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WO1988009171A1 - Phosphoethanolamine permettant le traitement de la maladie d'alzheimer - Google Patents

Phosphoethanolamine permettant le traitement de la maladie d'alzheimer Download PDF

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Publication number
WO1988009171A1
WO1988009171A1 PCT/US1988/001693 US8801693W WO8809171A1 WO 1988009171 A1 WO1988009171 A1 WO 1988009171A1 US 8801693 W US8801693 W US 8801693W WO 8809171 A1 WO8809171 A1 WO 8809171A1
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composition
hydrogen
alzheimer
pharmaceutically acceptable
dementia
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PCT/US1988/001693
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English (en)
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Stanley H. Appel
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Baylor College Of Medicine
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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • A61K31/13—Amines
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/66—Phosphorus compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

Definitions

  • the field of the invention is providing pharmaceutical compositions for the treatment of neurological disorders associated with dementia, such as Alzheimer's disease.
  • Alzheimer's disease is a disorder of the later decades of life characterized by dementia. In clinical terms, it consists of a diffuse deterioration of mental function, primarily in thought and memory, and secondarily in feeling and conduct. Alzheimer's disease has been used to designate dementia appearing before the age of 65 years. When the syndrome presents after that age, the term senile dementia of the Alzheimer's type is used. In fact, it appears reasonable to consider both types as representing a single syndrome. The true incidence of the disorder is unknown, although recent data suggest that the incidence of all dementia in the U.S. population may be over 100 cases per 100,000, with its prevalence being over 550 per 100,000 [1].
  • Alzheimer's disease probably affects at least 30 to 50% of patients with dementia, and in the United States there may be over one million individuals with severe dementia and several million more with mild to moderate dementia. It has been estimated that 1 out of every 6 persons over the age of 65 in the United States suffers from moderate dementia, and a majority of patients in the nursing home populations are affected with the disorder. The average age of onset is between 70 and 79 years, but without better information on the population at risk, a more accurate statement is not presently possible [1]. As in ALS and parkinsonism, the incidence of the syndrome clearly increases with advancing age. A family history of Alzheimer's disease is present in 5 to 10% of the patients.
  • Alzheimer's disease is one of exclusion. Secondary causes of loss of memory and impaired cognitive function may result from multiple infarcts, leading to so-called multinfarct dementia, or from intracranial mass lesions such as subdural hematomas, brain tumors, or granulomas. Central nervous system infections of viral and bacterial origin, or even slow viral disorders such as Jakob- Creutzfeldt disease, are part of the differential diagnosis. Furthermore, metabolic disorders involving vitamin B ⁇ metabolism, thiamine or folate deficiency, thyroid dysfunction, hepatic and renal failure, as well as drug toxicity, may present as dementia.
  • the pathological picture of Alzheimer's disease has been well characterized over the years. It consists of senile plaques, which result from degeneration of nerve endings, and neurofibrillary tangles, which represent an alteration in the cytoskeletal apparatus [4].
  • senile plaques which result from degeneration of nerve endings
  • neurofibrillary tangles which represent an alteration in the cytoskeletal apparatus [4].
  • intracellular cytoplasmic eosinophilic inclusions termed Hirano bodies, are present, primarily in the hippocampus. Granulovacuolar degeneration is also noted.
  • Senile plaques and neurofibrillary tangles in the brain are part of the "normal" aging process. However, at any age, patients with clinical Alzheimer's disease appear to have much higher concentration of these abnormalities than do normal individuals [5].
  • a prominent finding in Alzheimer's disease is a deficiency of the enzyme that synthesizes the neurotransmitter acetylcholine, namely, choline acetyltransferase (CAT) [6].
  • This deficiency is most marked in the cortex and hippocampus.
  • acetylcholine receptors in the brain are either unaffected or relatively less affected.
  • the defect in CAT reflects an alteration in the presynaptic cholinergic neuron.
  • the diminution in CAT correlates with the pres- ence of senile plaques: the greater the number of plaques, the lower the activity of CAT.
