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WO2003006426A1 - Guanylhydrazones aromatiques utilises comme composes efficaces contre les maladies nerveuses - Google Patents

Guanylhydrazones aromatiques utilises comme composes efficaces contre les maladies nerveuses Download PDF

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Publication number
WO2003006426A1
WO2003006426A1 PCT/EP2002/007859 EP0207859W WO03006426A1 WO 2003006426 A1 WO2003006426 A1 WO 2003006426A1 EP 0207859 W EP0207859 W EP 0207859W WO 03006426 A1 WO03006426 A1 WO 03006426A1
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prion
compound
diacetylphenyl
diseases
bis
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PCT/EP2002/007859
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English (en)
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Matthias Stein-Gerlach
Dorian Bevec
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Axxima Pharmaceuticals Ag
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Publication of WO2003006426A1 publication Critical patent/WO2003006426A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C281/16—Compounds containing any of the groups, e.g. aminoguanidine
    • C07C281/18—Compounds containing any of the groups, e.g. aminoguanidine the other nitrogen atom being further doubly-bound to a carbon atom, e.g. guanylhydrazones
    • 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

Definitions

  • the present invention relates to aromatic guanylhydrazone derivatives, the use of the aromatic guanylhydrazone derivatives as pharmaceutically active agents, especially for the prophylaxis and/or treatment of neurodiseases, such as neurological diseases, prion diseases and mental diseases, as well as compositions containing at least one aromatic guanylhydrazone derivative and/or pharmaceutically acceptable salts thereof, and methods for preventing and/or treating such neurological, prion, and mental diseases.
  • neurodiseases such as neurological diseases, prion diseases and mental diseases
  • compositions containing at least one aromatic guanylhydrazone derivative and/or pharmaceutically acceptable salts thereof and methods for preventing and/or treating such neurological, prion, and mental diseases.
  • Neurodegenerative diseases are caused by malfunctions within the motor sector of the nervous system. These malfunctions, which are caused by the presence or absence of hormones, are a direct result of neural cell deterioration within the brain.
  • biological problems of the brain, or rather predicaments arising between cellular connections within the brain, and the treatment of such conditions illustrate how the brain organizes movement and behavior.
  • the brain is the body's communication headquarters. It obtains a myriad of information from various parts of the sensory system and processes this information in an organized fashion. It then relays sensory input to different parts of the motor system. Such messages from the brain dictate specific muscular and behavioral patterns.
  • this neural system is highly depended on a cause and effect system, where the slightest offset to the assembly-line fashion of cellular interaction results in major behavioral abnormalities.
  • the substania nigra and the striatum the caudate nucleus and the putamen.
  • the cells of the nigra synapse with cells of the striatum, which serves as the controller of motor functions such as walking, balance, and muscular movement.
  • dopamine is a significant chemical transmitter in the brain. Because the existence of dopamine is essential to the function of the substania nigra, it is also essential for the various muscular activities controlled by the striatum, such as walking, balance, etc.
  • Parkinson's disease results from a depletion in the amount of dopamine produced by the brain.
  • dopamine-secreting cells of the substania nigra either because of genetic factors or environmental toxins, experience mass cell death.
  • the nigra cells are unable to form synapses through which they secrete and relay dopamine to the striatum in a neural circuit within the basal ganglia.
  • the striatum is also a coordination center for chemical messengers.
  • the striatum When there is a decrease in dopamine levels, the striatum experiences a chemical imbalance. Since the basal ganglia plays a largely inhibitory role on the spinal motor centers, the loss of control of the nigra of the striatum as well as the disabilities of the striatum due to abnormal dopamine levels cause inhibition of muscular movements. Therefore, as a consequence of microscopic dysfunctions, macroscopic abnormalities arise.
  • Neurodiseases can be classified as follows: NEUROLOGICAL DISEASES, such as PAIN
  • Prion diseases are a special kind of neurodegenerative diseases which belong to the subgroup of infectious diseases.
  • Prions are infectious agents which do not have a nucleic acid genome. It seems that a protein alone is the infectious agent. A prion has been defined as "small proteinaceous infectious particle which resists inactivation by procedures that modify nucleic acids". The discovery that proteins alone can transmit an infectious disease has come as a considerable surprise to the scientific community. Prion diseases are often called “transmissible spongiform encephalopathies", because of the post mortem appearance of the brain with large vacuoles in the cortex and cerebellum. Probably most mammalian species develop these diseases. Prion diseases are a group of neurodegenerative disorders of humans and animals and the prion diseases can manifest as sporadic, genetic or infectious disorders.
  • prion diseases acquired by exogenous infection are the Bovine spongiform encephalitis (BSE) of cattle and the new variant of Creutzfeld-Jakob disease (vCJD) caused by BSE. Further examples include kuru, Gerstmann-Straussler-Scheinker disease of humans as well as scrapie of animals. For many years, the prion diseases were thought to be caused by viruses despite interesting evidence to the contrary. The unique characteristic common to all of these disorders, whether sporadic, dominantly inherited, or acquired by infection, is that they involve the aberrant metabolism of the prion protein (PrP).
  • PrP prion protein
  • the cellular prion protein (PrP c ) ["c” refers to cellular] is converted into the scrapie isoform (PrP Sc ) ["Sc” refers to Scrapie] by a posttranslational process that involves a conformational change.
