EP1358204A1 - Tripeptide derivatives for the treatment of neurodegenerative diseases - Google Patents

Tripeptide derivatives for the treatment of neurodegenerative diseases

Info

Publication number
EP1358204A1
EP1358204A1 EP02716727A EP02716727A EP1358204A1 EP 1358204 A1 EP1358204 A1 EP 1358204A1 EP 02716727 A EP02716727 A EP 02716727A EP 02716727 A EP02716727 A EP 02716727A EP 1358204 A1 EP1358204 A1 EP 1358204A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
alkoxy
group
residue
cinnamoyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02716727A
Other languages
German (de)
English (en)
French (fr)
Inventor
Jean Rapin
Hans Klaus Witzmann
Jean-Marie Grumel
Jacques Gonella
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
NeuroTell AG
Original Assignee
NeuroTell AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by NeuroTell AG filed Critical NeuroTell AG
Publication of EP1358204A1 publication Critical patent/EP1358204A1/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • 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
    • A61P25/28—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • Tripeptide derivatives for the treatment of neurodegenerative diseases are Tripeptide derivatives for the treatment of neurodegenerative diseases
  • the invention relates to the use of tripeptide derivatives for the treatment of neurodegenerative diseases, particularly those caused by apoptotic processes.
  • Neurodegenerative diseases are characterised by a degradation or degeneration of nerves which are generally caused by apoptosis .
  • Examples of neurodegenerative diseases include Alzheimer's disease, mild cognitive impairment, Parkinson's disease as well as AIDS-related neurological disorders.
  • Alzheimer's disease the nerve degradation leads to a disruption of the ability to remember, speak, think and make decisions. The reasons for these disorders are not known in detail.
  • On the biochemical level a change in the cortical cholinergic systems with a decrease in the formation of the neurotransmitter acetylcholine is detectable.
  • the acetylcholine concentration is decreased by 20 to 40 %.
  • nerve ends are attacked, and this leads ultimately to the death of the cerebral cells, particularly those of the hippocampus .
  • Alzheimer's disease is characterized by three distinct phases: a phase of pre-dementia, a phase of light dementia, and a phase of severe dementia.
  • a neuronal degeneration is observed, particularly oh the level of the hippocampus.
  • the typical amyloid deposition occurs.
  • Classical treatments of Alzheimer's disease using nootropic substances only alleviate the symptoms of the disease, particularly cognitive disorders, during administration of the substance. Once the ' administration is discontinued, the symptoms reappear. This is in contrast to an anti- neurodegener tive effect in the hippocampus which results in a decrease and preferably stopping of the evolution of the hippocampal neuron degeneration.
  • Nootropic substances are for example disclosed in EP 0 316 218 Bl .
  • Recent therapeutic approaches for Alzheimer's disease therefore address the stabilisation of the acetylcholine concentration, particularly by inhibiting acetylcholine esterase which degrades acetylcholine to acetate and choline.
  • acetylcholine esterase inhibitors shows the drawback that this results in an only temporary improvement which is not suitable for stopping or even reversing the nerve degeneration.
  • neurotrophic factors or neurotrophines are known to which a significant influence on the survival, growth and differentiation of discrete neuronal populations is ascribed.
  • the neurotrophine family includes nerve growth factor (NGF) , brain derived neurotrophic factor (BDNF) , neurotrophine-3 (NT-3) , neurotrophine-4 (NT-4) and the CNTF-family (ciliary neurotrophic factor) .
  • NGF nerve growth factor
  • BDNF brain derived neurotrophic factor
  • NT-3 neurotrophine-3
  • NT-4 neurotrophine-4
  • CNTF-family ciliary neurotrophic factor
  • NGF peripheral nervous system
  • CNS central nervous system
  • NGF serves a trophic role in the development and maintenance of cholinergic neurons of the basal forebrain. It also plays a role in adult CNS tissues in neuronal regeneration.
  • X represents OH, (C1--5) alkoxy, NH2, NH-C ⁇ _5-alkyl, N(C 1 _ 5 alkyl) 2 ;
  • R]_ is a residue derived from any of the amino acids Phe, Tyr, Trp, Pro, each of which may optionally be substituted by a (C1-.5) alkoxy group, a (C1-. 5 ) alkyl group or a halogen atom, and Ala, Val, Leu, or lie;
  • R2 is a residue which is derived from any of the amino acids Gly, Ala, lie, Val, Ser, Thr, His, Arg, Lys, Pro, Glu, Gin, pGlu, Asp, Leu and Asn;
  • R 3 and R 4 independently represent H, OH, (C1-.C5) alkyl, or (C]__5) alkoxy, provided that R 3 and R 4 are not both OH or (C1-.5) alkoxy;
  • R 5 represents H, OH, (C ⁇ _ 5 ) alkyl or (Ci_5) alkoxy;
  • RQ represents a group of the formula
  • Z represents a halogen atom, a trifluormethyl group, (C1-- 4 ) alkoxy group, (C1--4) alkyl group; or wherein two neighbouring substituents may form a (C1-. 3 ) alkylendioxy group; and wherein n is 0 or an integer of from 1 to 5; or pharmaceutically acceptable salts thereof;
  • amino acid residues may be present both in the D-form as well as the L-form, the L-form being preferred.
  • R ⁇ is a residue derived from the amino acid lie or one of the amino acids Phe, Tyr, Trp, which each may be optionally substituted with one or more (C1--5) alkoxy groups, (C1-- 5 ) alkyl groups or one or more halogen atoms, particularly a residue which is derived from lie or Phe which is optionally substituted with one or more (C1.-5) alkoxy groups, (C1-.5) alkyl groups or one or more halogen atoms .
  • X is preferably (C1-.5) alkoxy, H2, NH-(C ⁇ _5) alkyl or N(C ⁇ _5 alkyl) 2 more preferred are NH2' NH(C ] __ 3 ) alkyl and (C ] __ 3 alkyl) 2 •
  • R2 is preferably a residue derived from the amino acid Gly or He.
