WO2000012623A2 - Use of 5-th receptor antagonists for the treatment of parkinson's disease - Google Patents

Use of 5-th receptor antagonists for the treatment of parkinson's disease Download PDF

Info

Publication number
WO2000012623A2
WO2000012623A2 PCT/EP1999/006219 EP9906219W WO0012623A2 WO 2000012623 A2 WO2000012623 A2 WO 2000012623A2 EP 9906219 W EP9906219 W EP 9906219W WO 0012623 A2 WO0012623 A2 WO 0012623A2
Authority
WO
WIPO (PCT)
Prior art keywords
group
alkyl
optionally substituted
heterocyclic ring
galkyl
Prior art date
Application number
PCT/EP1999/006219
Other languages
French (fr)
Other versions
WO2000012623A3 (en
Inventor
Carol Routledge
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 AU59706/99A priority Critical patent/AU5970699A/en
Publication of WO2000012623A2 publication Critical patent/WO2000012623A2/en
Publication of WO2000012623A3 publication Critical patent/WO2000012623A3/en

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
    • A61K31/495—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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs

Definitions

  • the present invention relates to the use of 5-HT6 receptor antagonist compounds in the treatment of certain CNS disorders. More particularly the invention relates to the 5 use of such compounds in the treatment of Parkinson's disease.
  • Parkinson's Syndrome refers to a collection of neurodegenerative diseases that are characterised by a disturbance of voluntary movement, and which includes both Idiopathic Parkinson's disease and Multiple System Atrophy. Typical features of these 0 diseases are that muscles become stiff and sluggish, movement becomes clumsy and difficult and uncontrollable rhythmic twitching of groups of muscles produces characteristic shaking or tremor. Parkinson's disease is also associated with cognitive dysfunction and, in a proportion of cases, concurrent dementia. These conditions are believed to be caused by extensive degeneration ofthe dopaminergic nigrostriatal tract.
  • WO 98/27081, WO 98/27058 and WO 99/02502 all disclose compounds that are said to possess 5-HTg receptor antagonist activity. These compounds are alleged to be of use in the treatment of various CNS disorders.
  • EPA 0815861 and EP 0930302 disclose 0 sulphonamide and sulphone compounds respectively that are to said to possess 5-HTg receptor antagonist activity and are claimed to be useful in the treatment of various CNS disorders including Parkinson's disease.
  • EP 0299602B1 discloses certain indolone derivatives that are useful in the treatment of Parkinson's disease and, advantageously, have anti-depressant and anxiolytic effects. 5
  • 5-HTg receptor antagonists selectively increases activity of the nigrostriatal pathway and consequently have utility in the treatment of Parkinson's disease.
  • the compounds ofthe present invention have additional effects on the central nervous system, namely, cognitive effects.
  • the cognitive effects ofthe compounds of the present invention are perceived to be advantageous as patients receiving current therapies often also need to take separate medication for the treatment of cognitive dysfunction and dementia. The presence of such qualities as a single compound may therefore reduce the need for such separate therapies.
  • the present invention therefore provides, in a first aspect, the use of a compound having 5-HTg receptor antagonist activity in the manufacture of a medicament for use in the treatment of Parkinson's Disease characterized in that the compound having 5-HTg receptor antagonist activity is selected from the group consisting of a compound of formula (A), (B) or (C)
  • P is phenyl, naphthyl, a bicyclic heterocyclic ring or is a 5 to 7-membered heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur;
  • A is a single bond, a C ⁇ .galkylene or a C ⁇ .galkenylene group
  • Rl is halogen, Cj.galkyl optionally substituted by one or more halogen atoms,
  • C3_6cycloalkyl, COCi.galkyl, C ⁇ _6alkoxy, OCF3, hydroxy, hydroxyC 1 _6alkyl, hydroxyC galkylamino or diCi .galkylamino, cyano or R ⁇ is phenyl, naphthyl, a bicyclic heterocyclic ring or is a 5 to 7-membered heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur; n is 0, 1, 2, 3, 4, 5 or 6,
  • R2 is hydrogen, Cj.g alkyl or aryl Ci .g alkyl; R is a group R ⁇ or together with R ⁇ forms a group (CPb ⁇ O or (CH2)3 ⁇ or R ⁇ is linked to R- to form a group (CH2 . 2 or (CH2)3;
  • R 4 is -X(CH2)p-R 6 where X is a single bond. CH2, O, NH or N- C ⁇ . ⁇ alkyl and p is 0 to
  • R 6 and R" is an optionally substituted 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulphur or oxygen, or R6 is NR ⁇ R ⁇ where R ⁇ and R8 are independently hydrogen, C 1 _g alkyl or aryl C 1.5 alkyl; and
