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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—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 methods for preventing and treating neurodegenerative disorders in patients in need thereof by administering a pharmaceutical composition comprising a compound of general formula I
• the present invention relates to the use of a compound of general formula I according to this invention for preparing a pharmaceutical composition for preventing and treating neurodegenerative disorders.
• Pyrazole-O-glycoside derivatives inhibit the sodium-dependent glucose cotransporters (SGLT), in particular SGLT2.
• SGLT sodium-dependent glucose cotransporters
• Reuptake of filtered glucose across epithelial cells of the kidney proceeds via sodium-dependent glucose cotransporters (SGLTs) located in the brush-border membranes in the proximal tubuli along the sodium gradient (1) .
• SGLTs sodium-dependent glucose cotransporters
• SGLT2 is exclusively expressed in the kidney (3) .
• AD Alzheimer's disease
• cognitive deficits including worsening of memory, judgement, and comprehension and deterioration in global functioning.
• motor, sensory, and linguistic abilities are also affected until there is global impairment of multiple cognitive functions. These cognitive losses occur gradually, but typically lead to severe impairment and eventual death in the range of four to twelve years. Current treatments are not efficacious in every patient.
• An aim of the present invention is to find a new method for treating of neurodegenerative disorders, in particular of a dementia.
• Another aim of the present invention is to find a new method for preventing or slowing, delaying or reversing progression of neurodegenerative disorders, in particular of a dementia.
• a further aim of the present invention is to find a new therapeutic use of a glucopyranosyloxy- pyrazole derivative.
• a further aim of the present invention is to provide new pharmaceutical compositions which are suitable for the treatment of neurodegenerative disorders, in particular dementia.
• the present invention relates to a method for treating of one or more neurodegenerative disorders in a patient in need thereof wherein said method comprises administering a glucopyranosyloxy-pyrazole of general formula (I)
• R 1 denotes hydrogen, Ci -6 -alkyl, a Ci -4 -alkyl group substituted by 1 to 3 fluorine atoms, a C 2- 4 -alkyl group substituted by a hydroxy or a Ci -3 -alkoxy group, C 3-6 -alkenyl, C 3-6 -cycloalkyl, Cs- ⁇ -cycloalkyl-d-s-alkyl, C 3- 6-alkynyl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranyl-Ci -3 -alkyl, or tetrahydropyranyl-Ci -3 -alkyl, and
• R 2 denotes Ci -4 -alkyl, a Ci -4 -alkyl group substituted by 1 to 3 fluorine atoms, or C 3-6 - cycloalkyl, and
• R 3 denotes hydrogen, fluorine, chlorine, bromine, Ci -6 -alkyl, C 2- 6-alkenyl, C 2- 6-alkynyl, C 3-6 - cycloalkyl, Cs-e-cycloalkylidenemethyl, Ci -6 -alkoxy, Cs-6-cycloalkyl-oxy, C 3-6 -cycloalkyl-Ci.
• R 4 and R 5 which may be identical or different, represent hydrogen, fluorine, chlorine, bromine, Ci -3 -alkyl, Ci -3 -alkoxy, a methyl or methoxy group substituted by 1 to 3 fluorine atoms, and
• R b , R' a , - A - R 7b , R 7c independently of one another have a meaning selected from the group hydrogen, (Ci -8 -alkyl)carbonyl, (Ci -8 -alkyl)oxycarbonyl, arylcarbonyl and aryl-(Ci -3 -alkyl)- carbonyl,
• R h denotes a fluorine, chlorine, bromine, iodine, C- ⁇ -3-alkyl, difluoromethyl, trifluoromethyl, d-3-alkoxy, difluoromethoxy, trifluoromethoxy or cyano,
• alkyl groups may be straight-chain or branched
• the present invention relates to a method for preventing or slowing, delaying or reversing progression of one or more neurodegenerative disorders in a patient in need thereof wherein said method comprises administering a glucopyranosyloxy-pyrazole of general formula (I), a tautomer, stereoisomer, mixture or salt thereof, as defined hereinbefore and hereinafter to the patient in need thereof.
• Another aspect of the present invention relates to the use of a glucopyranosyloxy-pyrazole of general formula (I), a tautomer, stereoisomer, mixture or salt thereof, as defined hereinbefore and hereinafter for the manufacture of a medicament for the treatment of one or more neurodegenerative disorders.
