, and legs, difficulty walking, back and neck muscle spasms, fast, irregular, or pounding heartbeat and eye pain.
  • levodopa can cause significant side effects including drowsiness, dizziness, headache, loss of appetite, stomach upset, nausea, vision changes, or trembling of the hands.
  • metabolism of levodopa is not exclusive to the CNS and may also occur in peripheral tissues, further adverse side- effects may result.
  • Amantadine has side-effects including nervousness, anxiety, agitation, insomnia, difficulty in concentrating, and exacerbations of pre-existing seizure disorders and psychiatric symptoms.
  • Bupoprion has side-effects including seizures, delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion, dry mouth, nausea, insomnia, tremor, excessive sweating and tinnitus.
  • Bromocriptine has side-effects including dizziness, upset stomach, headache, fatigue, vomiting, constipation, swelling of the feet or ankles, fast, irregular, or pounding heartbeat, confusion and watery discharge from nose.
  • Carbegoline has side-effects including depression, dyskinesia, hallucinations, sleep disturbances, vertigo, nausea, obstipation, dry mouth, gastric irritation, vomiting, dyspepsia, hypotension, peripheral edema, non-specific edema, arrhythmias and angina pectoris.
  • Pergolide has side-effects including associative learning difficulties, cardiac fibrosis and valvular damage.
  • Pramipexole has side-effects including dizziness, lightheadedness, or fainting, hallucinations weight gain, weight loss, nausea, insomnia twitching, twisting, or other unusual body movements or unusual tiredness or weakness.
  • Ropinirole has side-effects including nausea, hallucinations, drowsiness, vomiting and dizziness.
  • Apomorphine has side-effects include confusion, hallucinations, tremor (uncontrolled shaking, nausea or vomiting that continues after taking an anti-nausea medication, lightheadedness, falling or passing out, chest pain or heavy feeling, pain spreading to the arm or shoulder, sweating, general ill feeling, restless muscle movements in your eyes, tongue, jaw, or neck, and penis erection that is painful or lasts 4 hours or longer.
  • the present invention provides a method of alleviating one or more complications in a subject associated with administration of a dopaminergic agent, the method including administering to the subject an effective amount of a substance P receptor antagonist.
  • One or more substance P receptor antagonists and one or more dopaminergic agents may also be used in a pharmaceutical composition.
  • the present invention provides a pharmaceutical composition including a substance P receptor antagonist and a dopaminergic agent.
  • substance P receptor antagonists and dopaminergic agents are as previously discussed herein.
  • the dopaminergic agent is levadopa.
  • An example of a formulation of a substance P receptor antagonist and levodopa is a 50/100 mg (substance P receptor antagonist/levodopa) tablet formulation.
  • Levodopa may be wet granulated together with maize starch, mannitol, croscarmellose sodium and povidone in a conventional high shear mixer.
  • the substance P receptor anatgonist may be wet granulated separately with maize starch, mannitol, croscarmellose sodium and povidone in a high shear mixer.
  • the dry levodopa-granules, the dry substance P receptor granules, croscarmellose sodium, mannitol and magnesium stearate may be mixed together and the mass obtained compressed to tablets and coated with HPMC- coating containing a color pigment.
  • the present invention also provides a combination product including one or more substance P receptor antagonists and one or more dopaminergic agents.
  • the present invention provides a combination product including the following components: a substance P receptor antagonist; and a dopaminergic agent; wherein the components are provided in a form for separate administration to a subject, or in a form for co-administration to a subject.
  • the subject may be suffering from, or susceptible to, one or more of the various diseases, conditions or states associated with reduced dopaminergic neuron function, as previously described herein.
  • the components of the combination product may packaged separately or together in suitably sterilized containers such as ampoules, bottles, or vials, either in multi-dose or in unit dosage forms.
  • the containers are typically hermetically sealed. Methods are known in the art for the packaging of the components.
  • the effective amount of the substance P receptor antagonist, and/or one or more of the other agents of the present invention, to be administered to the subject in the various embodiments of the present invention is not particularly limited, so long as it is within such an amount and in such a form that generally exhibits a useful or therapeutic effect.