  • R5 is hydrogen, halogen.
  • P is phenyl. naphthyl, anthracenyl, a bicyclic heterocyclic ring, a tricyclic heteroaromatic ring or is a 5 to 7-membered heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur;
  • A is a single bond, a C ⁇ .galkylene or a C i . ⁇ alkenylene group; B is SO2; Rl is halogen, Cj.galkyl optionally substituted by one or more fluorine atoms,
  • C3_6cycloalkyl C2_6alkenyl, C2-6 lkynyl, Cj.galkanoyl, Ci.galkoxy, OCF3, hydroxy, hydroxyC i.galkyl, hydroxyC ] ⁇ alkoxy, C 1.galkoxyC j .galkoxy, nitro.
  • cyano NRlOR 1 1 where R*0 and Rl 1 are independently hydrogen, C i .galkyl or optionally substituted phenyl, SR 1 where R ⁇ is as defined above or R ⁇ is optionally substituted phenyl, naphthyl, a bicyclic heterocyclic ring or is a 5 to 7-membered heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur, or R ⁇ together with a second R 1 substituent forms a group -O-CH2-O-, OCH2CH2O-, -CH2CH2CH2- or -CH 2 CH 2 CH 2 CH2-, n is O, 1, 2.
  • R- is hydrogen, Ci .galkyl. arylCj .g alkyl or together with group P form a 5 to 8 membered ring optionally substituted with one or more Ci .galkyl groups
  • R J is hydrogen, halogen. C j .gal yl. C3_6cycloalkyl. Ci.galkanoyl. C j. ⁇ alkoxy optionally substituted with one or more fluorine atoms, hydroxy, hydroxyC j .galkyl, hydroxyC i.galkoxy, C 1.galkoxyC j .galkoxy, . nitro, trifluoromethyl.
  • R 5 forms a group (CH2>2O or (CH2)3O optionally substituted with 1 or more C ⁇ .galkyl groups
  • R * * is -X(CH2)p-R 6 where X is a single bond, CH , O, NH or N-alkyl and p is 0 to 6 and R6 is an optionally substituted 4- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulphur or oxygen, or
  • R ⁇ is NR ⁇ RS where R ⁇ and R8 are independently hydrogen, Cj.g alkyl or arylCj.galkyl; and R5 is a group R ⁇ or together with R ⁇ forms a group (CH2)2 ⁇ or (CH2)3O optionally substituted with 1 or more C j - ⁇ alkyl groups.
  • the preferred compounds for use in this invention demonstrate greater than 100- fold selectivity for 5-HTg receptors over other binding sites within the CNS, in particular, other 5-HT receptor sub-types and dopaminergic receptors.
  • the selectivity ofthe compounds of this invention for 5-HTg receptors can be determined using binding assays methods which are well known to those skilled in the art.
  • Particularly preferred compounds of this invention include 5-Chloro-3- methylbenzo[b]thiophene-2-sulfonic acid (4-methoxy-3-piperazm-l-ylphenyl) amide (Example 83 in WO 98/27081), that is to say, the compound of formula (I)
  • compounds of formulas (A), (B) and (C) may form acid addition salts.
  • suitable examples include pharmaceutically acceptable salts such as maleic, hydrochloric, hydrobromic. phosphoric, acetic, fumaric, salicylic, sulphate, citric, lactic, mandelic, tartaric and methanesulphonic.
  • a compound of formula (I) or formula (II) is used as the hydrochloride salt.
  • the compounds of formulas (A), (B) and (C) and their pharamaceutically acceptable salts can be prepared by the methods described in WO 98/27081 , WO 98/27058 and WO 99/02502 respectively.
  • the compounds for use in this invention can be evaluated for anti - Parkinson activity using procedures known to those skilled in the art such as the MPTP treated marmoset model.
  • the compounds for use in this invention are expected to have utility in treating any condition characterized by degeneration of the dopaminergic nigrostriatal tract. Consequently, these compounds will be useful in the treatment of both Idiopathic Parkinson's disease and Multiple System Atrophy.
  • Multiple System Atrophy includes olivopontocerebellar atrophy, striato-nigral degeneration type and Shy-Drager type atrophy.
  • the present invention further provides a method of treatment of Parkinson's
  • the compounds according to this invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, by co-administration with other anti-Parkinson's agents.
  • examples of such include levodopa or a dopamine agonists, and in particular, those described in EP 0299602B1.
  • the compounds of formula (A), (B) or (C) are usually formulated in a standard pharmaceutical composition.
  • Such compositions can be prepared using standard procedures.
  • a pharmaceutical composition ofthe 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 ofthe 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 ofthe compound.
  • the composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, ofthe active material, depending on the method of administration.
  • the dose ofthe compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight ofthe 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.
  • the compounds for use in this invention will be administered for a period of continuous therapy.