  • R3 and R 4 preferably independently from each other represent H, (C1--5) alkyl or (C1-.5) alkoxy, provided that R 3 and R 4 are not (C ] __5) alkoxy, more preferred are H, (C1-.3) alkyl or (C]__ 3 ) alkox .
  • R5 preferably represents H, (C1-.5) alkyl or (C1--5) alkoxy, particularly preferred are H, (C1-. 3 ) alkyl or (C1-- 3 ) alkoxy.
  • RQ is preferably a cinna oyl residue.
  • RQ is preferably a cinnamoyl residue
  • R]_ is a residue which is derived from Phe which is optionally substituted with one or more (C;j_-- 5 ) alkoxy groups, (C1--5) alkyl groups or one or more halogen atoms, or which is derived from the amino acid He
  • R2 is a residue derived from the amino acid Gly or He
  • R 3 , R 4 and R5 represent a hydrogen atom
  • X is N ⁇ 2, NH-(C ⁇ _ 3 ) alkyl or N(C ⁇ _ 3 alkyl) 2-
  • R]_ is a residue which is derived from Phe which is optionally substituted with one or more (C1--5) alkoxy groups, (C1-- 5 ) alkyl groups or one or more halogen atoms, or which is derived from the amino acid He
  • R 2 is a residue derived from the amino acid Gly or He
  • R 3 , R 4 and R5 represent a hydrogen atom
  • X is NH 2 / NH-(C ⁇ _3) alkyl or N(C ⁇ _ 3 alkyl) 2
  • Y ⁇ and Y2 independently from each other represent H or (C1-. 3 ) alkyl.
  • R is preferably a cinnamoyl residue.
  • Most preferred compounds of formula (I) are cinnamoyl-glycyl- L-phenylalanyl-L-prolineamide, cinnamoyl-isoleucyl- phenylalanyl-L-proline ethylamide, cinnamoyl-isoleucyl- isoleucyl-prolineamide, or a pharmaceutically acceptable salt thereof .
  • the synthesis of the tripeptide derivatives used according to the present invention is not particularly limited and can be carried out according to known methods, preferably stereo- specific processes of peptide chemistry in which the L- or D-configuration of the respective amino acids or their derivatives is maintained. Particularly suitable are the syntheses disclosed in EP 0 316 218 Bl .
  • the compounds of formula (I) used according to the present invention are lipophilic substances and suitable for enteral and in appropriate formulations for parenteral administration.
  • An administration in a dose of 1 to 5 mg per kilogram bodyweight per day, preferably 75 to 375 mg per day is usually effective.
  • an administration over several days for example at least 4 or 5 days is generally preferred.
  • the tripeptide derivatives to be used according to the present invention show a very low toxicity. In mice, using dosages of up to 1000 mg/kg p.o. according to the Irwin test, no lethal or cramp causing effects were observed.
  • the tripeptide derivatives may be used for the production of pharmaceutical compositions which are suitable for administration in different ways, e.g. parenteral (intravenous, intramuscular, subcutane) , via the respiratory tract (buccal, sublingual, nasal, bronchial) , the transdermal route (percutane) and the enteral route (peroral) .
  • the pharmaceutical compositions of the present invention further contain a pharmaceutically acceptable excipient, pharmaceutically acceptable diluents or adjuvants . Standard techniques may be used for their formulation, as e.g. disclosed in Remington's Pharmaceutical Sciences, 20 th edition Williamss-Wilkins, PA, USA.
  • the administration form is selected depending on the administration route and comprises inter alia tablets, capsules, powders and solutions.
  • tablets and capsules are preferably used which contain a suitable binding agent, e.g. gelatine or polyvinyl pyrrolidone, a suitable filler, e.g. lactose or starch, a suitable lubricant, e.g. magnesium stearate, and optionally further additives .
  • a suitable binding agent e.g. gelatine or polyvinyl pyrrolidone
  • a suitable filler e.g. lactose or starch
  • a suitable lubricant e.g. magnesium stearate
  • a particularly preferred formulation for oral administration is a coated tablet containing 100 mg Cinnamoyl-Gly-Phe-ProNH2 as well as microcristalline cellulose, maize starch, Povidon 25, Crospovidon, Macrogol 4000, titanium dioxide (E171) , and ferric oxide (E172) .
  • sterile ethanol-containing aqueous solutions are preferred.
  • Suitable sterile aqueous solutions or physiological saline solution may contain 10 % v/v ethanol.
  • a volume of 10 ml of such a solution is used to dissolve 100 mg of lyophilised Cinnamoyl-Gly-Phe-ProNH 2 , in an appropriate medical device for injection.
  • the anti-neurodegenerative effect of the tripeptide derivatives to be used according to the present invention is surprising, particularly when administered parenterally or enterally.
  • the nootropic effect of these substances is known from EP 0 316 218 Bl, the finding that these substances do not only show a temporary nootropic effect during administration, but a stopping of nerve degeneration could not be expected.
  • the administration of the substances to be used according to the present invention is preferred for the treatment of Alzheimer's disease, and particularly mild cognitive impairment .
  • the superior therapeutic properties of the tripeptide derivatives used according to the present invention will be further illustrated below using particularly useful models for Alzheimer's disease. Using these models, it could be demonstrated that the administration of the tripeptide derivatives used according to the present invention does not only result in an increase of the number of hippocampus neurons, but also results in an improvement of the learning behaviour of the rats used in the tests.
  • the transgenic mouse model is only of limited use as far as behavior is concerned. Therefore we present a battery of three rat models .
  • Each model reproduces one of the physiopathologic features of the disease : neurofibrillary degeneration in the vincristine model, degeneration by beta- amyloid in the Gpl20 model, and apoptosis in the dexamethasone model .
