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WO2000003714A1 - Produit medicinal et procede de traitement et de prevention de la dyskinesie - Google Patents

Produit medicinal et procede de traitement et de prevention de la dyskinesie Download PDF

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Publication number
WO2000003714A1
WO2000003714A1 PCT/SE1999/001274 SE9901274W WO0003714A1 WO 2000003714 A1 WO2000003714 A1 WO 2000003714A1 SE 9901274 W SE9901274 W SE 9901274W WO 0003714 A1 WO0003714 A1 WO 0003714A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkenyl
dyskinesia
alkyl
treatment
cycloalkyl
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/SE1999/001274
Other languages
English (en)
Inventor
Ross Nicholas Waters
Clas Åke SONESSON
Arvid Carlsson
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.)
Neurosearch Sweden AB
Original Assignee
A Carlsson Research AB
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 A Carlsson Research AB filed Critical A Carlsson Research AB
Priority to JP2000559849A priority Critical patent/JP2002520361A/ja
Priority to AU54568/99A priority patent/AU5456899A/en
Priority to EP99940783A priority patent/EP1096935A1/fr
Priority to CA002336998A priority patent/CA2336998A1/fr
Priority to BR9912051-8A priority patent/BR9912051A/pt
Publication of WO2000003714A1 publication Critical patent/WO2000003714A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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