  • the human prion diseases are transmissible to experimental animals and all of the inherited prion diseases segregate with PrP gene mutations. These prion diseases in animals and humans have a long incubation period and a long clinical course, and are always fatal leading via decerebration to death within an average period of 7 months (CJD).
  • Neuropathological features consist of neuronal vacuolization, neuronal death and gliosis with hyperastrocytosis. The precise diagnosis of transmissible neurodegenerative diseases can be established only by the examination of the central nervous system after biopsy or autopsy.
  • Clinical symptoms of the disease are progressive dementia, myoclonus and prominent ataxia with the additional clinical features of dysautonomia and delirious psychomotor excitement and with relatively preserved verbal responses.
  • the medical need in prion diseases today can be clearly defined as the establishment of a diagnostic system, that can detect the disease as early as possible in living humans and/or animals, to estimate the medical need for the treatment in the future and to identify the infected animals to remove them from the food chain.
  • the medical need for prion diseases in the future (approximately starting in 5-10 years) will be medical treatment that inhibits the disease symptoms, the manifestation and/or progression of the disease.
  • One aspect of the present invention relates to compounds of the general formula (I):
  • R', R" are independently of each other -OH, -SH, -NH 2 , methyl, ethyl or propyl;
  • a and A' are independently of each other -NH(CO)-, -NH- -(CO)NH- -NH(CO)NH- or -O-;
  • X 2 is independently of X 2 -H, -OCH 3 , -CHGhy, -C(CH 3 )Ghy, or
  • n and p are independently of each other an integer of 0 to 10; under the proviso that A ⁇ A'; and pharmaceutically acceptable salts thereof.
  • Another aspect of the present invention relates to the use of compounds of the general formula (I):
  • R', R" are independently of each other -OH, -SH, -NH 2 , methyl, ethyl or propyl;
  • a and A' are independently of each other -NH(CO)-, -NH- -(CO)NH-, -NH(CO)NH- or -O-;
  • n and p are independently of each other an integer of 0 to 10; under the proviso that A ⁇ A'; and pharmaceutically acceptable salts thereof as pharmaceutically active agents.
  • inventive compounds are preferably used for prophylaxis and/or treatment of infectious diseases, or in a more general sense, for prophylaxis and/or treatment of neurodegenerative diseases.
  • a further aspect of the present invention is directed to the use of the aromatic guanylhydrazone compounds of the general formula (I):
  • R', R" are independently of each other -OH, -SH, -NH 2 , methyl, ethyl or propyl;
  • a and A' are independently of each other -NH(CO)-, -NH-, -(CO)NH-, -NH(CO)NH- or -O-;
  • X' 2 is independently of X 2 -H, -OCH 3 , -CHGhy, -C(CH 3 )Ghy, or
  • n and p are independently of each other an integer of 0 to 10; and pharmaceutically acceptable salts thereof as pharmaceutically active agents for the preparation of a pharmaceutical composition for prophylaxis and/or treatment of neurological diseases, prion diseases and/or mental diseases.
  • Guanylhydrazone derivatives are known from US-A-5 599 984, US-A-5 750 573 and US-A-5 849 794 as active agents for the treatment of inflammatory diseases.
  • EP 97948263.5 discloses the use of guanylhydrazone compounds for treating diseases associated with T-cell activation.
  • neurode diseases comprises neurological and mental diseases selected from the group comprising addiction, alzheimer's disease, anxiety disorders, autism, blindness, cerebral palsy, chronic fatigue syndrome, Chorea Huntington, coping problems, down syndrome, mild depression, mental retardation, personality disorders, dyslexia, eating disorders, epilepsy, infectious diseases, prion diseases, prion infections, multiple sclerosis, muscular dystrophy, neurology, neurotoxicities, pain, parkinson's disease, schizophrenia, sleep disorders, stress, stroke, tourette syndrome, tumors, progressive supranuclear palsy (PSP), Parkinsonism dementia complex of Guam (PDC), Pick ' s disease (PiD), Pallido- ponto-nigral degeneration (PPND), Amyotrophic Iteral sclerosis (ALS).
  • addiction alzheimer's disease
  • anxiety disorders anxiety disorders
  • autism blindness
  • cerebral palsy chronic fatigue syndrome
  • Chorea Huntington coping problems
  • down syndrome mild depression, mental retardation, personality disorders, dyslexia, eating disorders,
  • one embodiment of the present invention disclosed herein is directed to a method for preventing and/or treating neurodiseases in an individual which method comprises administering to the individual an amount of at least one compound according to any one of claims 2 to 9 and/or pharmaceutically acceptable salts thereof effective to treat said neurodisease. Most preferred is the administration of compounds Nos. 1 to 21.
  • prion is used to describe the causative agents which underlie the transmissible spongiform encephalopathies.
  • a prion is proposed to be a novel infectious particle that differs from viruses and viroids. It is composed solely of one unique protein that resists most inactivation procedures such as heat, radiation, and proteases. The latter characteristic has led to the term protease- resistant isoform of the prion protein.
  • the protease-resistant isoform has been proposed to slowly catalyze the conversion of the normal prion protein into the abnormal form.
  • isoform in the context of prions means two proteins with exactly the same amino acid sequence that are folded into molecules with dramatically different tertiary structures.