• a glucopyranosyloxy-pyrazole of general formula (I) a tautomer, stereoisomer, mixture or salt thereof, as defined hereinbefore and hereinafter for the manufacture of a medicament for the treatment of one or more neurodegenerative disorders.
• Another aspect of the present invention relates to the use of a glucopyranosyloxy-pyrazole of general formula (I), a tautomer, stereoisomer, mixture or salt thereof, as hereinbefore and hereinafter for the manufacture of a medicament for preventing or slowing, delaying or reversing progression of one or more neurodegenerative disorders.
• a glucopyranosyloxy-pyrazole of general formula (I) a tautomer, stereoisomer, mixture or salt thereof
• Another aspect of the present invention relates to a pharmaceutical composition for the treatment of one or more neurodegenerative disorders comprising a glucopyranosyloxy- pyrazole of general formula (I), a tautomer, stereoisomer, mixture or salt thereof, as defined hereinbefore and hereinafter.
• a pharmaceutical composition for the treatment of one or more neurodegenerative disorders comprising a glucopyranosyloxy- pyrazole of general formula (I), a tautomer, stereoisomer, mixture or salt thereof, as defined hereinbefore and hereinafter.
• Another aspect of the present invention relates to a pharmaceutical composition for preventing or slowing, delaying or reversing progression of one or more neurodegenerative disorders
• a pharmaceutical composition for preventing or slowing, delaying or reversing progression of one or more neurodegenerative disorders comprising a glucopyranosyloxy-pyrazole of general formula (I), a tautomer, stereoisomer, mixture or salt thereof, as defined hereinbefore and hereinafter.
• the group R 1 preferably denotes hydrogen, Ci -4 -alkyl, a Ci -3 -alkyl group substituted by 1 to 3 fluorine atoms, C 3-6 -cycloalkyl, Cs-e-cycloalkyl-methyl, C 3-6 -alkynyl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranyl-methyl, tetrahydropyranyl-methyl.
• R 1 Even more preferred meanings of the group R 1 are H, methyl, ethyl, n-propyl, i-propyl, 2- propyn-1-yl, 2-butyn-1-yl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranylmethyl and tetrahydropyranylmethyl.
• Preferred meanings of the group R 2 according to the invention are methyl and trifluoromethyl, particularly methyl.
• Preferred meanings of the group R 3 are hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, tert. -butyl, 2-cyano-2-propyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, 1 ,1 ,2,2- tetrafluoroethoxy, cyclopropyl-oxy, cyclobutyl-oxy, cyclopentyl-oxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethyloxy, tetrahydropyranyl-methyloxy, ethynyl.
• Most particularly preferred meanings of the group R 3 are fluorine, chlorine, methyl, ethyl, isopropyl, tert. -butyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy.
• Preferred meanings of the group R 4 are hydrogen and fluorine.
• Preferred meanings of the group R 5 are hydrogen and fluorine.
• R 4 or R 5 denotes fluorine.
• the group R 6 according to the invention preferably denotes hydrogen, (Ci -8 -alkyl)oxycarbonyl or d- ⁇ -alkylcarbonyl, particularly H or (Ci -6 -alkyl)oxycarbonyl, particularly preferably H, methoxycarbonyl or ethoxycarbonyl.
• R 7a , R 7b , R 7c independently of one another preferably represent hydrogen or (Ci -8 -alkyl)carbonyl, particularly hydrogen or (Ci -8 -alkyl)carbonyl, particularly preferably hydrogen, methylcarbonyl or ethylcarbonyl. Most preferably, R 7a , R 7b and R 7c represent hydrogen.
• R 1 , R 3 , R 4 , R 5 and R 6 are defined in the following Table 1 are particularly preferred, wherein Me denotes methyl and Et denotes ethyl.
• halogen denotes an atom selected from the group consisting of F, Cl, Br and I, particularly F, Cl and Br.
• Ci -n -alkyl wherein n may have a value of 2 to 8, denotes a saturated, branched or unbranched hydrocarbon group with 1 to n C atoms.
• examples of such groups include methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, n-hexyl, iso-hexyl, etc.