Abstract

Use of 5-HT6 receptor antagonists for the preparation of medicaments for the treatment of Parkinson disease.

Description

Use
The present invention relates to the use of 5-HT6 receptor antagonist compounds in the treatment of certain CNS disorders. More particularly the invention relates to the 5 use of such compounds in the treatment of Parkinson's disease.
Parkinson's Syndrome refers to a collection of neurodegenerative diseases that are characterised by a disturbance of voluntary movement, and which includes both Idiopathic Parkinson's disease and Multiple System Atrophy. Typical features of these 0 diseases are that muscles become stiff and sluggish, movement becomes clumsy and difficult and uncontrollable rhythmic twitching of groups of muscles produces characteristic shaking or tremor. Parkinson's disease is also associated with cognitive dysfunction and, in a proportion of cases, concurrent dementia. These conditions are believed to be caused by extensive degeneration ofthe dopaminergic nigrostriatal tract.
15 The absence of adequate release of the chemical transmitter dopamine during neuronal activity thereby leads to the Parkinsonian symptomatology.
WO 98/27081, WO 98/27058 and WO 99/02502 all disclose compounds that are said to possess 5-HTg receptor antagonist activity. These compounds are alleged to be of use in the treatment of various CNS disorders. EPA 0815861 and EP 0930302 disclose 0 sulphonamide and sulphone compounds respectively that are to said to possess 5-HTg receptor antagonist activity and are claimed to be useful in the treatment of various CNS disorders including Parkinson's disease. EP 0299602B1 discloses certain indolone derivatives that are useful in the treatment of Parkinson's disease and, advantageously, have anti-depressant and anxiolytic effects. 5
It has now been found that certain compounds, known in the art as 5-HTg receptor antagonists, selectively increases activity of the nigrostriatal pathway and consequently have utility in the treatment of Parkinson's disease. In addition, the compounds ofthe present invention have additional effects on the central nervous system, namely, cognitive effects. In particular, the cognitive effects ofthe compounds of the present invention are perceived to be advantageous as patients receiving current therapies often also need to take separate medication for the treatment of cognitive dysfunction and dementia. The presence of such qualities as a single compound may therefore reduce the need for such separate therapies.
J _>
The present invention therefore provides, in a first aspect, the use of a compound having 5-HTg receptor antagonist activity in the manufacture of a medicament for use in the treatment of Parkinson's Disease characterized in that the compound having 5-HTg receptor antagonist activity is selected from the group consisting of a compound of formula (A), (B) or (C)
Compound of Formula (A)
Figure imgf000004_0001
(A) wherein:
P is phenyl, naphthyl, a bicyclic heterocyclic ring or is a 5 to 7-membered heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur;
A is a single bond, a C \ .galkylene or a C \ .galkenylene group;
Rl is halogen, Cj.galkyl optionally substituted by one or more halogen atoms,
C3_6cycloalkyl, COCi.galkyl, Cι_6alkoxy, OCF3, hydroxy, hydroxyC 1 _6alkyl, hydroxyC
Figure imgf000004_0002