Definitions

  • the present invention relates to the use of specific substituted 3-phenylpiperidines and 3-penylpyrrolidine analogs, for the production of a medicinal product for treatment and/or prevention of dyskinesia, such as tremor, dystonia or chorea.
  • Dyskinesia is characterised by involuntary movements affecting all parts of the body. Depending on the type of involuntary movement, dyskinesia can be divided into several different categories. Involuntary movements characterised by muscle activity leading to a state of irregular contractions of various parts of the body is gener- ally referred to as chorea, whereas dystonia is a condition characterised by sustained involuntary muscle contractions. Tremor is characterised by fine oscillating movements of higher frequency.
  • Dyskinesia may be the result of functional, struc- tural or pharmacologically-induced changes within certain areas of the brain. Dopamine is an abundant neurotrans- mitter closely linked to the control of movements. It is therefore plausible that drugs affecting the dopaminergic system have effects in these conditions. Dyskinesia is e.g. common in patients suffering of Huntington's disease. Huntington's disease is a hereditary neurodegenerative disorder affecting fronto-striatal neuronal systems. The clinical manifestations of the disorder include a wide variety of movement disorders in- eluding symptoms such as tremor, dystonia and chorea.
  • substituted 3-phenylpiperidine or 3-penyl- pyrrolidine analogs used according to the invention have the ability to modulate dopaminergic transmission by both direct and indirect interactions with dopamine receptors and will thus be useful in the treatment of dyskinesia.
  • Ri is S0 2 R 4 , OS0 2 R 4 , S0 2 NR 4 R 5 , COR 4 , CN, CF 3 , halogen, or H;
  • R 2 in position 2, 4, 5 or 6 is H, F, Cl , Br, or I ;
  • R 3 is H, CF 3 , CH 2 CF 3 , a C ⁇ C g alkyl, a C 3 -C 8 cycloalkyl, a C 4 -C 9 cycloalkylmethyl , a C 2 -C 8 alkenyl, a C 2 -C 8 alkynyl, 3, 3 , 3-trif luoropropyl, 4 , 4 , 4-trif luorobutyl , -(CH 2 ) m -R 6 (wherein m is 1-8) , or CH 2 SCH 3 ;
  • R 4 and R 5 are independently H, CF 3 , CH 2 CF 3 , a C 1 -C 8 alkyl, a C 3 -C 8 cycloalkyl, a C 4 -C 9 cycloalkylmethyl, a C 2 -C 8 alkenyl, a C 2 -C 8 alkynyl, 3 , 3 , 3-trif luoropropyl , 4,4, 4-trif luorobutyl, -(CH 2 ) m -R 6 (where m is 1-8), or pheny 1 ;
  • R 6 is phenyl, phenyl substituted with a CN, CF 3 , S0 2 CH 3 , halogen, CH 2 CF 3 , alkyl, C 3 -C 8 cycloalkyl, C 4 -C 9 cycloalkylmethyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkenyl, 2-thiophenyl , 3-thiophenyl, NR 7 C0NR 8 R 9 , or -C0NR 7 R 8 ;
  • R 7 , R 8 and R 9 are independently H, C ⁇ C,, alkyl, C 3 -C 8 cycloalkyl, C 4 -C 9 cycloalkylmethyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkynyl, or a pharmaceutically acceptable salt thereof, for the production of a medicinal product for treatment and/or prevention of dyskinesia, such as tremor, dystonia or chorea .
  • the present invention also relates to a method for treatment and/or prevention of dyskinesia, such as tremor, dystonia or chorea, said method comprising ad- ministration an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof .
  • the compounds used according to the present invention possess pharmacological effects, direct or indirect, on dopamine receptors. Among the different dyskinesias, e.g.
  • idiopatic torsion dystonia including the focal seg- mental and generalised dystonias, cerebral paresis, he- reditary dystonias, dystonia caused by hereditary metabolic diseases such as Wilson's disease, neuroleptic induced movement disorders, dyskinesias in schizophrenia, stuttering, movement disorders due to stroke, only L-DOPA induced dyskinesias show a direct relation to dopamin overactivity. In dyskinesias with other underlying patho- pysiology, dopamine receptor overactivity has not been shown. Therefore the effect of the compounds used according to the invention of dystonias, tremor and chorea in e.g. Huntington's disease is surprising.
  • the compounds used according to the invention may be both racemic mixtures and the pure enantiomers.
  • preferred compounds have the S absolute configuration, according to the Cahn-Ingold- Prelog priority rules. Depending on the N-substituent , some of these S-enantiomers are dextrorotatory while others are levorotatory.
  • patient refers to an individual in need of the treatment and/or prevention according to the invention.
  • C m -C n relates to compounds consisting of m-n carbon atoms, for example a C ⁇ C g alkyl refers to an alkyl containing 1-8 carbon atoms in any isomeric form.
  • the various carbon moieties are defined as follows.
  • Alkyl refers to an aliphatic hydrocarbon radical and includes branched or unbranched forms such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t- butyl, n-pentyl, i-pentyl, neo-pentyl, n-hexyl, i-hexyl, n-heptyl, i-heptyl and n-octyl .
  • Alkenyl refers to a radical of an aliphatic unsaturated hydrocarbon having a double bond and includes both branched and unbranched forms such as ethenyl, 1-methyl-1-ethenyl, 1-propenyl, 2- propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-l- butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl -4 -pentenyl, 3 -methyl -1-pentenyl, 3 -methyl-2- pentenyl , 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 1- methyl-4-hexenyl, 3 -methyl-1-hexenyl, 3 -methyl -2-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-methyl- 4-hepten
  • Cycloalkyl refers to a radical of a saturated cyclic hydrocarbon such as cyclo- propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl .
  • the compounds used according to the invention contain one chiral centre.
  • the compounds according to formula I contain an asymmetric carbon atom in the aliphatic ring moiety (carbon 3 in the heterocyclic ring relative to phenyl ring junction) . Some of these compounds have DA receptor modulating properties. Some of the therapeutic effects lies in the modulation of dopamine receptor properties.
  • the scope of this invention includes both the S and the R enantiomers of the compounds of formula I in their pure form, as well as mixtures thereof ..
  • Both organic and inorganic acids can be employed to form non-toxic pharmaceutically acceptable acid addition salts of the compounds of this invention.
  • Illustrative acids are sulfuric, nitric, phosphoric, hydrochloric, citric, acetic, lactic, tartaric, pamoic, ethanedisul- fonic, sulfamic, succinic, cyclohexylsulfamic, fumaric, maleic, and benzoic acid.
  • These salts are readily prepared by methods known in the art .
  • the compounds used according to the invention may e.g. be obtained by one of the methods in the Interna- tional Patent Publication WO 92/18475.
  • the medicinal product containing a compound according to the invention may also comprise substances used to facilitate the production of the pharmaceutical preparation or the administration of the preparations.
  • substances used to facilitate the production of the pharmaceutical preparation or the administration of the preparations are well known to people skilled in the art and may for example be pharmaceutically acceptable adjuvants, carriers and preservatives.
  • the compounds used according to the present invention will normally be administered orally, rectally, or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically acceptable non-toxic, acid addition salt, such as the hydrochloride, lactate, acetate, sulfamate salt, in association with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable non-toxic, acid addition salt such as the hydrochloride, lactate, acetate, sulfamate salt
  • an effective amount or a therapeutic amount of the compounds of the invention are from about 0.01 to about 500 mg/kg body weight daily, preferably 0.1-10 mg/kg body weight daily.
  • the compounds may be administered in any suitable way, such as orally or parentarally.
  • the daily dose will preferably be admin- istered in individual dosages 1 to 4 times daily.
  • the compounds used according the invention wherein R x is H and R 2 C1-C8 alkyl are DA receptor ligands. These compounds have central stabilising properties without self-administration liability. Uses for these compounds include preventing and treating dyskinesia.
  • the utilisation of the compounds of this invention in treatment of dyskinesia is shown by their ability to reduce symptoms, such as specially tremor, dystonia and chorea in patients suffering of Huntington's disease.
  • idiopatic torsion dystonia including the focal segmental and generalised dystonias, cerebral paresis, hereditary dystonias, dystonia caused by hereditary metabolic diseases such as Wilson's disease, neuroleptic induced movement disorders, dyskinesias in schizophrenia, stuttering, and movement disorders due to stroke.
  • hereditary metabolic diseases such as Wilson's disease
  • neuroleptic induced movement disorders such as schizophrenia, stuttering, and movement disorders due to stroke.
  • the motor symptoms in these disorders are not dependent on over-stimulation of central dopamine receptors, as is the case with L-DOPA induced dyskinesias
  • the symptom reduction obtained by the compounds used according to the invention in the disorders listed above, e.g. Huntington's disease must be achieved by different mechanisms than in L-DOPA induced dyskinesia.
  • the compounds used according to the invention have high oral availability and sufficient duration of action. Both these features are beneficial for effective clinical treatment.
  • Fig. 1 illustrates the effects of a substance according to the invention on postural tremor in patients with Huntington's disease. The ratings for tremor was done upon clinical examination according to the scale of Jankovic et al . before administration (baseline) and 5 hours after administration.
  • Fig. 2 illustrates the effects of a substance according to the invention on dystonia in patients with Huntington's disease. Dystonia was rated according to the UHDRS before administration (baseline) and one day after administration.
  • Fig. 3 illustrates the effects of a substance according to the invention on chorea in patients with Huntington's disease.
  • the average number of the patents' involuntary movement events for two peri- ods of two minutes each was determined before administration (baseline) and 1, 3 and 5 hours, respectively after administration.
  • Example This example describe how to prepare the various compounds and/or perform the various processes of the invention. Those skilled in the art will promptly recognise appropriate variations from the procedures both as to re- actants and as to reaction conditions and techniques.
  • Huntington's disease is used as a model disorder in order to establish a potential clinical efficacy on dyskinesia such as tremors, dystonia and chorea, but the application can be used for all types of dyskinesia.
  • the substance according to the invention used in the example was S- (-) -3- [3- (methylsulfonyl) phenyl] -1- propylpiperidine [below called (-) -OSU6162] .
  • the substance was administered intravenously in an amount of 0.5 g/kg to patients with Huntington's disease and the ef- feet on tremor, dystonia and chorea was studied.