  • the normal cellular isoform of the prion protein (PrP c ) has a high ⁇ -helix content, a low ⁇ -sheet content, and is sensitive to protease digestion.
  • the abnormal, disease-causing isoform (PrP Sc )has a lower ⁇ -helix content, a much higher ⁇ -sheet content, and is much more resistant to protease digestion.
  • X 2 (X' 2 ) is not hydrogen the meta position of Xi and X 2 (X' ⁇ and X' 2 ) to Z is most preferred, because of steric reasons.
  • A, A', and B represent the residues as mentioned above.
  • inventive guanylhydrazone compounds wherein Z is -NH(CO)-(CH 2 ) n -(CO)NHB and n is an integer of 3 to 10 and these compounds wherein Z stands for -NH(COHCH 2 )n-C 6 H 4 -(CH 2 ) p -(CO)NHB J
  • B represents another benzene substituted with one or two guanylhydrazone residues as shown above.
  • inventive compounds selected from the group comprising:
  • Ligands are messengers that bind to specific receptors on the surface of target cells.
  • the receptors trigger the activation of a cascade of downstream signaling molecules, thereby transmitting the message from the exterior of the cell to its nucleus.
  • the message reaches the nucleus, it initiates the modulation of specific genes, resulting in the production of RNA and finally proteins that carry out a specific biological function.
  • Disturbed activity of signal transduction molecules may lead to the malfunctioning of cells and disease processes.
  • interference of the pathogenic PrP Sc from prion diseases with neuronal cells is necessary for the prion protein to induce its neuropathological features such as neuronal vacuolization, neuronal death and gliosis with hyperastrocytosis.
  • novel and known aromatic guanylhydrazone compounds of the general formula (I) represent a new class of pharmaceuticals highly useful for the prophylaxis and treatment of prion infections and prion diseases.
  • a further aspect of the present invention describes the use of a compound of the general formula (I) and/or pharmaceutically acceptable salts thereof for the manufacture of a pharmaceutical formulation for prophylaxis and/or treatment of prion infections and/or diseases induced or caused by prion infection.
  • prion diseases refers to transmissible spongiform encephalopathies. This group of neurologic diseases affects humans and many species of animals causing a "sponge-like" degeneration of brain tissue. Among other unique features, all of these diseases are associated with the accumulation of an abnormal form of the prion protein in nerve cells that eventually leads to the death of the host. While prion diseases can all be transmitted from one host to another, it remains contentious as to whether a virus-like infectious agent or the abnormal prion protein itself, the prion, causes the conversion of normal to abnormal protein.
  • CWD chronic wasting disease
  • deer elk
  • BSE bovine spongiform encephalopathy
  • the human prion diseases include kuru, sporadic Creutzfeldt-Jakob disease (sCJD), familial CJD (fCJD), iatrogenic CJD (iCJD), Gerstmann-Straussler- Scheinker (GSS) disease, fatal familial insomnia (FFI), and, more recently, new variant CJD (nvCJD or vCJD).
  • sCJD sporadic Creutzfeldt-Jakob disease
  • fCJD familial CJD
  • iCJD iatrogenic CJD
  • GSS Gerstmann-Straussler- Scheinker
  • FFI fatal familial insomnia
  • nvCJD or vCJD new variant CJD
  • Scrapie is a naturally occurring disease of sheep and goats that causes ataxia, behavioral changes, and a severe pruritus that leads to scraping behavior, from which the disease was named.
  • TAE transmissible mink encephalopathy
  • CWD chronic wasting disease
  • FSE feline spongiform encephalopathy
  • BSE bovine spongiform encephalopathy
  • the etiologic agent of the TSEs was proposed to be a "slow virus" to explain its transmissible nature and the prolonged incubation period observed during experimental transmission studies.
  • protein may be a critical component of the infectious agent.
  • the term "prion" was coined to indicate an /nfectious agent with proteinlike properties.
  • the unusual properties of the pathogen were demonstrated in early experiments in which conditions that degrade nucleic acids, such as exposure to ionizing and ultraviolet radiation, did not reduce the infectivity of scrapie fractions.
  • treatments that degrade protein such as prolonged exposure to proteases, correlated with a reduction in infectivity.
  • a protein with relative resistance to protease digestion was found to be consistently present in the brains of animals and humans with TSE. Surprisingly, this protein was found to be one that is normally encoded by a chromosomal gene of the host.
  • PrP c the nonpathogenic or cellular form
  • PrP SG the pathogenic or scrapie-inducing form
  • Both PrP c and PrP Sc have the same amino acid sequence, yet they differ in their biochemical properties: PrP c is soluble in nondenaturing detergents and completely degraded by proteases, whereas PrP Sc is insoluble in nondenaturing detergents arid shows a relative resistance to proteases.
  • PrP c is predominantly helical
  • PrP Sc contains at least 40% pleated sheet structure. Conversion to this sheet structure appears to be the fundamental event in prion disease. The ultimate mechanism of how cells die coincident with the generation of prions is still unclear. Simple accumulation of pathogenic protein may not be sufficient to explain disease, however, it may constitute a critical step in cellular dysfunction.
  • aromatic guanylhydrazone compounds of the general formula (I) are highly effective for the prophylaxis and/or treatment of prion infections and/or prion diseases selected from the group comprising Scrapie, TME, CWD, BSE, CJD, vCJD, GSS, FFI, Kuru, and Alpers Syndrome.