• Ci -n -alkylene wherein n may have a value of 2 to 8, denotes a saturated, branched or unbranched hydrocarbon bridge with 1 to n C atoms.
• groups include methylene (-CH 2 -), ethylene (-CH 2 -CH 2 -), 1-methyl-ethylene (-CH(CH 3 )-CH 2 -), 1 ,1-dimethyl- ethylene (-C(CHs) 2 -CH 2 -), n-prop-1 ,3-ylene (-CH 2 -CH 2 -CH 2 -), 1-methylprop-1 ,3-ylene (- CH(CHa)-CH 2 -CH 2 -), 2-methylprop-1 ,3-ylene (-CH 2 -CH(CH 3 )-CH 2 -), etc., as well as the corresponding mirror-symmetrical forms.
• groups include vinyl, 1-propenyl, 2-propenyl, iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1- propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2- hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl etc..
• C 2-n -alkynyl wherein n has a value of 3 to 6, denotes a branched or unbranched hydrocarbon group with 2 to n C atoms and a C ⁇ C triple bond.
• groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 2-methyl-1-propynyl, 1- pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5- hexynyl etc..
• Ci -n -alkoxy or Ci -n -alkyloxy denotes a Ci -n -alkyl-0 group, wherein Ci -n -alkyl is as hereinbefore defined.
• groups include methoxy, ethoxy, n-propoxy, iso- propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, neo-pentoxy, tert-pentoxy, n-hexoxy, iso-hexoxy etc.
• groups include methylcarbonyl, ethylcarbonyl, n- propylcarbonyl, iso-propylcarbonyl, n-butylcarbonyl, iso-butylcarbonyl, sec-butylcarbonyl, tert- butylcarbonyl, n-pentylcarbonyl, iso-pentylcarbonyl, neo-pentylcarbonyl, tert-pentylcarbonyl, n- hexylcarbonyl, iso-hexylcarbonyl, etc..
• C 3-n -cycloalkyl denotes a saturated mono-, bi-, tri- or spirocarbocyclic group with 3 to n C atoms.
• groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo[3.2.1.]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl, etc.
• C 3-7 -cycloalkyl denotes saturated monocyclic groups.
• C 5-n -cycloalkenyl denotes a monounsaturated mono-, bi-, tri- or spirocarbocyclic group with 5 to n C atoms.
• groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, etc.
• Cs- n -cycloalkyloxy denotes a Cs- n -cycloalkyl-O group, wherein C 3 - n -cycloalkyl is as hereinbefore defined. Examples of such groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc.
• the compounds according to the invention may be obtained using methods of synthesis known in principle.
• the compounds are obtained by methods as described for example in WO 02/36602, WO 02/088157, WO 01/16147, WO 02/053573, WO 02/068439, WO 02/068440, WO 02/098893, WO 05/021566 and in the literature cited therein.
• the compounds of general formula I according to the invention and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly an inhibitory effect on the sodium-dependent glucose cotransporter SGLT, preferably SGLT2.
• the compounds according to the invention of general formula I and the physiologically acceptable salts thereof are potential therapeutic agents in the treatment and/or prevention of neurodegenerative disorders, in particular dementia.
• Dementia is characterized by the development of multiple cognitive deficits and memory impairment.
• Such cognitive deficits may include one or more of aphasia, apraxia, agnosia and disturbance in executive functioning (see for example "Diagnostic and statistical manual of mental disorders", 4 th edition, American Psychiatric Association, 2000).
• the compounds according to this invention are potentially valuable in the treatment of one or more neurodegenerative disorders and in preventing or slowing, delaying or reversing progression of one or more neurodegenerative disorders in a patient in need thereof.
• the patient whose illness or condition is to be treated or prevented according to the invention is a mammal, particularly a human being.
• the term patient comprises an individual diagnosed to have a neurodegenerative disorder, in particular a dementia, especially dementia of the Alzheimer type.
• patient also comprises an individual diagnosed to have an increased risk to develop a neurodegenerative disorder, in particular a dementia, especially dementia of the Alzheimer type.
• the term neurodegenerative disorder denotes in particular dementia.