  • terapéuticaally effective amount is the quantity which, when administered to a subject in need of treatment, improves the prognosis and/or state of the subject.
  • the amount to be administered to a subject will depend on the particular characteristics of the disease, condition or state in the subject, the mode of administration, and the characteristics of the subject, such as general health, other diseases, age, sex, genotype, body weight and tolerance to drugs.
  • administration and delivery of the compositions may be for example by the intravenous, intraperitoneal, subcutaneous, intramuscular, oral, or topical route, or by direct injection.
  • the mode and route of administration in most cases will depend on the type of disease, condition or state being treated.
  • the dosage form will depend on the mode and route of administration.
  • the administration of the substance P receptor antagonist and other agents may also include the use of one or more pharmaceutically acceptable additives, including pharmaceutically acceptable salts, amino acids, polypeptides, polymers, solvents, buffers, excipients, preservatives and bulking agents, taking into consideration the particular physical, microbiological and chemical characteristics of the agents to be administered.
  • pharmaceutically acceptable additives including pharmaceutically acceptable salts, amino acids, polypeptides, polymers, solvents, buffers, excipients, preservatives and bulking agents, taking into consideration the particular physical, microbiological and chemical characteristics of the agents to be administered.
  • the substance P receptor antagonist and/or the other agents can be prepared into a variety of pharmaceutically acceptable compositions in the form of, e.g., an aqueous solution, an oily preparation, a fatty emulsion, an emulsion, a lyophilised powder for reconstitution, etc. and can be administered as a sterile and pyrogen free intramuscular or subcutaneous injection or as injection to an organ, or as an embedded preparation or as a transmucosal preparation through nasal cavity, rectum, uterus, vagina, lung, etc.
  • the composition may be administered in the form of oral preparations (for example solid preparations such as tablets, caplets, capsules, granules or powders; liquid preparations such as syrup, emulsions, dispersions or suspensions).
  • compositions containing the substance P receptor antagonist and/or the other agents may also contain one or more pharmaceutically acceptable preservatives, buffering agents, diluents, stabilisers, chelating agents, viscosity enhancing agents, dispersing agents, pH controllers, or isotonic agents.
  • suitable preservatives are benzoic acid esters of para-hydroxybenzoic acid, propylene glycol, phenols, phenylethyl alcohol or benzyl alcohol.
  • suitable buffers are sodium phosphate salts, citric acid, tartaric acid and the like.
  • Suitable stabilisers are, antioxidants such as alpha-tocopherol acetate, alpha- thioglycerin, sodium metabisulphite, ascorbic acid, acetylcysteine, 8-hydroxyquinoline, chelating agents such as disodium edetate.
  • suitable viscosity enhancing agents, suspending or dispersing agents are substituted cellulose ethers, substituted cellulose esters, polyvinyl alchohol, polyvinylpyrrolidone, polyethylene glycols, carbomer, polyoxypropylene glycols, sorbitan monooleate, sorbitan sesquioleate, polyoxy ethylene hydrogenated castor oil 60.
  • pH controllers examples include hydrochloric acid, sodium hydroxide and the like.
  • suitable isotonic agents are glucose, D-sorbitol or D-mannitol, sodium chloride.
  • a substance P receptor antagonist and/or the other agents in the various embodiments of the present invention may also be in the form of a composition containing a pharmaceutically acceptable carrier, diluent, excipient, suspending agent, lubricating agent, adjuvant, vehicle, delivery system, emulsifier, disintegrant, absorbent, preservative, surfactant, colorant, glidant, anti-adherant, binder, flavorant or sweetener, taking into account the physical, chemical and microbiological properties of the agents being administered.
  • composition may be administered orally, parenterally, by inhalation spray, adsorption, absorption, topically, rectally, nasally, mucosally, transdermally, bucally, vaginally, intraventricularly, via an implanted reservoir in dosage formulations containing conventional non-toxic pharmaceutically-acceptable carriers, or by any other convenient dosage form.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, and intracranial injection or infusion techniques.