  • the aromatic guanylhydrazone derivatives are used for preventing and/or treating BSE, vCJD, or CJD.
  • aromatic guanylhydrazone compounds of the general formula (I) and/or pharmaceutically acceptable salts thereof are administered in a dosage corresponding to an effective concentration in the range of 0.01 - 100 ⁇ M, preferably in the range of 0.01 - 50 ⁇ M, more preferably in the range of 0.5 - 10 ⁇ M, still more preferably in the range of , and most preferably in the range of 0.5 - 5 ⁇ M.
  • PrP c does convert to PrP Sc ?
  • Potential mechanisms that initiate conversion of PrP c to PrP Sc include a germ line mutation of the human prion protein gene (PRNP), a somatic mutation within a particular neuron, and spontaneous conversion of PrP c to an aberrant conformation that is not refolded appropriately to its native structure.
  • the prion protein gene (PRNP) is the single gene on the short arm of chromosome 20 in humans which encodes the normal cellular isoform of the prion protein.
  • PrP Sc appears to act as a conformational template by which PrP c is converted to a new molecule of PrP So through protein- protein interaction of PrP Sc and PrP c .
  • This concept is supported by several studies which show that mice with the normal PrP gene deleted (PrP knockout mice) do not develop prion disease after inoculation with scrapie.
  • PrP knockout mice mice with the normal PrP gene deleted (PrP knockout mice) do not develop prion disease after inoculation with scrapie.
  • transgenic (Tg) mice that express a chimeric PrP gene made of human and mouse segments develop protease-resistant chimeric mouse-human PrP Sc in their brains when inoculated with brain extracts from humans with prion disease.
  • CJD In its sporadic or nonfamilial form, CJD is the most common of the human prion diseases. Confusion and forgetfulness which progress rapidly to severe cortical dementia in combination with ataxia, myoclonus, and an abnormal electroencephalogram (EEG) represents the "classic tetrad" of CJD.
  • EEG electroencephalogram
  • Familial CJD includes those cases with a dominantly inherited mutation of the- PRNP gene, in which the pathologic features of spongiform change occur in the absence of GSS-type plaques. Although, familial cases of CJD tend to have a clinical and pathologic phenotype similar to that of sCJD.
  • FFI is a genetic disorder which manifests itself by many symptoms due to the degeneration of a certain part of the brain, the thalamus.
  • the affected area of the brain is the area responsible for sleep, the thalamus.
  • the thalamus is the center which communications from the brain to the body and the body to the brain pass through for proper directions to where a signal should be received.
  • sleep takes place, it is thought that the thalamus becomes less efficient at this signal transfer function allowing for the vegetative state of sleep to come over an individual. Consequently, the symptoms of fatal familial insomnia are directly related to the malfunction of the responsibilities of the thalamus, namely sleep.
  • the first stage is progressive insomnia, the trade mark of fatal familial insomnia. By now, there is no cure for this illness.
  • milial means: affecting several members of the same family, usually as a result of an underlying genetic mutation.
  • vCJD vCJD
  • vCJD vCJD
  • the pathologic features and clinical presentation of vCJD differ significantly from those of sCJD, it is considered a new "strain” of human prion disease.
  • the same "protein signature" was observed following experimental transmission of BSE to several animal hosts, supporting the idea that vCJD results from the infection of humans with BSE.
  • vCJD occurs primarily in younger individuals (average age 27) with a somewhat protracted course of approximately 16 months.
  • the brain shows diffuse vacuolation and the presence of distinctive dense core PrP- containing plaques surrounded by a halo of spongiform change.
  • Kuru is the condition which first brought prion diseases to prominence in the 1950s. Found in geographically isolated tribes in New Guinea. Established that ingesting brain tissue of dead relatives for religious reasons was likely to be the route of transmission.
  • CWD is a fatal neurodegenerative disease of deer and elk, now known to be a transmissible spongiform encephalopathy. To date, affected animals have been found exclusively in the United States.
  • BSE Bovine spongiform encephalopathy or "mad cow disease” appears to have originated from scrapie that has been recognized in Europe since the mid-18th century. It has since spread to most sheep-breeding countries and is widespread in the United Kingdom, where until 1988 the rendered carcasses of livestock (including sheep) were fed to ruminants and other animals as a protein-rich nutritional supplement.
  • the present invention provides also a method for preventing and/or treating prion infections and/or diseases induced by prion infections in an individual which comprises administering to the individual an amount of at least one compound of the general formula (I) and/or pharmaceutically acceptable salts thereof effective to treat said prion infection and/or prion disease.
  • the term "individual” preferably refers to mammals, especially humans or ruminants. Ruminants are, for instance, muledeer, elk, cow, cattle, sheep, goat, deer, or buffalo. Minks are an example for mammals which do not belong to the specie of ruminants.
  • ruminants refers to an animal, for instance, cattle, sheep, goat, deer, elk, or buffalo that has four separate stomach chambers, and is therefore able to digest a wide range of organic and plant foods.
  • the term “ruminants” refers also to exotic ruminants, like captive nyala, gemsbok, Arabian oryx, eland, kudu, scimitar-horned oryx, ankole, or bison which are also accessible to develop Spongiform encephalopathy.
  • said prion infection and/or prion disease is selected from the group comprising Scrapie, TME, CWD, BSE, vCJD, CJD, GSS, FFI, Kuru, and Alpers Syndrome.