  • Enzymes synthesizing several other neurotransmitters including dopamine, norepinephrine, serotonin, and gamma- aminobutyric acid, as well as levels of vasoactive intestinal peptide, are all relatively unaffected compared to the loss of CAT activity. Somatostatin-like activity has recently been reported to be decreased in the cerebral cortex [7].
  • the CAT activity found in the hippocampus appears to derive largely from nerve terminals for which the cell of origin is in the septal nucleus.
  • almost 70% of CAT activity in the cortex appears to reside in terminals with cell bodies located in the nucleus basalis of Meynert [8].
  • these cholinergic neurons lie intermingled with and beneath the medial globus pallidus, whereas in primates comparable cells are found exclusively outside the pallidum.
  • the nucleus basalis of Meynert is situated in the fibrous zone beneath the globus pallidus and is a major component of the substantial innominata [9].
  • the cholinergic input to hippocampus and cortex may derive from a group of cells extending from the septal nuclei to constituents of the substantia innominata and may well be impaired in Alzheimer's disease [9].
  • the following references are relevant to the invention:
  • Bottenstein JE, Sato GH Growth of a rat neuroblastoma cell line in serum-free supplemented media. Proc Natl Acad Sci USA 76:514-517, 1979
  • Finch CE Catecholamine metabolism in the brains of aging male mice. Brain Res 52:261-276, 1973
  • Fonnum F Radiochemical micro assays for the determination of choline acetyltransferase and acetycholinesterase activities. Biochem J 115:465-472, 1969
  • Hemmendinger LM Garber BB, Hoffman PC, Heller A: Target neuron-specific process formation by embryonic mesencephalic dopamine neurons in vitro. Proc Natl Acad Sci USA 78:1264- 1268, 1981
  • U.S. Patent 4,294,818 discloses a diagnostic method for multiple sclerosis comprised of antibody preparations reactive with antigenic substances associated with lymphocytes.
  • U.S. Patent 3,864,481 discloses a synthetic amino acid for suppression and diagnosis of multiple sclerosis.
  • the present invention is based upon the discovery that phosphoethanolamine, a natural product isolated from the brains of animals, and related compounds are cholinergic fac- tors in that treatment of explant cultures of medial septal nuclei with phosphoethanolamine or related compounds results in an increased capacity of these cultures to synthesize the neurotransmitter acetylcholine.
  • Treatment of Alzheimer's disease with cholinergic factors is based upon the ability of these compounds to improve the function of acetylcholine producing neurons which are impaired in Alzheimer's disease.
  • the present invention discloses a method of treating a patient having a neurological disorder associated with dementia of the Alzheimer's type comprising administering to said patient an amount of a composition effective in amelioration of the dementia comprising a pharmaceutically acceptable excipient and an active sterioisomeric form of a compound having the structure
  • R 1 is hydrogen or a lower alkyl
  • the R 2 and R 3 groups may each be hydrogen, or different groups selected from the group consisting of hydrogen, the lower alkyls, and -COOM groups wherein M is hydrogen or a pharmaceutically acceptable cation
  • R 4 is selected from the group consisting of -OH, -PO 3 H 2 , -OPO 3 H 2 , cytidine 5'-diphosphate, and their pharmaceutically acceptable salts.
  • an object of the present invention to provide an effective treatment for patients suffering from central nervous system disorders, especially those connected with cerebral senescence, such as Alzheimer's disease. Patients are treated by administering an effective amount of an active sterioisomeric form of a compound of the present invention which is in admixture with a pharmaceutically acceptable excipient.
  • a further object of the present invention is to provide numerous compounds which are effective in increasing the synthesis of acetyltransferase, and therefore are available for use in the treatment of neurological disorders.
  • Figure 1 depicts a flow chart for the purification of the central cholinergic factor isolated from brain extracts.
  • Figure 2 is an illustration of a mass spectrometric analysis of the phenylisothiocyanate derivatives of a central cholinergic factor isolated from cortical and hippocampal tissues.