galkylamino or diCi .galkylamino, cyano or RΪ is phenyl, naphthyl, a bicyclic heterocyclic ring or is a 5 to 7-membered heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur; n is 0, 1, 2, 3, 4, 5 or 6,
R2 is hydrogen, Cj.g alkyl or aryl Ci .g alkyl; R is a group R^ or together with R^ forms a group (CPb^O or (CH2)3θ or R^ is linked to R- to form a group (CH2.2 or (CH2)3;
R4 is -X(CH2)p-R6 where X is a single bond. CH2, O, NH or N- C\.β alkyl and p is 0 to
6 and R" is an optionally substituted 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulphur or oxygen, or R6 is NR^R^ where R^ and R8 are independently hydrogen, C 1 _g alkyl or aryl C 1.5 alkyl; and
R5 is hydrogen, halogen. C]_6alkyl, C3_6cycloalkyl, Ct _6alkoxy, hydroxy, hydroxyC j. galkyl, hydroxyC j .galkoxy, Ci.galkoxyCj.galkoxy, C \ .galkanoyl, nitro, trifluoromethyl, cyano or aryl.
Compounds of Formula (B)
. ? .
Figure imgf000005_0001
(B) where R - R^, P, A and n are as defined in formula (A)
Compounds of Formula (C)
Figure imgf000005_0002
(C) wherein: P is phenyl. naphthyl, anthracenyl, a bicyclic heterocyclic ring, a tricyclic heteroaromatic ring or is a 5 to 7-membered heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur;
A is a single bond, a C\ .galkylene or a C i .βalkenylene group; B is SO2; Rl is halogen, Cj.galkyl optionally substituted by one or more fluorine atoms,
C3_6cycloalkyl, C2_6alkenyl, C2-6 lkynyl, Cj.galkanoyl, Ci.galkoxy, OCF3, hydroxy, hydroxyC i.galkyl, hydroxyC ] ^alkoxy, C 1.galkoxyC j .galkoxy, nitro. cyano, NRlOR11 where R*0 and Rl 1 are independently hydrogen, C i .galkyl or optionally substituted phenyl, SR 1 where R^ is as defined above or R^ is optionally substituted phenyl, naphthyl, a bicyclic heterocyclic ring or is a 5 to 7-membered heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur, or R^ together with a second R1 substituent forms a group -O-CH2-O-, OCH2CH2O-, -CH2CH2CH2- or -CH2CH2CH2CH2-, n is O, 1, 2. 3, 4, 5 or 6; R- is hydrogen, Ci .galkyl. arylCj .g alkyl or together with group P form a 5 to 8 membered ring optionally substituted with one or more Ci .galkyl groups; RJ is hydrogen, halogen. C j .gal yl. C3_6cycloalkyl. Ci.galkanoyl. C j.βalkoxy optionally substituted with one or more fluorine atoms, hydroxy, hydroxyC j .galkyl, hydroxyC i.galkoxy, C 1.galkoxyC j .galkoxy, . nitro, trifluoromethyl. cyano or aryl or together with the group R5 forms a group (CH2>2O or (CH2)3O optionally substituted with 1 or more C \ .galkyl groups; R** is -X(CH2)p-R6 where X is a single bond, CH , O, NH or N-alkyl and p is 0 to 6 and R6 is an optionally substituted 4- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulphur or oxygen, or R^ is NR^RS where R^ and R8 are independently hydrogen, Cj.g alkyl or arylCj.galkyl; and R5 is a group R^ or together with R^ forms a group (CH2)2θ or (CH2)3O optionally substituted with 1 or more C j -βalkyl groups.
The preferred compounds for use in this invention demonstrate greater than 100- fold selectivity for 5-HTg receptors over other binding sites within the CNS, in particular, other 5-HT receptor sub-types and dopaminergic receptors. The selectivity ofthe compounds of this invention for 5-HTg receptors can be determined using binding assays methods which are well known to those skilled in the art.
