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WO2008031799A1 - Utilisation de composés de pipérazine pour le traitement de maladies neurodégénératives - Google Patents

Utilisation de composés de pipérazine pour le traitement de maladies neurodégénératives Download PDF

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Publication number
WO2008031799A1
WO2008031799A1 PCT/EP2007/059473 EP2007059473W WO2008031799A1 WO 2008031799 A1 WO2008031799 A1 WO 2008031799A1 EP 2007059473 W EP2007059473 W EP 2007059473W WO 2008031799 A1 WO2008031799 A1 WO 2008031799A1
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WO
WIPO (PCT)
Prior art keywords
furanyl
dimethyl
phenyl
methyloxy
piperazinyl
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.)
Ceased
Application number
PCT/EP2007/059473
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English (en)
Inventor
Robert Ian Grundy
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.)
Glaxo Group Ltd
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Glaxo Group Ltd
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Filing date
Publication date
Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd
Publication of WO2008031799A1 publication Critical patent/WO2008031799A1/fr
Anticipated expiration legal-status Critical
Ceased 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to the use of piperazine derivatives in the treatment of diseases or disorders characterised by elevated ⁇ - amyloid levels or ⁇ - amyloid deposits, particularly Alzheimer's disease.
  • AD Alzheimer's disease
  • Citron M (2002) Nat. Neurosci 5, Suppl 1055-1057
  • the earliest stages of the disease are characterized by a progressive loss of memory with associated cognitive decline and language and behavioural deficits.
  • patients develop global amnesia and have greatly reduced motor function.
  • Death typically occurs 9 years following diagnosis and is often associated with other conditions, typically pneumonia (Davis K.L. and Samules S. C. (1998) in Pharmacological Management of Neurological and Psychiatric Disorders eds Enna SJ. and Coyle J. T. (McGraw-Hill, New York pp267-316)).
  • ⁇ -amyloid peptide is key to the progression of Alzheimer's disease.
  • Alzheimer's disease is considered a degenerative brain disorder in which extracellular deposition of ⁇ -amyloid peptide in the form of senile plaques represents a key pathological hallmark (Selkoe, D. J. (2001) Physiological Reviews 81 : 741-766).
  • the presence of senile plaques is accompanied by a prominent inflammatory response and neuronal loss, ⁇ -amyloid (A ⁇ ) exists in soluble and insoluble, fibrillar forms and a specific fibrillar form has been identified as the predominant neurotoxic species (Vassar, R. and Citron, M.
  • a ⁇ is known to be produced through the cleavage of the beta amyloid precursor protein (also known as APP) by an aspartyl protease enzyme known as Asp2 (also known as ⁇ -secretase, BACEl or Memapsin-2) (De Strooper, B. and Konig, G. (1999) Nature 402: 471-472).
  • amyloid peptide In normal individuals, the most abundant form of amyloid peptide is the 1-40 species (A ⁇ 40) forming approximately 90% of the detectable amyloid, with the more fibrillogenic 1-42 species (A ⁇ 42) forming approximately 10%. In AD patients, however, the levels of A ⁇ 40 drop to approximately 50% whereas the levels of A ⁇ 42 rise to approximately 50%, whilst, concurrently, the total CNS amyloid load increases dramatically.
  • a ⁇ in the brain includes cerebral amyloid angiopathy, multi-infarct dementia, dementia pugilistica and Down's syndrome.
  • Ghrelin is a 28 amino acid peptide predominantly produced by the stomach and to a lesser extent by the bowel, pancreas, kidney, placenta, pituitary and the arcuate nucleus of the hypothalamus.
  • GGS-R growth hormone secretagogue receptors
  • rat adiposity Tsch ⁇ p et al., Nature 2000, 407(6806), 908
  • gastric acid secretion Mosuda et al., Biochemical and Biophysical Research Communications 2000; 276: 905
  • Kojima et al. Nature 1999; 402: 656; Lu et al., Neuroscience Letters.
  • Agonists of the ghrelin receptor have been described as possibly being useful in treating in treating AD in combination with PDE4 inhibitors (WO04/087157).
  • WO06/010629 discloses certain novel piperazine derivatives that have agonist activity at the GHS receptor. We have now found that certain compounds described in WO06/010629 may have therapeutic utility in the treatment of diseases or disorders characterised by elevated ⁇ - amyloid levels or ⁇ -amyloid deposits, particularly Alzheimer's disease.
  • the present invention therefore provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof: in which R is hydrogen, methyl, halogen or trifluoromethyl;
  • R 1 is hydrogen or methyl; and the furan ring is attached to the phenyl ring via the 2 or 3 position for the treatment of diseases or disorders characterised by elevated ⁇ - amyloid levels or ⁇ -amyloid deposits, particularly Alzheimer's disease.
  • halogen is used herein to describe, unless otherwise stated, a group selected from fluorine, chlorine, bromine or iodine.
  • R is hydrogen, chloro or fluoro: and/or
  • R 1 is methyl
  • the furan ring is attached to the phenyl ring via the 2 position.
  • Pharmaceutically acceptable salts of compounds of formula (I) include any pharmaceutically acceptable salt, of a compound of formula (I) which, upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolic or residue thereof.
  • the compounds of formula (I) can form acid addition salts thereof. It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in J. Pharm. Sci., 1977, 66, 1-19, such as acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and organic acids e.g.
  • succinic maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic, salicylic, lactic, mandelic or naphthalenesulfonic acid