  • the method is used for prophylaxis and/or treatment of BSE, vCJD, or CJD.
  • aromatic guanylhydrazone compounds of the present invention and/or pharmaceutically acceptable salts thereof are administered in a dosage corresponding to an effective concentration in the range of 0.01 - 50 ⁇ M, preferably in the range of 0.01 - 10 ⁇ M, more preferably in the range of 0.01 - 1 ⁇ M, and most preferably in the range of 0.01 - 0.1 ⁇ M.
  • Still a further aspect of the present invention is directed to pharmaceutical compositions comprising at least one aromatic guanylhydrazone compound of the general formula (I) as an active ingredient together with a pharmaceutically acceptable carrier, excipient or diluents.
  • the aromatic guanylhydrazone compounds of the present invention are basic and form pharmaceutically acceptable salts with organic and inorganic acids.
  • suitable acids for such acid addition salt formation are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p-aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, sulfonic acid, phosphonic acid, perchloric acid, nitric acid, formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic acid
  • salts may be formed with inorganic as well as organic bases such as, for example, NaOH, KOH, NH OH, tetraalkylammonium hydroxide, and the like.
  • the compounds of the general formula (I) can also be administered in form of their pharmaceutically active salts optionally using substantially nontoxic pharmaceutically acceptable carriers, excipients or diluents.
  • the medications of the present invention are prepared in a conventional solid or liquid carrier or diluents and a conventional pharmaceutically-made adjuvant at suitable dosage level in a known way.
  • the preferred preparations are in administratable form which is suitable for oral application. These administratable forms, for example, include pills, tablets, film tablets, coated tablets, capsules, powders and deposits.
  • the subject of the present invention also includes pharmaceutical preparations for parenteral, including dermal, intradermal, intragastrical, intracutaneous, intravasal, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutaneous, rectal, subcutaneous, sublingual, topical or transdermal application, which in addition to typical vehicles and diluents contain a aromatic guanylhydrazone compound of the general formula (I) and/or a pharmaceutically acceptable salt thereof as active ingredient.
  • parenteral including dermal, intradermal, intragastrical, intracutaneous, intravasal, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutaneous, rectal, subcutaneous, sublingual, topical or transdermal application, which in addition to typical vehicles and diluents contain a aromatic guanylhydrazone compound of the general formula (I) and/or a pharmaceutically acceptable salt thereof as active ingredient.
  • compositions of the present invention containing aromatic guanylhydrazone derivatives of the general formula (I) as active ingredients, will typically be administered in admixture with suitable carrier materials selected with respect to the intended form of administration, i.e. oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices.
  • suitable carrier materials selected with respect to the intended form of administration, i.e. oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices.
  • the active drug component may be combined with any oral nontoxic pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and the like.
  • suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated in the mixture.
  • Powders and tablets may be comprised of from about 5 to about 95 percent inventive composition.
  • Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes.
  • lubricants there may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrants include starch, methylcellulose, guar gum and the like. Sweetening and flavoring agents and preservatives may also be included where appropriate.
  • compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimize the therapeutic effects, i.e. antihistaminic activity and the like.
  • Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.
  • Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injections or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier such as inert compressed gas, e.g. nitrogen.
  • a pharmaceutically acceptable carrier such as inert compressed gas, e.g. nitrogen.
  • a low melting wax such as a mixture of fatty acid glycerides such as cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein by stirring or similar mixing. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidifies.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • the inventive aromatic guanylhydrazone compounds of the present invention may also be deliverable transdermally.
  • the transdermal compositions may take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • capsule refers to a special container or enclosure made of methyl cellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing compositions comprising the active ingredients.
  • Hard shell capsules are typically made of blends of relatively high gel strength bone and pork skin gelatins.
  • the capsule itself may contain small amounts of dyes, opaquing agents, plasticizers and preservatives.
  • Tablet means compressed or molded solid dosage form containing the active ingredients with suitable diluents.
  • the tablet can be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation or by compaction well known to a person skilled in the art.
  • Oral gels refers to the active ingredients dispersed or solubilized in a hydrophillic semi-solid matrix.
  • Powders for constitution refers to powder blends containing the active ingredients and suitable diluents which can be suspended in water or juices.
  • suitable diluents are substances that usually make up the major portion of the composition or dosage form.
  • Suitable diluents include sugars such as lactose, sucrose, mannitol and sorbitol, starches derived from wheat, corn rice and potato, and celluloses such as microcrystalline cellulose.
  • the amount of diluents in the composition can range from about 5 to about 95% by weight of the total composition, preferably from about 25 to about 75%, more preferably from about 30 to about 60% by weight.
  • disintegrants refers to materials added to the composition to help it break apart (disintegrate) and release the medicaments.
  • Suitable disintegrants include starches, "cold water soluble" modified starches such as sodium carboxymethyl starch, natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar, cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, microcrystalline celluloses and cross-linked microcrystalline celluloses such as sodium croscarmellose, alginates such as alginic acid and sodium alginate, clays such as bentonites, and effervescent mixtures.
  • the amount of disintegrant in the composition can range from about 2 to about 20% by weight of the composition, more preferably from about 5 to about 10% by weight.