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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)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Neurosurgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

L'invention porte sur l'utilisation de composés de la formule (I) dans laquelle n vaut de préférence 2; R1 représente de préférence SO2CH3, R2 représente de préférence H, et R3 représente de préférence C1-C8 alkyle ou des sels pharmaceutiquement acceptables de celui-ci. Ces composés sont utilisés dans la fabrication d'un produit médicinal pour le traitement et/ou la prévention de la dyskinésie telle que la dystonie, le tremblement ou la chorée. Cette invention porte également sur des procédés de traitement et de prévention de la dyskinésie telle que la dystonie, le tremblement ou la chorée et consistent à administrer un composé de la formule (I).
PCT/SE1999/001274 1998-07-15 1999-07-15 Produit medicinal et procede de traitement et de prevention de la dyskinesie Ceased WO2000003714A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP2000559849A JP2002520361A (ja) 1998-07-15 1999-07-15 運動異常を処置、保護および予防するための薬用物質および方法
AU54568/99A AU5456899A (en) 1998-07-15 1999-07-15 Medicinal product and method for treatment and prevention of dyskinesia
EP99940783A EP1096935A1 (fr) 1998-07-15 1999-07-15 Produit medicinal et procede de traitement et de prevention de la dyskinesie
CA002336998A CA2336998A1 (fr) 1998-07-15 1999-07-15 Produit medicinal et procede de traitement et de prevention de la dyskinesie
BR9912051-8A BR9912051A (pt) 1998-07-15 1999-07-15 Uso de composto, e, processo para tratamento e prevenção de discinesia.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9802546A SE9802546D0 (sv) 1998-07-15 1998-07-15 Medicinal product and method for treatment and prevention of dyskinesia
SE9802546-3 1998-07-15

Publications (1)

Publication Number Publication Date
WO2000003714A1 true WO2000003714A1 (fr) 2000-01-27