  • the compounds of formula (I) and their pharmaceutically acceptable salts may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be hydrated or solvated.
  • This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water.
  • Compounds of formula (I) and their pharmaceutically acceptable salts are of use in the treatment of diseases or disorders characterised by elevated ⁇ - amyloid levels or ⁇ -amyloid deposits, particularly Alzheimer's disease.
  • treatment includes prophylaxis as well as alleviation of established symptoms.
  • the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance, in particular in the treatment of diseases or disorders characterised by elevated ⁇ - amyloid levels or ⁇ -amyloid deposits, particularly Alzheimer's disease. It is to be understood that compounds of the invention may also be used in combination with other therapeutic substances.
  • the invention provides for the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of diseases or disorders characterised by elevated ⁇ - amyloid levels or ⁇ -amyloid deposits, particularly Alzheimer's disease.
  • compositions which comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutical composition which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.
  • Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); tabletting lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); and acceptable wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • tabletting lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium starch glycollate
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents (e.g. sorbitol syrup, cellulose salts or hydrogenated edible fats), emulsifying agents (e.g. lecithin or acacia), non-aqueous vehicles (which may include edible oils e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g.
  • Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
  • fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle.
  • Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose, utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle, optionally with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents. Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, stabilising agents, solubilising agents or suspending agents. They may also contain a preservative.
  • the compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble salts, for example, as a sparingly soluble salt.
  • the compounds of the invention may be formulated as solutions for administration via a suitable metered or unitary dose device or alternatively as a powder mix with a suitable carrier for administration using a suitable delivery device.
  • compounds of the invention may be formulated for oral, buccal, parenteral, topical (including ophthalmic and nasal), depot or rectal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose).
  • the compounds of the invention may be formulated for topical administration in the form of ointments, creams, gels, lotions, pessaries, aerosols or drops (e.g. eye, ear or nose drops).
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Ointments for administration to the eye may be manufactured in a sterile manner using sterilised components.
  • the composition may contain from 0.1 % to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
  • the dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors.
  • suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three times a day. Such therapy may extend for a number of weeks or months.
  • Fig 1 Total exploration time (Tl) between objects in rat novel object recognition (NOR) assay.
  • Fig 2 Total exploration time (Tl) for treatment groups in rat NOR assay
  • Fig 3 Total exploration time (T2-24hr delay) between novel and familiar objects in rat (NOR) assay.
  • Fig 4 Discrimination (d2) index (T2-24hr delay) between objects in rat novel object recognition (NOR) assay.
  • Example 1 (Example 109 in WO06/010629)
  • Example 2 (Example 1 12 in WO06/010629) yV-[5-(cw-3,5-Dimethyl-l-piperazinyl)-2-(methyloxy)phenyl]-2-fluoro-4-(2- furanyl)benzenesulfonamide (E2)
  • Example 3 (Example 116 in WO06/010629)
  • Example 4 (Example 118 in WO06/010629) yV-[5-(m-3,5-Dimethyl-l-piperazinyl)-2-(methyloxy)phenyl]-4-(3- furanyl)benzenesulfonamide (E4)
  • Example 6 (Example 165 in WO06/010629) yV-[5-(cw-3,5-Dimethyl-l-piperazinyl)-2-(methyloxy)phenyl]-2-fluoro-4-(3- furanyl)benzenesulfonamide (E6)
  • Example 7 (Example 180 in WO06/010629)
  • Example 8 (Example 183 in WO06/010629) 2-Chloro- ⁇ 5-(ds-3,5-dimethyl-l ⁇ iperazinyl)-2-(methyloxy)pheiiyl]-4-(3- furanyl)benzenesulfonamide (E8)
  • Example 9 (Example 184 in WO06/010629)
  • Example 10 (Example 247 in WO06/010629)
  • Example 11 (Example 248 in WO06/010629)
  • Example 12 (Example 306 in WO06/010629)
  • Example 13 (Example 307 in WO06/010629)
  • Example 14 (Example 308 in WO06/010629)
  • Example 15 (Example 309 in WO06/010629) yV-[5-(c «-3,5-Dimethyl-l-piperazinyl)-2-(methyloxy)phenyl]-2-fluoro-4-(5- methyI-2-furanyl)benzenesulfonamide (El 5)
  • NOR performance is used to assess enhancement in learning and memory function.
  • Forty-eight male Lister hooded rats (BWT: 340-442g, Harlan, UK) were handled for 8 min, tail-marked, weighed, sham-dosed (p.o twice daily) and habituated for lhr to observation cages for a total of two days prior to the Tl trial.
  • the hydrochloride salt of Example 10 (0.3 or 3 mg/kg @ lmL/kg; p.o.) or vehicle 1% methylcellulose were administered p.o. 2hr prior to Tl and T2 trial.
  • mice were placed in the observation arena cage for 3 minutes, twenty four hours after Tl and presented with one familiar and one novel object (using a randomized presentation). Total exploration for each object was scored and video data was recorded.