• dementia comprises dementia of the Alzheimer type, vascular dementia, dementia in Parkinson and dementia due to other general medical conditions.
• Dementia due to other medical conditions comprises dementia in chorea Huntington, dystonias, degenerative ataxias, AIDS-related dementia, Creutzfeld-Jakob's syndrome, bovine spongiform encephalopathy, prion-related infections, diseases involving mitochondrial dysfunction, Down's syndrome, hepatic encephalopathy, amyotrophic lateral sclerosis, multiple sclerosis, olivoponto-cerebellar atrophy, post-operative cognitive deficit, mild cognitive impairment, hypoxia, ischaemia resulting from cardiac arrest, stroke, glioma and other tumours, attention deficit hyperactivity disorder, autism, convulsions, epilepsy, Korsakoff syndrome, depression and schizophrenia.
• the course of dementia of the Alzheimer Type is characterized by gradual onset and continuing cognitive decline.
• the compounds according to this invention may improve cognitive abilities and memory, in particular in a patient as defined hereinbefore. Therefore by the administration of a compound to a patient according to this invention a cognitive decline or memory impairment may be attenuated, slowed, delayed or even reversed.
• the Morris water maze is a device to investigate spatial learning and memory in rodents. It consists of a large circular pool filled with opaque water in which a small escape platform is submerged underneath the water surface. During a number of training trials, animals learn to find the platform and escape from the pool, using the different extra- maze cues contained in the experimental room. Details are described by D'Hooge R. and De Deyn P.P. (2001 ) "Applications of the Morris water maze in the study of learning and memory.”, Brain Research Reviews 36, 60-90.
• Another method to test cognitive abilities is based on contextual fear conditioning.
• Classical fear conditioning is a reference task to investigate fear memory. It is assessed in operant chambers where the animals receive a mild electric shock. The association between the experimental chamber and the shock is tested 24 hours later by returning the animals in the chambers in which training occurred (context) and measuring their freezing behaviour, i.e. the tendency of the animals to remain in motionless, defensive posture. Details are described by Kim JJ. and Jung M. W. (2006) "Neural circuits and mechanisms involved in Pavlovian fear conditioning: A critical review.”, Neuroscience and Biobehavioral Reviews 30, 188-202.
• a further test of cognitive abilities is related to the recognition of novel objects.
• the test is based on differential exploration of familiar and new objects.
• T1 first trial
• T2 second Trial
• two dissimilar objects two dissimilar objects, a familiar (the sample) and a new one.
• Increased exploration of the novel object is a measure of recognition memory.
• Prickaerts J. et al. (2004) "Phosphodiesterase type 5 inhibition improves early memory consolidation of object information", Neurochemistry International 45, 915-928.
• the aforementioned tests of cognitive abilities can also be performed with Alzheimer disease animal models, for example with a transgenic mouse model, such as the Tg2576 mice.
• the dosage required to achieve the corresponding activity for treatment or prevention usually depends on the compound which is to be administered, the patient, the nature and gravity of the illness or condition and the method and frequency of administration and is for the patient's doctor to decide.
• the dosage may be from 1 to 500 mg, preferably 1 to 100 mg, by intravenous route, and 1 to 1000 mg, preferably 10 to 600 mg, by oral route, in each case administered 1 to 4 times a day.
• the compounds of formula I prepared according to the invention may be formulated, optionally together with other active substances, together with one or more inert conventional carriers and/or diluents, e.g.
• active substance denotes a pyrazole-O-glucoside derivative according to this invention.
• Example 1 Dry ampoule containing 75 mg of active substance per 10 ml
• Active substance and mannitol are dissolved in water. After packaging the solution is freeze- dried. To produce the solution ready for use, the product is dissolved in water for injections.
• Example 2 Dry ampoule containing 35 mg of active substance per 2 ml
• Active substance and mannitol are dissolved in water. After packaging, the solution is freeze- dried. To produce the solution ready for use, the product is dissolved in water for injections.
• Example 3 Tablet containing 50 mg of active substance Composition:
• Example 4 Tablet containing 350 mg of active substance
• Example 5 Capsules containing 50 mg of active substance Composition:
• Example 6 Capsules containing 350 mg of active substance Composition:
• Example 7 Suppositories containing 100 mg of active substance Composition:

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