  • compositions When administered parenterally, the compositions will normally be in a unit dosage, sterile, pyrogen free injectable form (solution, suspension or emulsion, which may have been reconstituted prior to use) which is generally isotonic with the blood of the recipient with a pharmaceutically acceptable carrier.
  • sterile injectable forms are sterile injectable aqueous or oleaginous suspensions. These suspensions may be formulated according to techniques known in the art using suitable vehicles, dispersing or wetting agents and suspending agents.
  • the sterile injectable forms may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides, corn, cottonseed, peanut, and sesame oil.
  • Fatty acids such as ethyl oleate, isopropyl myristate, and oleic acid and its glyceride derivatives, including olive oil and castor oil, especially in their polyoxyethylated versions, are useful in the preparation of injectables.
  • These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants.
  • the carrier may contain minor amounts of additives, such as substances that enhance solubility, isotonicity, and chemical stability, for example anti-oxidants, buffers and preservatives.
  • additives such as substances that enhance solubility, isotonicity, and chemical stability, for example anti-oxidants, buffers and preservatives.
  • compositions may be in a form to be reconstituted prior to administration.
  • examples include lyophilisation, spray drying and the like to produce a suitable solid form for reconstitution with a pharmaceutically acceptable solvent prior to administration.
  • Compositions may include one or more buffers, bulking agents, isotonic agents and cryoprotectants and lyoprotectants.
  • excipients include, phosphate salts, citric acid, non-reducing such as sucrose or trehalose, polyhydroxy alcohols, amino acids, methylamines, and lyotropic salts which are usually used instead of reducing sugars such as maltose or lactose.
  • the substance P receptor antagonist and/or the other agents will usually be formulated into unit dosage forms such as tablets, caplets, cachets, powder, granules, beads, chewable lozenges, capsules, liquids, aqueous suspensions or solutions, or similar dosage forms, using conventional equipment and techniques known in the art.
  • Such formulations typically include a solid, semisolid, or liquid carrier.
  • exemplary carriers include excipients such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, mineral oil, cocoa butter, oil of theobroma, alginates, tragacanth, gelatin, syrup, substituted cellulose ethers, polyoxyethylene sorbitan monolaurate, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and the like.
  • a tablet may be made by compressing or molding the agent optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active, or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine, a mixture of the powdered active ingredient and a suitable carrier moistened with an inert liquid diluent.
  • the administration of the substance P receptor antagonist and/or the other agents may also utilize controlled release technology.
  • the substance P receptor antagonist and/or the other agents may also be administered as a sustained-release pharmaceutical composition.
  • the agent may be formulated with additional components such as vegetable oil (for example soybean oil, sesame oil, camellia oil, castor oil, peanut oil, rape seed oil); middle fatty acid triglycerides; fatty acid esters such as ethyl oleate; polysiloxane derivatives; alternatively, water-soluble high molecular weight compounds such as hyaluronic acid or salts thereof, carboxymethylcellulose sodium hydroxypropylcellulose ether, collagen polyethylene glycol polyethylene oxide, hydroxypropylmethylcellulosemethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone.
  • the substance P receptor antagonist and/or the other agents may be incorporated into a hydrophobic polymer matrix for controlled release over a period of days.
  • the agent may then be moulded into a solid implant, or externally applied patch, suitable for providing efficacious concentrations of the agents over a prolonged period of time without the need for frequent re-dosing.
  • Such controlled release films are well known to the art.
  • Other examples of polymers commonly employed for this purpose that may be used include nondegradable ethylene-vinyl acetate copolymer a degradable lactic acid-glycolic acid copolymers, which may be used externally or internally.
  • Certain hydrogels such as poly(hydroxyethylmethacrylate) or poly(vinylalcohol) also may be useful, but for shorter release cycles than the other polymer release systems, such as those mentioned above.
  • the carrier may also be a solid biodegradable polymer or mixture of biodegradable polymers with appropriate time -release characteristics and release kinetics.
  • the agent may then be moulded into a solid implant suitable for providing efficacious concentrations of the agents over a prolonged period of time without the need for frequent re-dosing.
