WO2000037082A1 - Utilisation d'antagonistes du recepteur 5-ht7 pour le traitement de la degenerescence neuronale due a des accidents ischemiques - Google Patents

Utilisation d'antagonistes du recepteur 5-ht7 pour le traitement de la degenerescence neuronale due a des accidents ischemiques Download PDF

Info

Publication number
WO2000037082A1
WO2000037082A1 PCT/EP1999/010174 EP9910174W WO0037082A1 WO 2000037082 A1 WO2000037082 A1 WO 2000037082A1 EP 9910174 W EP9910174 W EP 9910174W WO 0037082 A1 WO0037082 A1 WO 0037082A1
Authority
WO
WIPO (PCT)
Prior art keywords
receptor antagonists
neuronal degeneration
methyl
degeneration resulting
receptor
Prior art date
Application number
PCT/EP1999/010174
Other languages
English (en)
Inventor
Peter Machin
Original Assignee
Smithkline Beecham P.L.C.
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 Smithkline Beecham P.L.C. filed Critical Smithkline Beecham P.L.C.
Priority to AU24334/00A priority Critical patent/AU2433400A/en
Publication of WO2000037082A1 publication Critical patent/WO2000037082A1/fr

Links

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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to the use of 5-HT7 receptor antagonists as neuroprotectants. More particularly, the present invention relates to the use of 5-HT7 5 receptor antagonists in the treatment and/or prophylaxis of stroke.
  • 5-HT ⁇ receptors have been cloned from rat 1 ' 2 ' 3 , mouse 4 , guinea-pig 5 and human 6 cDNA and exhibit a high degree of interspecies homology (95%). 5-HT7 receptors are positively coupled to adenylate cyclase in recombinant systems 1 ' 2 ' 3 ' 6 ,
  • the receptor possesses moderate affinity (pKi 6.7 - 7.9) for the antagonists 8-OH-DPAT (8-hydroxy-2-
  • 5-HT7 receptor mRNA The greatest abundance of 5-HT7 receptor mRNA is in the brain where it is discretely localised within thalamus, hypothalamus and various limbic and cortical regions 1 ' 3 ' 6 ' 8 . Autoradiographic techniques confirm that the distribution of 5-HT7 binding sites in rat and guinea-pig brain 8 ' 9 ' 1 1 matches the mRNA distribution.
  • 5-HT is released as a consequence of focal cerebral ischaemia and ischaemic damage has been reported to be ameliorated by drugs such as ( + ) 8-hydroxy-2- dipropylaminotetralin (8-OH-DPAT).
  • 8-OH-DPAT is known as a selective 5-HT ⁇ A receptor agonist and this receptor subtype was thought to mediate its neuroprotective effects 12 .
  • 8-OH-DPAT can act, in some systems, as a
  • Patent applications WO 97/29097, WO 97/48681 and WO 97/49695 all disclose compounds that are claimed to possess 5-HT7 receptor antagonist activity and which are useful in the treatment of various CNS disorders.
  • the compound (R)-3, N-Dimethyl-N- [l-methyl-3-(4-methyl-piperidin-l-yl)propyl] benzenesulfonamide is claimed to be the
  • the present invention therefore provides, in a first aspect, the use of a 5-HT 7 receptor antagonist in the manufacture of a medicament for use in the treatment and/or prophylaxis of disorders associated with neuronal degeneration resulting from ischaemic events in mammals, such as humans.
  • Suitable ischaemic events include cerebral ischaemia after cardiac arrest, stroke and multi-infarct dementia. Further ischaemic events include cerebral ischaemia which may result from surgery and also those which may occur in newborns during birth.
  • a 5-HT7 antagonist for use in this invention must be selective for 5-HT7 receptors. Where used herein, this is intended to mean that the 5-HT7 antagonist must have a greater than 30-fold selectivity for this receptor over other binding sites within the CNS, in particular, other 5-HT receptor sub-types and dopaminergic receptors.
  • the most preferred compounds of this invention demonstrate greater than 100-fold selectivity for 5- HT7 receptors.
  • the selectivity of the compounds of this invention for 5-HT7 receptors can be determined using binding assays methods which are well known to those skilled in the art.
  • Preferred compounds of this invention include those specifically and generically disclosed in WO 97/29097, WO 97/48681 and WO 97/49695 (all in the name of SmithKline Beecham pic).
  • Other preferred compounds include those generically and specifically disclosed in patent applications WO 98/00400 and WO 99/33804 (both in the name of Meiji Seika Kaisha Ltd).
  • Particularly preferred compounds for use in this invention include: (R)-l-[(3-Hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-l-piperidinyl)ethyl]pyrrolidine, (R)-3 , N-Dimethyl-N-[ 1 -methyl-3-(4-methyl-piperidin- 1 -yl)propyl]-benzenesulfonamide or a pharmaceutically acceptable salt thereof.
  • Such compounds can be prepared by methods described in WO 97/48681 and WO 97/29097 respectively.
  • Certain compounds exhibiting 5-HT7 antagonist activity are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of these compounds and the mixtures thereof including racemates. Tautomers also form an aspect of the invention.
  • Certain compounds exhibiting 5-HT 7 antagonist activity can usually form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, sulphate, citric, lactic, mandelic, tartaric and methanesulphonic. Salts of 5-HT 7 receptor antagonists therefore form an aspect of the invention.
  • the present invention further provides a method for the treatment and/or prophylaxis of disorders associated with neuronal degeneration resulting from ischaemic events in mammals which comprises administering to a host in need thereof an effective amount of a 5-HT7 receptor antagonist or a pharmaceutically acceptable salt thereof.
  • the 5-HT7 receptor antagonists are usually formulated in a standard pharmaceutical composition. Such compositions can be prepared using standard procedures.
  • a pharmaceutical composition of the invention 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, fillers, tabletting lubricants, disintegrants and acceptable wetting agents.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • 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, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colorants.
  • fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle.
  • 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.
  • 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 a day. Such therapy may extend for a number of weeks or months.
  • the following pharmacological data illustrate the neuroprotectant acivity in tests which are indicative of compounds of potential use in the treatment of the invention.
  • NMF neutral buffered formalin
  • a target plasma concentration of approximately 0.03uM (89 ug/kg/h for 23h) produced a significant reduction in lesion size.
  • Vehicle treated animals exhibited a total infarct volume of 207 +_11 mm 3 and animals treated with Compound A exhibited a total infarct of 176 + 9 mm 3 .