  • Binders characterize substances that bind or "glue” powders together and make them cohesive by forming granules, thus serving as the "adhesive" in the formulation. Binders add cohesive strength already available in the diluents or bulking agent. Suitable binders include sugars such as sucrose, starches derived from wheat, corn rice and potato; natural gums such as acacia, gelatin and tragacanth; derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate; cellulosic materials such as methylcellulose and sodium carboxymethylcellulose and hydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganics such as magnesium aluminum silicate.
  • the amount of binder in the composition can range from about 2 to about 20% by weight of the composition, more preferably from about 3 to about 10% by weight, even more preferably from about 3 to about 6% by weight.
  • Lubricant refers to a substance added to the dosage form to enable the tablet, granules, etc. after it has been compressed, to release from the mold or die by reducing friction or wear.
  • Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; high melting point waxes; and water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and D,L- leucine.
  • Lubricants are usually added at the very last step before compression, since they must be present on the surfaces of the granules and in between them and the parts of the tablet press.
  • the amount of lubricant in the composition can range from about 0.2 to about 5% by weight of the composition, preferably from about 0.5 to about 2%, more preferably from about 0.3 to about 1.5% by weight.
  • Glidents are materials that prevent caking and improve the flow characteristics of granulations, so that flow is smooth and uniform.
  • Suitable glidents include silicon dioxide and talc.
  • the amount of glident in the composition can range from about 0.1% to about 5% by weight of the total composition, preferably from about 0.5 to about 2% by weight.
  • Coloring agents are excipients that provide coloration to the composition or the dosage form. Such excipients can include food grade dyes and food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide. The amount of the coloring agent can vary from about 0.1 to about 5% by weight of the composition, preferably from about 0.1 to about 1%.
  • Fig. 1 shows selected guanylhydrazone derivatives which are suitable pharmaceutically active compounds for prophylaxis and/or treatment of neurodiseases
  • Fig. 2 shows a selected guanylhydrazone derivative which is a suitable pharmaceutically active compound for prophylaxis and/or treatment of neurodiseases, especially of prion infections and prion diseases.
  • the mouse neuroblastoma cell line 3F4-ScN2a represents a stably transfected clone of ScN2a cells (PrP Sc infected N2a cells) which overexpress 3F4-epitope- tagged murine PrP. Residues 109 and 112 of murine PrP were replaced by methionine to introduce the epitope for reactivity with the monoclonal anti-PrP antibody 3F4. Cells were maintained in Dulbecco's modified Eagle's (DMEM) or Opti-MEM medium containing 10 % fetal calf serum, antibiotics and glutamin.
  • DMEM Dulbecco's modified Eagle's
  • Opti-MEM medium containing 10 % fetal calf serum, antibiotics and glutamin.
  • PK proteinase K
  • Confluent cell cultures were lysed in cold lysis buffer (10 mM Tris-HCI, pH 7.5; 100 mM NaCI; 10 mM EDTA; 0.5 % Triton X-100; 0.5 % DOC) (EDTA: ethylene diamine tetraacetate; Triton X-100: t-octylphenoxypolyethoxyethanol; DOC: deoxycholic acid).
  • Postnuclear lysates were split between those with and without proteinase K digestion.
  • Samples without proteinase K digestion were supplemented with proteinase inhibitors (5 mM PMSF, 0.5 mM Pefabloc, and aprotinin) (PMSF: phenylmethylsulfonyl fluoride) and directly precipitated with ethanol.
  • PMSF proteinase inhibitors
  • Samples for proteinase K digestion were incubated with 20 ⁇ g/ml proteinase K for 30 min at 37°C; digestion was stopped with proteinase inhibitors, and samples were ethanol precipitated. After centrifuging for 30 min at 3,500 rpm the pellets were redissolved in TNE buffer (10 mM Tris-HCI pH7.5, 100 mM NaCI, 1 mM EDTA) and gel loading buffer was then added.
  • TNE buffer 10 mM Tris-HCI pH7.5, 100 mM NaCI, 1 mM EDTA
  • Table 1 shows the inhibition of the activity of prion propagation: Table 1 : Inhibition of rion ro a ation
  • prion infections and prion diseases may comprise diseases such as Transmissible spongiform encephalitis (TSE) infections which include Bovine spongiform encephalitis (BSE) or the new variant of Creutzfeld Jakob disease (vCJK).
  • TSE Transmissible spongiform encephalitis
  • BSE Bovine spongiform encephalitis
  • vCJK Creutzfeld Jakob disease
  • ⁇ /-Ethyldiisopropylamine (7.10 g, 55 mmol) was added dropwise at 0°C to a stirred mixture of 3-aminoacetophenone (3.4 g, 25 mmol), 4-(tert- butoxycarbonylamino)butyric acid (5.0 g, 24.6 mmol), 1-hydroxybenzotriazole hydrate (3.72 g, 24.3 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (5.27 g, 27.5 mmol) and dichloromethane (75 ml), the mixture was stirred at ambient temperature for 18 hours, then it was washed with water (3 x 100 ml) and saturated aqueous sodium chloride solution (100 ml) and dried (MgSO 4 ).
  • ⁇ /-(3-Acetylphenyl)-4-(fert-butoxycarbonylamino)butyramide (2.39 g, 7.5 mmol) was added in portions at ambient temperature under nitrogen to a stirred solution of trifluoroacetic acid (25 ml) in dichloromethane (25 ml), the mixture was stirred at ambient temperature for 1 hour, then the solvents were removed in vacuo to leave the amine as an orange oil which was used without further purification.