Particularly preferred compounds of this invention include 5-Chloro-3- methylbenzo[b]thiophene-2-sulfonic acid (4-methoxy-3-piperazm-l-ylphenyl) amide (Example 83 in WO 98/27081), that is to say, the compound of formula (I)
Figure imgf000006_0001
(I) and N-(2.5-Dibromo-3-fluorophenyl)-4-methoxy-3-piperazin- 1 -ylbenzenesulfonamide (Example 140 in WO 99/02502) that is to say. the compound of formula (II)
Figure imgf000006_0002
(II)
It will be apparent to those skilled in the art that compounds of formulas (A), (B) and (C) may form acid addition salts. Suitable examples include pharmaceutically acceptable salts such as maleic, hydrochloric, hydrobromic. phosphoric, acetic, fumaric, salicylic, sulphate, citric, lactic, mandelic, tartaric and methanesulphonic. Suitably, a compound of formula (I) or formula (II) is used as the hydrochloride salt.
Certain compounds of formulas (A), (B) and (C) 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 ofthe invention.
The compounds of formulas (A), (B) and (C) and their pharamaceutically acceptable salts can be prepared by the methods described in WO 98/27081 , WO 98/27058 and WO 99/02502 respectively.
The compounds for use in this invention can be evaluated for anti - Parkinson activity using procedures known to those skilled in the art such as the MPTP treated marmoset model.
The compounds for use in this invention are expected to have utility in treating any condition characterized by degeneration of the dopaminergic nigrostriatal tract. Consequently, these compounds will be useful in the treatment of both Idiopathic Parkinson's disease and Multiple System Atrophy. Multiple System Atrophy includes olivopontocerebellar atrophy, striato-nigral degeneration type and Shy-Drager type atrophy. The present invention further provides a method of treatment of Parkinson's
Disease and other related disorders which comprises administering to a host in need thereof an effective amount of a compound of formula (A), (B) or (C) or a pharmaceutically acceptable salt thereof.
It will be appreciated by those skilled in the art that the compounds according to this invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, by co-administration with other anti-Parkinson's agents. Examples of such include levodopa or a dopamine agonists, and in particular, those described in EP 0299602B1.
When used in therapy, the compounds of formula (A), (B) or (C) are usually formulated in a standard pharmaceutical composition. Such compositions can be prepared using standard procedures.
A pharmaceutical composition ofthe 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.
For parenteral administration, fluid unit dosage forms are prepared utilising a compound ofthe 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. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, 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. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution ofthe compound.
The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, ofthe active material, depending on the method of administration. The dose ofthe compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight ofthe sufferer, and other similar factors. However, as a general guide 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. Suitably the compounds for use in this invention will be administered for a period of continuous therapy.