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ID=20412091

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE1999/001274 Ceased WO2000003714A1 (fr) 1998-07-15 1999-07-15 Produit medicinal et procede de traitement et de prevention de la dyskinesie

Country Status (7)

Country Link
EP (1) EP1096935A1 (fr)
JP (1) JP2002520361A (fr)
AU (1) AU5456899A (fr)
BR (1) BR9912051A (fr)
CA (1) CA2336998A1 (fr)
SE (1) SE9802546D0 (fr)
WO (1) WO2000003714A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001055132A1 (fr) * 2000-01-28 2001-08-02 Novartis Ag Pyrrolidines 1,3-disubstituees en tant qu'antagonistes du recepteur adrenergique alpha 2
WO2002036123A3 (fr) * 2000-10-31 2002-09-19 Upjohn Co Nouveaux traitements destines au syndrome des jambes sans repos
US6653325B2 (en) * 2000-10-12 2003-11-25 Pharmacia & Upjohn Company Method of treating parkinson's disease
US6670378B2 (en) * 2001-05-08 2003-12-30 Pharmacia & Upjohn Company Method of treating Parkinson's disease
WO2012039660A1 (fr) * 2010-09-20 2012-03-29 A. Carlsson Research Ab Composés de phénylpipéridine pour le traitement de troubles neurologiques et psychiatriques
USRE46117E1 (en) 1999-12-22 2016-08-23 Teva Pharmaceuticals International Gmbh Modulators of dopamine neurotransmission

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4426386A (en) * 1979-12-05 1984-01-17 Astra Lakemedel Aktiebolag Substituted phenyl piperidines
US4719219A (en) * 1982-03-30 1988-01-12 Per A. E. Carlsson Phenyl-azacycloalkanes and use thereof in treatment of central nervous system disorders
US4937346A (en) * 1979-12-05 1990-06-26 Per Arvid Emil Carlsson Phenyl-azacykloalkanes

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4426386A (en) * 1979-12-05 1984-01-17 Astra Lakemedel Aktiebolag Substituted phenyl piperidines
US4937346A (en) * 1979-12-05 1990-06-26 Per Arvid Emil Carlsson Phenyl-azacykloalkanes
US4719219A (en) * 1982-03-30 1988-01-12 Per A. E. Carlsson Phenyl-azacycloalkanes and use thereof in treatment of central nervous system disorders

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ANNA EKESBO ET AL: "(-)-OSU 6162 Inhibits Levodopa-Induced Dyskinesias in a Monkey Model of Parkinson's Disease", NEUROREPORT, vol. 8, no. 11, 1997, pages 2567 - 2570, XP002941929 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE46117E1 (en) 1999-12-22 2016-08-23 Teva Pharmaceuticals International Gmbh Modulators of dopamine neurotransmission
WO2001055132A1 (fr) * 2000-01-28 2001-08-02 Novartis Ag Pyrrolidines 1,3-disubstituees en tant qu'antagonistes du recepteur adrenergique alpha 2
US7012085B2 (en) 2000-01-28 2006-03-14 Novartis Ag 1,3 disubstituted pyrrolidines as α-2-adrenoceptor antagonists
CN1305847C (zh) * 2000-01-28 2007-03-21 诺瓦提斯公司 用作α－2－肾上腺素受体拮抗剂的1,3－二取代吡咯烷
US6653325B2 (en) * 2000-10-12 2003-11-25 Pharmacia & Upjohn Company Method of treating parkinson's disease
WO2002056745A3 (fr) * 2000-10-12 2004-01-08 Upjohn Co Methode de traitement de la maladie de parkinson
WO2002036123A3 (fr) * 2000-10-31 2002-09-19 Upjohn Co Nouveaux traitements destines au syndrome des jambes sans repos
US6602868B2 (en) 2000-10-31 2003-08-05 Pharmacia & Upjohn Company Treatments for restless legs syndrome
US6716854B2 (en) 2000-10-31 2004-04-06 Pfizer, Inc. Treatments for restless legs syndrome
US6670378B2 (en) * 2001-05-08 2003-12-30 Pharmacia & Upjohn Company Method of treating Parkinson's disease
WO2012039660A1 (fr) * 2010-09-20 2012-03-29 A. Carlsson Research Ab Composés de phénylpipéridine pour le traitement de troubles neurologiques et psychiatriques

Also Published As

Publication number Publication date
BR9912051A (pt) 2001-04-03
EP1096935A1 (fr) 2001-05-09
JP2002520361A (ja) 2002-07-09
SE9802546D0 (sv) 1998-07-15
CA2336998A1 (fr) 2000-01-27
AU5456899A (en) 2000-02-07

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