  • a mixture of the orange oil, ⁇ -ethyldiisopropylamine (4.78 g, 37 mmol) and dichloromethane (30 ml) was stirred at 0 °C for 15 minutes.
  • Sebacoyl chloride (1.2 g, 5 mmol) was added dropwise at ambient temperature under nitrogen to a stirred solution of 3,5-diacetylaniline (1.77 g, 10 mmol) and pyridine (2.37 g, 30 mmol) in dichloromethane (25 ml), then the mixture was stirred at ambient temperature for 18 hours. The resulting solid was collected by filtration, washed with water (30 ml) and dried in vacuo to give N,N'-bis-(3,5- diacetylphenyl)sebacamide (2.33 g) as a white solid, m.pt.
  • the product was crystallised from 50% aqueous ethanol and dried in vacuo at 35 °C to give ⁇ ,/V-o/s-(3,5-diacetylphenyl)sebacamide fefra/r/ ' s-[(4,5-dihydroimidazol- 2-yl)hydrazone] tetrahydrobromide 4.5 hydrate (0.73 g) as a white solid, m.pt.
  • Oxalyl chloride (1.33 g, 10.5 mmol) was added dropwise at ambient temperature to a stirred solution of ethyl hydrogen sebacate (2.3 g, 10 mmol) and dimethylformamide (2 drops) in dichloromethane (25 ml), the mixture was stirred at ambient temperature for 1 hour, then it was cooled to 0 °C.
  • 3,5-Diacetylaniline (1.77 g, 10 mmol) followed by pyridine (1.98 g, 25 mmol) were added in portions at 2-12 °C, then the mixture was stirred at ambient temperature for 18 hours and poured into water (100 ml).
  • Ethyl 9-(3,5-diacetylphenylcarbamoyl)nonanoate o/s-(guanylhydrazone) dihydrobromide (0.4 g, 0.6 mmol) was dissolved in the minimum volume of industrial methylated spirit, and a solution of sodium hydroxide (0.121 g, 3 mmol) in the minimum volume of water was added. The mixture was stirred at ambient temperature for 18 hours, then water (5 ml) and dichloromethane (5 ml) were added. The mixture was stirred for 10 minutes, then the aqueous phase was separated and acidified to pH 3 by the addition of 2M hydrochloric acid.
  • ⁇ /-Ethyldiisopropylamine (1.61 g, 12.46 mmol) was added dropwise at ambient temperature to a vigorously stirred mixture of 38% aqueous ammonia solution (0.314 ml, 6.24 mmol) and dichloromethane (10 ml), the mixture was cooled to 0 °C and stirred at that temperature for 10 minutes, then it was added dropwise via syringe to the stirred 9-(3,5-diacetylphenylcarbamoyl)nonanoic acid solution. The mixture was stirred at ambient temperature under nitrogen for 16 hours, then the resulting solid was collected by filtration and dried in vacuo.
  • Diphenyl phosphoryl azide (4.67 g, 17 mmol) was added to a stirred solution of ethyl hydrogen sebacate (3.73 g, 16.2 mmol) and triethylamine (1.72 g, 17 mmol) in toluene (35 ml), the mixture was stirred at 80 °C for 2 hours, then it was cooled to 40 °C.
  • fe/f-Butanol (10 ml) was added, the mixture was heated under reflux for 18 hours, then the solvents were removed in vacuo. The residue was dissolved in ether (200 ml), the solution was filtered through a short column of silica, and the product was eluted with ether (500 ml).
  • ⁇ /-Ethyldiisopropylamine (1.6 g, 12.4 mmol) was added dropwise at ambient temperature to a stirred solution of 3,5-diacetylaniline (1.1 g, 6.2 mmol) in dichloromethane (10 ml), then the mixture was cooled to 0 °C and stirred at that temperature for 10 minutes.
  • Trifluoroacetic acid (15 ml) was added dropwise at ambient temperature under nitrogen to a stirred solution of /V-(3,5-diacetyIphenyl)-9-(terf- butoxycarbonylamino)nonanamide (1.08 g, 2.5 mmol) in dichloromethane (30 ml), the mixture was stirred at ambient temperature for 30 minutes, then the solvent and other volatile materials were removed in vacuo to give 9-amino- ⁇ /-(3,5- diacetylphenyl)nonanamide (0.83 g) as an orange oil which was used without further purification.
  • the mixture was stirred at 0 °C for 10 minutes and at ambient temperature for 18 hours, then it was poured into water (100 ml).
  • the organic layer was separated, further product was extracted from the aqueous layer using dichloromethane (100 ml), the combined organic solutions were washed with water (100 ml), then they were dried (MgSO ) and the solvents were removed in vacuo.
  • the residue was triturated with cold dichloromethane (10 ml) followed by hexane (30 ml) and the resulting solid was collected by filtration and dried in vacuo.
  • ⁇ /-Ethyldiisopropylamine (1.61 g, 12.5 mmol) was added dropwise at ambient temperature to a stirred solution of 9-amino- ⁇ /-(3,5-diacetylphenyl)nonanamide (0.83 g, 2.5 mmol; prepared in a manner similar to that described above) in dichloromethane (30 ml), then the mixture was cooled to 0 °C and stirred at that temperature for 10 minutes.