  • ALS represents pathological change in Betz cells, cranial motor neurons, and anterior horn cells; parkinsonism, in substantial nigra neurons; and Alzheimer's disease, in the cholinergic input from nucleus basalis and septal neurons to cortex and hippocampus, respectively.
  • compositions of the present invention are a modification of the notion of intrinsic aging of selected neurons; that is, the presence of specific extrinsic factors influence the maintenance and survival of neurons.
  • system degeneration Is due to diminished availability of a specific neurotrophic factor normally released by the post-synaptic cell, taken up by the presynaptic terminal, and exerting its effect by retrograde transport up the presynaptic axon to the soma and nucleus.
  • cholinergic factors can be demonstrated in vitro which increase the activity of the neurotransmitter synthesis enzymes in the innervating cell.
  • the same factors responsible for increasing neurotransmitter synthesis in vitro may also be responsible for increasing neurotransmitter synthesis in vivo.
  • a well-defined cholinergic system in the rat brain and one that is analogous to the neuronal networks affected in Alzheimer's disease is the projection from the medial septal nucleus to the hippocampus.
  • the septo-hippocampal system has been extensively studied with respect to its anatomic relations, developmental neurogenesis, neurotransmitter distribution and capacity for regeneration.
  • Explant cultures of the medial septal nucleus are organotypic such that the associations with glia and other neurons are maintained in the microenvironment of the cholinergic neurons .
  • the in vitro development of cholinergic parameters in such cultures may therefore closely resemble those which normally occur in vivo.
  • Biological compounds added to these cultures which result in the enhancement of these properties would be expected to exist outside the immediate embryonic environment of these neurons. These cultures are therefore suitable for observing the pharmacologic effect of putative cholinergic factors on these cultures. Similar or related factors may also be indirectly responsible for maintenance of neurons throughout the life cycle in vivo, and may decrease as a normal function of aging.
  • a primary manifestation of ALS, Parkinson disease, or Alzheimer's disease is failure of the target tissue to supply the necessary neurotrophic factor. Marked pathological change in the tissue need not be present. Impaired synthesis or release (or both) of the relevant hormone would represent the sine qua non of disease. For example, in Alzheimer's disease, the failure would be in hippocampus and cortical cell to supply the relevant cholinergic neurotrophic factor. Thus, in this system, the lack of an appropriate factor released from post-synaptic cells impairs the viability of the presynaptic cells and leads to the gradual deterioration of septal and basal nuclei.
  • the present invention discloses a pharmaceutical composition for the treatment of a patient having a neurological disorder associateded with dementia of the Alzheimer's type wherein said pharmaceutical composition comprises a pharmaceutically acceptable excipient and an effective amount of an active sterioisomeric form of a compound having the structure
  • R 1 is hydrogen or a lower alkyl
  • the R 2 and R 3 groups may be the same when hydrogen, or different and are selected from the group consisting of hydrogen, the lower alkyls, and -COOM groups wherein M is hydrogen or a pharmaceutically acceptable cation
  • R 4 is selected from the group consisting of -OH, -PO 3 ,H 2 , -OPO 3 H 2 , cytidine 5'-diphosphate, and their pharmaceutically acceptable salts.
  • Also disclosed is a method of treating a patient having a neurological disorder associated with dementia which method comprises administering to said patient an effective dementia-treating amount of the pharmaceutical composition of the invention.
  • “Lower alkyl” means a branched or unbranched saturated hydrocarbon group of one to eight carbon atoms such as , methyl, ethyl, i-propyl and n-butyl and the like.
  • “Pharmaceutically acceptable cations or anions”, or “pharmaceutically acceptable salts” refers to any cation or anion which is pharmaceutically consistent with the mode of administration and does not produce any untoward pharmaceutical effects. Thus, cations may include ions.
  • alkali metalsand alkaline earth and transition metals such as calcium, barium, magnesium, sodium, zinc and potassium
  • anions may include ions of the mineral acids such as halides, nitrates, sulfates, or phosphates as well as anions of organic acids such as acetate and gluconate.