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

L'invention concerne un nouveau traitement médical et notamment le traitement ou la prophylaxie des troubles associés à la dégénérescence neuronale due à des accidents ischémiques aigus.
PCT/EP1999/010174 1998-12-18 1999-12-13 Utilisation d'antagonistes du recepteur 5-ht7 pour le traitement de la degenerescence neuronale due a des accidents ischemiques WO2000037082A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU24334/00A AU2433400A (en) 1998-12-18 1999-12-13 Use of 5-ht7 receptor antagonists for treating neuronal degeneration resulting from ischemic events

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9828004.3 1998-12-18
GBGB9828004.3A GB9828004D0 (en) 1998-12-18 1998-12-18 Use

Publications (1)

Publication Number Publication Date
WO2000037082A1 true WO2000037082A1 (fr) 2000-06-29

Family

ID=10844566

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1999/010174 WO2000037082A1 (fr) 1998-12-18 1999-12-13 Utilisation d'antagonistes du recepteur 5-ht7 pour le traitement de la degenerescence neuronale due a des accidents ischemiques

Country Status (3)

Country Link
AU (1) AU2433400A (fr)
GB (1) GB9828004D0 (fr)
WO (1) WO2000037082A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008013556A1 (fr) 2006-07-27 2008-01-31 Janssen Pharmaceutical N.V. Multithérapie avec antagoniste du récepteur 5-ht7 et inhibiteur du recaptage de la sérotonine
US7683077B2 (en) 2003-05-20 2010-03-23 Ajinomoto Co., Inc. Piperidine derivative
US8618288B2 (en) 2003-09-17 2013-12-31 Janssen Pharmaceutica Nv Pyrimidine compounds as serotonin receptor modulators
WO2020065090A3 (fr) * 2018-09-28 2020-05-07 Medizinische Hochschule Hannover (Mhh) Traitement de tauopathies associées à une démence

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997029097A1 (fr) * 1996-02-09 1997-08-14 Smithkline Beecham Plc Derives de sulfonamide en tant qu'antagonistes du recepteur de 5ht¿7?
WO1997048681A1 (fr) * 1996-06-20 1997-12-24 Smithkline Beecham Plc Derives du sulfonamide et leur utilisation dans le traitement des troubles du systeme nerveux central
WO1997049695A1 (fr) * 1996-06-25 1997-12-31 Smithkline Beecham P.L.C. Derives de sulfonamide utilises comme antagonistes du recepteur 5ht7
WO1998000400A1 (fr) * 1996-06-28 1998-01-08 Meiji Seika Kaisha, Ltd. Composes de tetrahydrobenzindole
WO1999033804A1 (fr) * 1997-12-25 1999-07-08 Meiji Seika Kaisha, Ltd. Derives de tetrahydrobenzindole
WO1999059499A2 (fr) * 1998-05-19 1999-11-25 Alcon Laboratories, Inc. Composes a affinite pour le recepteur de 5ht7 serotoninergique, destines au traitement de troubles oculaires et du systeme nerveux central