  • Vincristine is an anticarcinogen that is used as a synchronizing agent. This molecule binds to the spindle of microtubules, thus blocking the cellular multiplication during the metaphase. It is a spindle poison. The neurons do not multiply under physiologic conditions, but the axons are made of neurofibrils whose structure is similar to the one of the microtubules of the spindle. Vincristine binds to these neurofibrils thus causing peripheral neural conduction disorders in patients who are treated for neoplasm. These effects mainly affect the white matter of the axons. As vincristine does not pass the blood-brain barrier it has to be given by intracerebroventricular administration.
  • the repeated ICV administration of vincristine causes a degeneration of the conduction pathways with the appearance of abnormal neurofibrils similar to those observed in Alzheimer's disease. This degeneration mainly affects the periventricular structures . The hippocampi are affected through a decrease of their ramifications, while the cell bodies of the neurons are not altered.
  • the repeated administration of vincristine is only possible for a short time (5 days at a maximum) . After this period, a protective layer forms on the glia cells that prevent the diffusion of vincristine from the CSF to the neighboring nerve cells.
  • mice Male Wistar rats (Charles River, Saint Aubin les Elbeuf, France) , each weighing on average 280-300 grams, were used in the animal experiments. For a period of one week, the animals were placed in stablings in an animal laboratory where the following parameters were controlled :
  • the animals got drinking water and a standard feed UAR A03 ad libitum.
  • the injections were given at 9.00 a.m.
  • the first group of 10 rats received 1 ml/kg water under the same conditions .
  • the rats were placed under the common learning conditions of the three models between 10.00 a.m. and 11.00 a.m. (see below) .
  • the rats were placed under the common learning conditions of the three models between 10.00 a.m. and 11.00 a.m. (see below) .
  • the number of glucocorticoid receptors was determined by a binding method using a labeled c ⁇ rticoid and a specific inhibitor to the binding of the corticoid to the receptor (here a total agonist) .
  • the protein content was measured by Lowry's method.
  • the hippocampi of each rat were homogenized in 2ml of sodium EDTA Glycerol molybdate buffer. The homogenate was centrifugated at 100.000 g for 60 minutes. An aliquot of the supernatant was diluted in distilled water, and the protein content was measured by Lowry's method. This protein concentration was between 1.3 and 1.7 mg/ml .
  • the rest of the supernatant was divided into three parts of 0.2ml each. Increasing concentrations (25, 50 and 75 nmoles/ml) of dexamethasone 3H (Amersham 50Ci/mM) were added to these parts . Three other preparations were carried out under the same conditions, while a saturating quantity of a total antagonist of the receptors (RU 28362) was added to obtain a non-specific binding of the labeled dexamethasone. After one night of incubation at 4°C, charcoal/dextran was added to absorb the proteins and the bound dexamethasone. After centrifugation, the radioactivity of the supernatant was measured by liquid scintillation.
  • results are expressed in femtomoles of the labeled corticoid bound to the receptor per mg of proteins .
  • Results are expressed as percentage of adequate responses, and the kinetics of the responses is represented by a multi-exponential maximum curve.
  • the curve maximum represents the learning capacities .
  • the slope of the curve evaluates the learning speed.
  • the area under the curve (AUC) represents a good evaluation of all conditioning parameters.
  • the maximum value of the area under the curve is 500, if the animals show 100% adequate responses as early as Day 0. In fact, an average area under the curve is calculated per day, what amounts to a maximum value of 100. In the absolute control animals, this average area under the curve is equal to 40+/-4.
  • All reagents used are grade I reagents, and are provided by Aldrich (Saint Quentin Fallavier, France) .
  • Dexamethasone 3H is provided by Amersham (England) .
  • the specific agonist ( RU 28362) is provided by Roussel.
  • Results are expressed as an average with the standard error of mean (SEM) of the results obtained from ten rats par experimental group.
  • the variability is calculated as a function of the least squares for each experimentation day. Significance is determined by a t-test.
  • the rats were sacrificed by means of decapitation, and the brain was isolated and frozen to -80°C with liquid nitrogen. Cuts of a thickness of 50 ⁇ m were obtained in a "cryo-cut", and the neurons are counted in the CA III layers of the hippocampus under a microscope. The results are expressed as percentage of the control group.
  • dexamethasone induces a very drastic decrease in the number of corticoide receptors in the hippocampus .
  • a decrease in the order of 60 % was found.
  • the administration of the tripeptide to be used according to the present invention results in a significant increase of the number of receptors of hippocampus neurons . Tacrine does not show any effect under the same conditions.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Biomedical Technology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Virology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • AIDS & HIV (AREA)
  • Molecular Biology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Psychology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
EP02716727A 2001-02-05 2002-02-05 Tripeptide derivatives for the treatment of neurodegenerative diseases Withdrawn EP1358204A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10105039 2001-02-05
DE10105039A DE10105039A1 (de) 2001-02-05 2001-02-05 Tripeptid-Derivate für die Behandlung neurodegenerativer Krankheiten
PCT/EP2002/001181 WO2002062830A1 (en) 2001-02-05 2002-02-05 Tripeptide derivatives for the treatment of neurodegenerative diseases