  • “Pharmacological precursor” means any biological precursor of the present compounds set forth in the structural formula given in the Summary of the Invention which, upon breakdown of the precursor by normal biological processes, releases serine, phosphoserine, ethanolamine or phosphoethanolamine such that an increase in the levels of these latter compounds in the central nervous system occurs.
  • “Active sterioisomeric form” of the present invention is intended to include racemic mixtures composed of varying concentrations of both active and inactive racemates but in such ratios that the overall racemic mixture is effec- tive in stimulating acetylcholine sythesis in cultures of septal neurons, an index of cholinergic maturation.
  • compositions of the invention which are set forth in the structural formula given in the Summary of the Invention are well known and are commercially available.
  • phosphoethanolamine, phosphoserine, CDP- ethanolamine and ethanolamine are available from Sigma (St. Louis, MO).
  • Monomethylethanolamine and the active propanol compounds are available from Aldrich Chemical Co., Inc. (Milwaukee, WI).
  • R 4 derivatives of ethanolamine and serine of the present invention are commercially available and can be used to construct the R 1 substituted compounds disclosed in this invention by reaction with activated alkyl and activated amino acid derivatives.
  • R 1 substituted compounds used in this invention can be prepared as follows.
  • R 1 is an alkyl group
  • the compound is obtained through one of numerous procedures for N-alkylation that are well known in the art.
  • alkyl halides react readily with amines to yield N-alkylated derivatives. Therefore, the reaction of R 1 -X wherein X is a halogen such as Br or Cl with the appropriate R. substituted ethanolamine or serine results in the R 1 -N derivative.
  • Another method is reductive alkylation in which the appropriate activated carboxylic acid derivative of the alkyl reacts with an amino group resulting in the amide condensation product which may then be reduced to give the R 1 -N derivative.
  • the R 1 derivatives may be produced first followed by esterification to yield the appropriate activated R 4 group.
  • Methods for activating phosphate groups in order to obtain phosphate esters by condensation with alcohols are well known in the art.
  • the reactive group on the R 4 substituent may be protected during the alkylation reaction, for example, by derivatization with a tertbutyloxycarbonyl group.
  • phosphoethanolamine has been identified as a brain derived cholinergic factor present in corti- cal and hippocampal tissues.
  • the discovery that phosphoethanolamine is effective in the treatment of Alzheimer's disease was made through efforts to isolate cholinergic factors from the target regions of cholinergic innervation in the brain, such as cortical and hippocampal brain tissues.
  • Phosphoethanolamine was isolated using the purification scheme outlined in Figure 1 and assaying for stimulation of acetylcholine synthesis in the appropriate assay system described below.
  • brain tissue containing the cortex, hippocampus and striatum from young rats and/or calves was homogenized in a buffer solution such as phosphate-buffered saline (PBS) and centrifuged to yield a crude extract.
  • PBS phosphate-buffered saline
  • the supernatant was acidified using acetic acid (1 to 2 M) and then recentrifuged.
  • an appropriate filter for example, an Amicon YM-5 filter.
  • the extracted factor may be directly purified by gel filtration chromatography using an appropriate matrix, such as a Biogel P-2 polyacrylamide column, to resolve proteins having molecular weights less than 1,500 daltons.
  • fractionation procedures which can be used singly or in combination to increase purity of a composition are well known in the art. These include size fractionation using molecular sieve (or gel filtration) chromatography, ion exchange chromatography under suitable conditions; affinity chromatography using, for example, antibodies directed to the biologically active form of the neurotrophic factor; absorp tion chromatography using nonspecific supports, such as hydroxyapatite, silica, alumia, and so forth; and also gel- supported electrophoresis.
  • the cholinergic factor in fractions corresponding to an apparent molecular weigh to the ⁇ 1,000 daltons, is eluted from a P-2 gel filtration column.
  • the cholinergic factor is then bound to an anion exchange column (AG-1-X2) at ⁇ pH 8.5 in low salt and then eluted with a low pH (pH 5-5), high ionic strength buffer.
  • AG-1-X2 anion exchange column
  • Final purification can be achieved by cycling and recycling over different reverse phase matrices which effectively remove most protein since the active factor does not bind to these matrices in 0.1% trifluoroacetic acid (TFA).