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997029097A1 (fr) * 1996-02-09 1997-08-14 Smithkline Beecham Plc Derives de sulfonamide en tant qu'antagonistes du recepteur de 5ht¿7?
WO1997048681A1 (fr) * 1996-06-20 1997-12-24 Smithkline Beecham Plc Derives du sulfonamide et leur utilisation dans le traitement des troubles du systeme nerveux central
WO1997049695A1 (fr) * 1996-06-25 1997-12-31 Smithkline Beecham P.L.C. Derives de sulfonamide utilises comme antagonistes du recepteur 5ht7
WO1998000400A1 (fr) * 1996-06-28 1998-01-08 Meiji Seika Kaisha, Ltd. Composes de tetrahydrobenzindole
WO1999033804A1 (fr) * 1997-12-25 1999-07-08 Meiji Seika Kaisha, Ltd. Derives de tetrahydrobenzindole
WO1999059499A2 (fr) * 1998-05-19 1999-11-25 Alcon Laboratories, Inc. Composes a affinite pour le recepteur de 5ht7 serotoninergique, destines au traitement de troubles oculaires et du systeme nerveux central

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7683077B2 (en) 2003-05-20 2010-03-23 Ajinomoto Co., Inc. Piperidine derivative
US8618288B2 (en) 2003-09-17 2013-12-31 Janssen Pharmaceutica Nv Pyrimidine compounds as serotonin receptor modulators
US7598255B2 (en) 2005-08-04 2009-10-06 Janssen Pharmaceutica Nv Pyrimidine compounds as serotonin receptor modulators
US8883808B2 (en) 2005-08-04 2014-11-11 Janssen Pharmaceutica N.V. Combination of 5-HT7 receptor antagonist and serotonin reuptake inhibitor therapy
WO2008013556A1 (fr) 2006-07-27 2008-01-31 Janssen Pharmaceutical N.V. Multithérapie avec antagoniste du récepteur 5-ht7 et inhibiteur du recaptage de la sérotonine
WO2020065090A3 (fr) * 2018-09-28 2020-05-07 Medizinische Hochschule Hannover (Mhh) Traitement de tauopathies associées à une démence

Also Published As

Publication number Publication date
AU2433400A (en) 2000-07-12
GB9828004D0 (en) 1999-02-10

Similar Documents

Publication Publication Date Title
HUT76852A (en) Use of benzotiophene derivatives for production of pharmaceutical compositions useful for inhibiting conditions associated with neuro-peptide y
EP0977558B1 (fr) Utilisation d'antagonistes du recepteur de 5ht4 pour lutter contre les effets gastro-intestinaux d'inhibiteurs de reabsorption de la serotonine
JPH10513463A (ja) うっ血性心不全の治療へのカルバゾール化合物の利用
BRPI0609952A2 (pt) métodos para modular a função da bexiga
JPH0555484B2 (fr)
CZ284363B6 (cs) Použití protikřečových činidel k přípravě léčiv určených k léčení Parkinsonovy choroby a Parkinsonových syndromů
JPH0393718A (ja) 早発射精治療剤
AU653521B2 (en) Use of 5-HT4 receptor antagonists in the treatment of arrythmias and stroke
JP4324266B2 (ja) α１Ａアドレナリン受容体の変異体、当該変異体を用いた測定方法及び前立腺肥大に伴う排尿困難症治療剤
JPH07223948A (ja) ターナー症候群を抑制するための医薬組成物
WO1992000103A1 (fr) Preparations pharmaceutiques
WO2000037082A1 (fr) Utilisation d'antagonistes du recepteur 5-ht7 pour le traitement de la degenerescence neuronale due a des accidents ischemiques
US5049588A (en) Novel treatment for ischemia using an aminotetralin
IE83342B1 (en) Use of a 5-HT4-receptor antagonists in the treatment of atrial fibrillation, including the prevention of stroke
EP0617620B1 (fr) Utilisation d'antagonistes au recepteur 5-ht 4 pour fabriquer un medicament pour le traitement de l'incontinence urinaire
CZ285633B6 (cs) Použití indolových derivátů pro výrobu léčiv a farmaceutický prostředek
US5162375A (en) Treatment of neuronal degeneration with 5HT1A agonists
PT1441723E (pt) Utilização do irbesartan para a prevenção ou o tratamento da hipertensão pulmonar
WO1998004261A1 (fr) Utilisation de la nefazodone dans la prophylaxie de la migraine
US6750195B2 (en) Use of 5-HT4 modulators for the manufacture of a medicament for the treatment of the bladder diseases
EP1104301B1 (fr) Traitement des psychoses et des symptômes neuropsychiatriques associés à la maladie d'Alzheimer
WO1993014745A1 (fr) Utilisation d'antagonistes de recepteur de 5-ht4 comme medicaments pour traiter la migraine
JPH04247036A (ja) 縮瞳をおこすことなく眼圧を下げる治療方法
JP2004262812A (ja) 眼圧低下剤
HUT77381A (hu) Eljárás növekedési hormonok hatásainak inhibiálására alkalmas benzotiofén-származékokat tartalmazó gyógyszerkészítmények előállítására

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
CFP Corrected version of a pamphlet front page

Free format text: REVISED ABSTRACT RECEIVED BY THE INTERNATIONAL BUREAU AFTER COMPLETION OF THE TECHNICAL PREPARATIONS FOR INTERNATIONAL PUBLICATION