  • Oxalyl chloride (1.33 g, 10.5 mmol) was added dropwise at 20-25 °C to a stirred solution of ethyl hydrogen sebacate (2.3 g, 10 mmol) and dimethylformamide (1 drop) in dichloromethane (5 ml), the mixture was stirred at ambient temperature for 1 hour, then the solvent was removed in vacuo.
  • Oxalyl chloride (0.533 g, 4.2 mmol) was added dropwise at 20-28 °C to a stirred suspension of 9-carbamoylnonanoic acid (0.402 g, 2 mmol) and dimethylformamide (2 drops) in dichloromethane (5 ml), the mixture was stirred at ambient temperature for 2 hours, then it was cooled to 0 °C.
  • 3,5-Diacetylaniline (0.354 g, 2 mmol) followed by pyridine (0.4 ml) were added, the mixture was stirred at ambient temperature for 18 hours, then it was poured into 2M hydrochloric acid (25 ml).

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Abstract

La présente invention concerne de nouveaux composés de guanylhydrazone aromatique et l'utilisation d'une classe de composés de guanylhydrazone aromatique comme agents pharmaceutiquement actifs, en particulier dans la prophylaxie et/ou le traitement de maladies nerveuses telles que la toxicomanie, la maladie d'Alzheimer, les troubles de l'anxiété, l'autisme, la cécité, l'infirmité motrice cérébrale, le syndrome de fatigue chronique, la maladie de Huntington, la dépression, la dyslexie, l'épilepsie, les maladies infectieuses, les maladies à prions, les infections à prions, la sclérose en plaque, la dystrophie musculaire, la neurologie, les neurotoxicités, la douleur, la maladie de Parkinson, la schizophrénie, les troubles du sommeil, le stress, l'accident vasculaire cérébral, le syndrome de Tourette, et les tumeurs. L'invention se rapporte également à des compositions pharmaceutiques contenant au moins un composé de guanylhydrazone aromatique et/ou un sel pharmaceutiquement acceptable de ce dernier. Les compositions pharmaceutiques de l'invention peuvent être utilisées dans le cadre de procédés de prévention et/ou traitement de maladies neurologiques et/ou mentales, en particulier les infections à prions et les maladies à prions.
PCT/EP2002/007859 2001-07-13 2002-07-15 Guanylhydrazones aromatiques utilises comme composes efficaces contre les maladies nerveuses WO2003006426A1 (fr)

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WO2005039494A2 (fr) * 2003-10-21 2005-05-06 Message Pharmaceuticals, Inc. Inhibiteurs de rnase p proteines en tant que composes antibacteriens
FR2887879A1 (fr) * 2005-07-01 2007-01-05 Trophos Sa Nouveaux composes chimiques et leurs utilisations comme medicament,particulierement dans le traitement des maladies neurodegeneratives
WO2007016338A2 (fr) * 2005-07-29 2007-02-08 Goverment Of The U.S.A., As Represented By The Secretary, Department Of Health And Human Services Utilisation d’inhibiteurs de la chk2 kinase pour le traitement du cancer
EP1758569A2 (fr) * 2004-06-25 2007-03-07 Cytokine Pharmasciences, Inc. Sels de guanylhydrazone, compositions a base de ceux-ci, procedes et production et d'utilisation de ceux-ci
EP1778265A2 (fr) * 2004-08-17 2007-05-02 Cytokine Pharmasciences, Inc. Composes de guanylhydrazone, compositions de guanylhydrazone, ainsi que leurs methodes de fabrication
EP1908465A1 (fr) * 2006-10-04 2008-04-09 Centre National De La Recherche Scientifique (Cnrs) Utilisation de dérivées chlores du guanabenz dans le traitement des maladies à prions
WO2008002465A3 (fr) * 2006-06-23 2008-10-16 The Feinstein Inst Medical Res INHIBITEURS DE L'AGRÉGATION DES βA ET DE LA SYNUCLÉINE
WO2008156573A1 (fr) * 2007-06-12 2008-12-24 Provid Pharmaceuticals, Inc. Inhibiteurs de kinases, leurs compositions et procédés d'utilisation
EP2351836A1 (fr) 2002-02-01 2011-08-03 Life Technologies Corporation Compositions oligonucléotides dotées d'une efficacité améliorée
US20130225545A1 (en) * 2010-10-06 2013-08-29 Aeolus Sciences, Inc. Porphyrin treatment of neurodegenerative diseases
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US20220213030A1 (en) * 2019-04-01 2022-07-07 Ospedale San Raffaele Srl Aminoguanidine hydrazones as retromer stabilizers useful for treating neurological diseases
CN116102468A (zh) * 2023-02-22 2023-05-12 中国科学技术大学 靶向人脂质运载蛋白2的先导化合物或其药学上可接受的盐及其制备方法与应用
CN116854604A (zh) * 2023-06-27 2023-10-10 中国科学院微生物研究所 一种ω-氨基脂肪酸甲酯、长链尼龙的制备方法
US12006294B2 (en) 2017-01-13 2024-06-11 Regents Of The University Of Minnesota Therapeutic compounds

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JP2012121905A (ja) * 2004-06-25 2012-06-28 Ferring Bv グアニルヒドラゾンの塩、組成物、製造方法、及び使用方法
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