  • the ⁇ 1,000 dalton cholinergic factor was assayed on explant cultures of septal neurons obtained from mammalian species. It is preferred to use explants of the medial septal nuclei obtained from the forebrains of E16 rat embryos.
  • the preferred method of assay is to incubate explants of rat septal nuclei with or without the cholinergic compounds for 6 days and then to measure the effect of the compound on the ability of the cells to synthesize acetylcholine.
  • Assays employing survival, cell growth or the enhancement of other cholinergic properties in this and other types of cultures can also be used to assay for these neurotrophic compounds.
  • Phosphoethanolamine has been purified from the target regions of cholinergic innervation in the rat and has been shown to enhance the ability of medial septal explants to synthesize acetylcholine, an Index of cholinergic maturation. Since phosphoethanolamine is effective in enhancing the in vitro cholinergic properties of neurons, the exogenous administration of this and related compounds may be an effective therapy in cases of Alzheimer's disease and general aging of the nervous system if cholinergic function is enhanced in vivo.
  • compositions of this invention are useful for parenteral administration, for example, intravenous, sub- cutaneous, intramuscular, intraorbital, ophthalmic, intraventricular, intracranial, intracapsular, intraspinal, intrasternal, topical, intranasal aerosol, scarification, and also for oral administration.
  • the compositions can be formulated for parenteral administration to humans or other mammals in therapeutically effective amounts (e.g., amounts which eliminate or reduce the patient's pathological condition) to provide therapy for Alzheimer's disease.
  • compositions can be formulated into pharmaceutical compositions by admixture with pharmaceutically acceptable nontoxic excipients and carriers.
  • pharmaceutically acceptable nontoxic excipients and carriers may be prepared for use for parenteral (subcutaneous, intramuscular, intraspinal, or Intravenous) administration particularly in the form of liquid solutions or suspensions; for oral administration, particularly in the form of tablets or capsules; or intranasally, particularly in the form of powders, nasal drops or aerosols.
  • compositions may conveniently be administered in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art, for example, as described in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, 1970.
  • Formulations for parenteral administration may contain as common excipients sterile water or saline, polyalkylene glycols such as poly- ethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like.
  • Formulations for inhalation administration contain as excipients, for example, lactose or may be aqueous, such as glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops .
  • the materials of this invention can be employed as the sole active agent in a pharmaceutical or can be used in combination with other active ingredients .
  • the concentration of the compounds described herein in a therapeutic composition will vary depending on a number of factors, including the dosage of the drug to be administered, the chemical characteristics, e.g., hydrophobicity of the compounds employed, and the mode of administration.
  • the neurotrophic compounds are provided in an aqueous physiological buffer solution containing about 0.1 to 10% w/v factor for parenteral administration. Typical dose ranges are from about 10 ug/kg to about 1 g/kg of body weight per day; a preferred dose range is from about 1 mg/kg to 100 mg/kg of body weight per day.
  • the present invention will be further illustrated by the following examples. These examples are not to be construed as limiting the scope of the invention, which is to be determined solely by the appended claims.
  • the filtrate was lyophilized, redissolved in 0.2 M acetic acid (0.05 times the original volume), filtered and applied to a 2.5 x 100 cm Bio-Rad P-2 column for chromatography in the same buffer.
  • the elution profile was monitored at 0.D.280, and a peak with an apparent molecular weight of 1000 daltons was collected, lyophilized and redissolved in a buffer containing 130 mM N-ethylmorpholine, 250 mM pyridine, and 17 mM acetic acid, pH 8.3 (Buffer A).
  • the lyophilized extract was resuspended in 50 ml/ 0.2 M acetic acid, and a slight insoluble residue removed by filtration through a 0.45 u filter prior to application on a P-2 polyacrylamide molecular sieving column.
  • Molecular sieving was accomplished on a 5 x 140 cm column (Bio-Rad) eluted with 0.2 M acetic acid at a linear flow rate of 5 cm/hr. Fractions were collected only in the molecular weight range, including the void volume, through 700 mw. The fractions were assayed in the tissue culture system outlined below. The peak of activity migrating near 1000 mw was pooled and lyophilized to dryness.