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  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention propose l'utilisation d'un composé de formule (I) ou d'un sel pharmaceutiquement acceptable de celui-ci, pour le traitement de maladies ou de troubles caractérisés par des taux de β- amyloïde ou des dépôts de β-amyloïde élevés, en particulier la maladie d'Alzheimer.
PCT/EP2007/059473 2006-09-11 2007-09-10 Utilisation de composés de pipérazine pour le traitement de maladies neurodégénératives Ceased WO2008031799A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0617865.1A GB0617865D0 (en) 2006-09-11 2006-09-11 Novel use
GB0617865.1 2006-09-11

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WO2008031799A1 true WO2008031799A1 (fr) 2008-03-20

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018005713A1 (fr) * 2016-06-29 2018-01-04 Congxin Liang Dérivés de pipérazine en tant que modulateurs de trpml

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003072063A2 (fr) * 2002-02-28 2003-09-04 Temple University - Of The Commonwealth System Of Higher Education Sulfonanilides a substitution amino et leurs derives, destines au traitement de troubles proliferatifs
WO2006010629A1 (fr) * 2004-07-28 2006-02-02 Glaxo Group Limited Derives de piperazine convenant pour le traitement de troubles gastro-intestinaux

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003072063A2 (fr) * 2002-02-28 2003-09-04 Temple University - Of The Commonwealth System Of Higher Education Sulfonanilides a substitution amino et leurs derives, destines au traitement de troubles proliferatifs
WO2006010629A1 (fr) * 2004-07-28 2006-02-02 Glaxo Group Limited Derives de piperazine convenant pour le traitement de troubles gastro-intestinaux

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018005713A1 (fr) * 2016-06-29 2018-01-04 Congxin Liang Dérivés de pipérazine en tant que modulateurs de trpml

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