  • the agent can be incorporated into the biodegradable polymer or polymer mixture in any suitable manner known to one of ordinary skill in the art and may form a homogeneous matrix with the biodegradable polymer, or may be encapsulated in some way within the polymer, or may be moulded into a solid implant.
  • the substance P receptor antagonist and/or the other agents may be in the form of a solution, spray, lotion, cream (for example a non-ionic cream), gel, paste or ointment.
  • the composition may be delivered via a liposome, nanosome, rivosome, or nutri-diffuser vehicle.
  • Substance P concentration increases in dopaminergic neurons in early state Parkinson 's disease.
  • Intrastriatal injection of the 6-OHDA neurotoxin (20 ⁇ g dissolved in saline containing 0.01% ascorbic acid) results in Parkinson's disease, and particularly motor symptoms of Parkinson's disease, as assessed by the Rotarod test (Hamm RJ et al., 1994, J. Neurotrauma 11 :197-196) ( Figure 2).
  • animals injected with the 6-OHDA vehicle did not develop any such deficits, and had no indication of Parkinson's disease.
  • Intrastriatal injection of the 6-OHDA neurotoxin (20 ⁇ g dissolved in saline containing 0.01% ascorbic acid) results in Parkinson's disease, and particularly motor symptoms of Parkinson's disease, as assessed by the Rotarod test (Hamm RJ et al., 1994, J. Neurotrauma 11 :197-196) ( Figure 3).
  • animals injected with the 6-OHDA vehicle did not develop any such deficits, and had no indication of Parkinson's disease.
  • NKl substance P receptor
  • a number of commercially synthesised substance P receptor (NKl) antagonists are currently available from standard scientific chemical suppliers.
  • Figure 4 shows that an animal that is administered saline vehicle but no neurotoxin (normal) shows few rotations over a 14 day assessment period.
  • an animal that has induced Parkinson's disease (6-OHDA) has an increased number of rotations per minute relative to controls, indicative of lesion formation in the substantia nigra.
  • Simultaneous administration of substance P with the neurotoxin resulted in a significantly greater number of rotations, and a greater lesion size, in the affected hemisphere than in those animals treated with the neurotoxin alone.
  • simultaneous administration of the NKl antagonist reduced the lesion size in the affected hemisphere.
  • substance P played an integral role in the death of dopamine neurons in the substantia nigra, and the development of Parkinson's disease lesions.
  • a substance P receptor antagonist in an animal model of dopaminergic cell loss in Parkinson 's disease Having established the effects of substance P and NKl antagonists on motor function and lesion size in Parkinson's disease, we chose to characterise the effects of these compounds on early dopaminergic cell loss in the substantia nigra (SN) in this animal model of Parkinson's disease.
  • Dopaminergic cell loss can be assessed using an antibody for tyrosine hydroxylase (TH), an enzyme involved in dopamine metabolism that is only localized to dopaminergic neurons.
  • TH tyrosine hydroxylase

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Abstract

La présente invention concerne un procédé de prévention et/ou de traitement d’une maladie, d’une condition ou d’un état associés à une fonction réduite des neurones dopaminergiques chez un sujet. Le procédé comprend l’étape consistant à administrer au sujet une quantité efficace d’un antagoniste du récepteur de la substance P. La présente invention concerne également l’administration d’un antagoniste du récepteur de la substance P à un sujet dans des procédés d’inhibition de la progression d’une maladie, d’une condition ou d’un état associés à une fonction réduite des neurones dopaminergiques chez le sujet, ou de soulagement d’une ou plusieurs complications chez le sujet qui sont associées à l’administration d’un agent dopaminergique. La présente invention concerne également des compositions pharmaceutiques et des produits de combinaison qui comprennent un antagoniste du récepteur de la substance P.
PCT/AU2009/000257 2008-03-04 2009-03-04 Procédé de prévention et/ou de traitement d’une maladie, d’une condition ou d’un état associés à une fonction réduite des neurones dopaminergiques WO2009109001A1 (fr)

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KR20200006454A (ko) * 2018-07-10 2020-01-20 성균관대학교산학협력단 N-벤즈히드릴 퀴뉴클리딘 유도체를 포함하는 나트륨 누출 채널 억제용 조성물

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