  • Example 3 Assay Method for Stimulation of Acetylcholine Synthesis In Explants of the Medial Septal Nucleus Whole septal nuclei were dissected from the forebrains of 16 day old rat embryos (ED 0 being the day of sperm positivity). The dorsal, caudal and lateral tissues were removed and the remaining medial fragments were sectioned into 0.3 mm pieces by pressing a nickel grid (Ladd Research, #10080) over them.
  • a modified N 2 defined medium consisting of insulin (5 ug/ml), transferrin (100 ug/ml), putrescine (100 uM), progesterone (20 nM), selenium (30 nM), glutamine (4 mM),vitamin B-12 (350 nM) and gentamicin (50 ug/ml) in high glucose (0.6%) DMEM.
  • Cultures were maintained in a humidified atmosphere of 5% CO 2 at 37°C Cultures were fed two days after plating by removing 0.5 ml of the plating medium and adding 1.0 ml of fresh medium containing a 2% rabbit serum supplement and the substances being tested. Partially purified fractions were lyophilized and redissolved at concentrations ranging from 10 ng to 1 ug protein per ml. Phosphoethanolamine purified from rat brain and authentic compounds purchased from Sigma Chemical Co. (St. Louis, MO) or Aldrich Chemical Co.
  • Total [3H] dpm was calculated relative to the recovery of [14C] dpm and the net [3H] dpm was determined by subtracting the [3H] dpm recovered from culture dishes without explants.
  • the activity of a compound was measured by calculating the increase in [3H] acetylcholine formed per explant as compared to that of nontreated control cultures.
  • a unit of activity was defined as the amount of material needed to give a stimulation equal to 50% of the maximum response, which was typically a 2-fold Increase over controls.
  • Phosphoethanolamine gave a maximal saturating response at 3 x 10 -5 molar, thereby exhibiting an ⁇ 2.2 fold increase over controls.
  • Example 4 Structure Determination The highly purified rC-CF (rat) was analyzed for amino acid content. The results suggested the presence of an unexpectedly large amount of a compound with molecular weight of 141. The only additional component present had a molecular weight of 531 and was a minor component. Amino acid analysis of a lesser amount of material indicated the presence of a very large amount of a primary amine which was not a known amino acid. Based on the absorption of the phenylisothiocyanate (PITC) derivative, there were ⁇ 8 micromoles of this amine in the entire preparation from 250 brains.
  • PITC phenylisothiocyanate
  • FIG. 2A depicts the mass spectrometric profile of the isolated PITC derivatives of acid hydrolyzed rC-CF. Acid hydrolysis of phosphoethanolamine should yield ethanolamine, which would react with PITC to generate a derivative of mass 195 daltons. In fact, a (protonated) molecular ion of 196 is actually observed in field desorption mass spectroscopy.
  • Figure 2B depicts the mass spectrometric profile of the puri- fied PITC derivative of rC-CF without acid hydrolysis.
  • Example 6 Activities of Compound Analogs Compounds related to phosphoethanolamine were assayed in substantial accordance with the teaching of Example 3. Cultures of medial septal explants, which had been treated for six days with two additions of the compound of interest, were examined for their ability to convert choline to acetylcholine. A dose-response curved (1 uM to 1 mM) was generated for each compound to determine the effect on acetylcholine synthesis. The results of these experiments are provided in Table 2. As used therein, 1 unit of activity is equal to the molar concentration of the compound required to enhance acetylcholine synthesis 2-fold relative to untreated controls. EC 50 is the molar concentration at which 50% of the maximum stimulation is induced. These data taken together support the specificityect of ethanolamine and ethanolamine-like compounds in the present invention, on cholinergic neurons.