Publications (1)

Publication Number Publication Date
EP1358204A1 true EP1358204A1 (en) 2003-11-05

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EP02716727A Withdrawn EP1358204A1 (en) 2001-02-05 2002-02-05 Tripeptide derivatives for the treatment of neurodegenerative diseases

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EP (1) EP1358204A1 (enExample)
JP (1) JP2004531480A (enExample)
DE (1) DE10105039A1 (enExample)
WO (1) WO2002062830A1 (enExample)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2007204314A1 (en) * 2006-01-13 2007-07-19 Oncoreg Ab Use of TPP II inhibitors in combination with gamma-irradiation for the treatment of cancer
JP6344796B2 (ja) * 2014-09-30 2018-06-20 森永乳業株式会社 高齢者用アルツハイマー型認知症改善剤
JP6589011B2 (ja) * 2018-05-17 2019-10-09 森永乳業株式会社 脳機能障害改善用経口組成物

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Publication number Priority date Publication date Assignee Title
FR2622581B1 (fr) * 1987-11-03 1990-02-16 Inorgan Sa Rech Develop Pharm Nouveaux derives de l-proline, leur preparation et leurs applications biologiques
DE4007869A1 (de) * 1990-03-13 1991-09-19 Merck Patent Gmbh Aminosaeurederivate
US5716929A (en) * 1994-06-17 1998-02-10 Vertex Pharmaceuticals, Inc. Inhibitors of interleukin-1β converting enzyme
EP0840614A1 (en) * 1995-06-13 1998-05-13 Sanofi Winthrop, Inc. Calpain inhibitors for the treatment of neurodegenerative diseases

Non-Patent Citations (1)

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Title
See references of WO02062830A1 *

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Publication number Publication date
DE10105039A1 (de) 2002-08-08
JP2004531480A (ja) 2004-10-14
WO2002062830A1 (en) 2002-08-15

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