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Abstract

La présente invention est basée sur la découverte du fait que la phosphoéthanolamine, produit naturel isolé à partir du cerveau d'animaux, ainsi que des composés apparentés, sont des facteurs cholinergiques; en effet, le traitement de cultures d'explants de noyaux septaux médians avec la phosphoéthanolamine ou avec des composés apparentés a pour résultat d'augmenter la capacité qu'ont ces cultures de synthétiser l'acétylcholine servant de neurotransmetteur. L'invention offre des compositions pharmaceutiques comprenant de l'éthanolamine ou des composés apparentés et leurs dérivés, destinés à être utilisés dans le traitement de la maladie d'Alzheimer.
PCT/US1988/001693 1987-05-19 1988-05-18 Phosphoethanolamine permettant le traitement de la maladie d'alzheimer WO1988009171A1 (fr)

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Application Number Priority Date Filing Date Title
US5189787A 1987-05-19 1987-05-19
US051,897 1987-05-19
US18800588A 1988-05-11 1988-05-11
US188,005 1994-01-28

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US5652214A (en) * 1989-06-05 1997-07-29 Cephalon, Inc. Treating disorders by application of insulin-like growth factors and analogs
US5760021A (en) * 1992-05-29 1998-06-02 The Procter & Gamble Company Phosphonocarboxylate compounds pharmaceutical compositions, and methods for treating abnormal calcium and phosphate metabolism
EP0774252A4 (fr) * 1994-05-06 2000-04-26 Kanebo Ltd Potentialisateur de cytokine et remede pour des maladies dans lesquelles l'activite de la cytokine est reduite
WO2001010428A3 (fr) * 1999-08-10 2002-06-13 Yeda Res & Dev Utilisation de bases n-methyl d'ethanolamine pour prevenir la mort cellulaire induite par le stress oxydant
US6407061B1 (en) 1989-12-05 2002-06-18 Chiron Corporation Method for administering insulin-like growth factor to the brain
EP1004301A4 (fr) * 1997-07-28 2002-11-13 Riken Agent promoteur de protection et de survie des cellules du systeme nerveux central
EP1060750A3 (fr) * 1993-03-29 2003-03-26 Queen's University at Kingston Procédé de traitement de l'amyloidose
US6693076B1 (en) 1989-06-05 2004-02-17 Cephalon, Inc. Treating disorders by application of insulin-like growth factors and analogs
US6723699B1 (en) 1989-06-05 2004-04-20 Cephalon, Inc. Treating disorders by application of insulin-like growth factors and analogs
JP2005526046A (ja) * 2002-02-27 2005-09-02 インスパイアー ファーマシューティカルズ，インコーポレイティド 上皮及び網膜組織疾患の治療のための組成物及び治療方法
US7041314B2 (en) 2001-05-24 2006-05-09 Neuren Pharmaceuticals Ltd. GPE analogs and peptidominetics
US7244764B2 (en) 2003-06-23 2007-07-17 Neurochem (International) Limited Methods and compositions for treating amyloid-related diseases
US7273618B2 (en) 1998-12-09 2007-09-25 Chiron Corporation Method for administering agents to the central nervous system
US7414076B2 (en) 2003-06-23 2008-08-19 Neurochem (International) Limited Methods and compositions for treating amyloid-related diseases
US7560447B2 (en) 2000-05-08 2009-07-14 N.V. Nutricia Preparation for the prevention and/or treatment of vascular disorders
US7605177B2 (en) 2001-05-24 2009-10-20 Neuren Pharmaceuticals Limited Effects of glycyl-2 methyl prolyl glutamate on neurodegeneration
US7714020B2 (en) 2001-05-24 2010-05-11 Neuren Pharmaceuticals Limited Treatment of non-convulsive seizures in brain injury using G-2-methyl-prolyl glutamate
US7754761B2 (en) 1993-03-29 2010-07-13 Bellus Health (International) Limited Sulfonated compounds and compositions for treating amyloidosis
US8372886B2 (en) 2005-12-22 2013-02-12 Kiacta Sarl Treatment of renal disorders, diabetic nephropathy and dyslipidemias
US8835654B2 (en) 2004-12-22 2014-09-16 Bhi Limited Partnership Method and compositions for treating amyloid-related diseases
US9499480B2 (en) 2006-10-12 2016-11-22 Bhi Limited Partnership Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid
CN114099487A (zh) * 2021-12-22 2022-03-01 上海市第一人民医院 乙醇胺在制备预防、缓解和/或治疗神经炎症相关疾病的产品中的应用

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US4386078A (en) * 1980-03-03 1983-05-31 The Ohio State University Research Foundation Therapeutic agents for preventing phospholipid degradation and free fatty acid proliferation
EP0147185A2 (fr) * 1983-12-22 1985-07-03 Massachusetts Institute Of Technology Emploi thérapeutique du cytidyl diphosphocholine pour augmenter l'acétylcholine neuronale

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US5652214A (en) * 1989-06-05 1997-07-29 Cephalon, Inc. Treating disorders by application of insulin-like growth factors and analogs
US5703045A (en) * 1989-06-05 1997-12-30 Cephalon, Inc. Treating disorders by application of insulin-like growth factors and analogs
US6723699B1 (en) 1989-06-05 2004-04-20 Cephalon, Inc. Treating disorders by application of insulin-like growth factors and analogs
US5776897A (en) * 1989-06-05 1998-07-07 Cephalon, Inc. Treating disorders by application of insulin-like growth factors and analogs
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EP1060750A3 (fr) * 1993-03-29 2003-03-26 Queen's University at Kingston Procédé de traitement de l'amyloidose
US7754761B2 (en) 1993-03-29 2010-07-13 Bellus Health (International) Limited Sulfonated compounds and compositions for treating amyloidosis
EP0774252A4 (fr) * 1994-05-06 2000-04-26 Kanebo Ltd Potentialisateur de cytokine et remede pour des maladies dans lesquelles l'activite de la cytokine est reduite
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US7273618B2 (en) 1998-12-09 2007-09-25 Chiron Corporation Method for administering agents to the central nervous system
WO2001010428A3 (fr) * 1999-08-10 2002-06-13 Yeda Res & Dev Utilisation de bases n-methyl d'ethanolamine pour prevenir la mort cellulaire induite par le stress oxydant
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US7560447B2 (en) 2000-05-08 2009-07-14 N.V. Nutricia Preparation for the prevention and/or treatment of vascular disorders
US7714020B2 (en) 2001-05-24 2010-05-11 Neuren Pharmaceuticals Limited Treatment of non-convulsive seizures in brain injury using G-2-methyl-prolyl glutamate
US7605177B2 (en) 2001-05-24 2009-10-20 Neuren Pharmaceuticals Limited Effects of glycyl-2 methyl prolyl glutamate on neurodegeneration
US7041314B2 (en) 2001-05-24 2006-05-09 Neuren Pharmaceuticals Ltd. GPE analogs and peptidominetics
JP2005526046A (ja) * 2002-02-27 2005-09-02 インスパイアー ファーマシューティカルズ，インコーポレイティド 上皮及び網膜組織疾患の治療のための組成物及び治療方法
JP4745610B2 (ja) * 2002-02-27 2011-08-10 インスパイアー ファーマシューティカルズ，インコーポレイティド 上皮及び網膜組織疾患の治療のための組成物及び治療方法
US7598269B2 (en) 2003-06-23 2009-10-06 Bellus Health (International) Limited Methods and compositions for treating amyloid-related diseases
US7414076B2 (en) 2003-06-23 2008-08-19 Neurochem (International) Limited Methods and compositions for treating amyloid-related diseases
US7244764B2 (en) 2003-06-23 2007-07-17 Neurochem (International) Limited Methods and compositions for treating amyloid-related diseases
US8835654B2 (en) 2004-12-22 2014-09-16 Bhi Limited Partnership Method and compositions for treating amyloid-related diseases
US8372886B2 (en) 2005-12-22 2013-02-12 Kiacta Sarl Treatment of renal disorders, diabetic nephropathy and dyslipidemias
US9499480B2 (en) 2006-10-12 2016-11-22 Bhi Limited Partnership Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid
US10238611B2 (en) 2006-10-12 2019-03-26 Bellus Health Inc. Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid
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