Claims

Claims:
1. The use of a compound having 5-HTg receptor antagonist activity in the manufacture of a medicament for use in the treatment of Parkinson's Disease characterized in that the compound having 5-HTg receptor antagonist activity is selected from the group consisting of a compound of formula (A), (B) or (C)
Compound of Formula (A)
Figure imgf000009_0001
(A) wherein:
P is phenyl, naphthyl, a bicyclic heterocyclic ring or is a 5 to 7-membered heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur; A is a single bond, a C \ .galkylene or a C j . alkenylene group;
Rl is halogen, C╬╣ _6alkyl optionally substituted by one or more halogen atoms, C3_gcycloalkyl, COCi .galkyl, Cj.galkoxy, OCF3, hydroxy, hydroxyC \ .galkyl, hydroxyC j .galkoxy, Ci .╬▓alkoxyCi-╬▓alkoxy, C╬╣ _5alkanoyl, nitro, amino, C\. 6alkylamino or diCj.galkylamino, cyano or Rl is phenyl. naphthyl, a bicyclic heterocyclic ring or is a 5 to 7-membered heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur; n is O, 1. 2, 3, 4, 5 or 6,
R- is hydrogen, C1.5 alkyl or aryl Cj.g alkyl; R is a group R^ or together with R^ forms a group (CH2)2O or (CH2)3╬╕ or R^ is linked to R2 to form a group (CH )2 or (CH2)3;
R4 is -X(CH2)p-R6 where X is a single bond, CH2. O, NH or N- C ] .5 alkyl and p is 0 to 6 and R" is an optionally substituted 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulphur or oxygen, or R^ is NR^R^ where R^ and R" are independently hydrogen. C \. alkyl or aryl C \. alkyl; and R3 is hydrogen, halogen. C i .galkyl, C3_6cycloalkyl, Cj^alkoxy, hydroxy, hydroxyC]. galkyl. hydroxyC i .galkoxy, C j.galkoxyC j .galkoxy, Ci .galkanoyl. nitro, trifluoromethyl. cyano or aryl.
Compounds of Formula (B)
Figure imgf000010_0001
(B) where Rl - R^, P, A and n are as defined in formula (A)
Compounds of Formula (C)
Figure imgf000010_0002
(C) wherein: P is phenyl, naphthyl, anthracenyl, a bicyclic heterocyclic ring, a tricyclic heteroaromatic ring or is a 5 to 7-membered heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur;
A is a single bond, a C i _6alkylene or a C .galkenylene group; B is SO2; Rl is halogen, Ci .galkyl optionally substituted by one or more fluorine atoms,
C3_6cycloalkyl, C2-6alkenyl, C2-6alkynyl, Cj.galkanoyl, C^alkoxy, OCF3, hydroxy, hydroxyC i .galkyl, hydroxyC j.galkoxy, Ci.galkoxyCj.galkoxy, nitro, cyano, NRI ORI where R 0 and Rl 1 are independently hydrogen, C^alkyl or optionally substituted phenyl, SRI 1 where R* 1 is as defined above or Rl is optionally substituted phenyl, naphthyl, a bicyclic heterocyclic ring or is a 5 to 7-membered heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur, or Rl together with a second R1 substituent forms a group -O-CH2-O-, OCH2CH2O-, -CH2CH2CH2- or -CH2CH2CH2CH2-, n is 0, 1, 2, 3, 4, 5 or 6; R- is hydrogen. C 1. alkyl, arylC \ .5 alkyl or together with group P form a 5 to 8 membered ring optionally substituted with one or more C ╬╣ _5alkyl groups; RJ is hydrogen, halogen. C j.galkyl. C3_6cycloalkyl, Cj.galkanoyl. C j^alkoxy optionally substituted with one or more fluorine atoms, hydroxy. hydroxyC j.galkyl, hydroxyC ]_5alkoxy, C j .^alkoxyC j .galkoxy. , nitro. trifluoromethyl. cyano or aryl or together with the group R5 forms a group (CH2)2╬╕ or (CH2)3O optionally substituted with 1 or more Cj ^alkyl groups; R4 is -X(CH2)p-R6 where X is a single bond, CH2, O, NH or N-alkyl and p is 0 to 6 and R6 is an optionally substituted 4- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulphur or oxygen, or R6 is NR R8 where R and R8 are independently hydrogen, C╬╣ _6alkyl or arylCi .5 alkyl; and R5 is a group R3 or together with R forms a group (CH2)2O or (CH2)3O optionally substituted with 1 or more Cj.galkyl groups.
2. The use according to claim 1 wherein the 5-HTg receptor antagonist is the compound of formula (I) - 5-Chloro-3-methylbenzo[b]thiophene-2- sulfonic acid (4-methoxy-3-piperazin-l -ylphenyl) amide or a pharmaceutically acceptable salt thereof
Figure imgf000011_0001
(I)
3. The use according to claim 1 wherein the 5-HTg receptor antagonist is the compound of formula (II) - N-(2,5-Dibromo-3-fluorophenyl)-4- methoxy-3-piperazin-l -ylbenzenesulfonamide or a pharmaceutically acceptable salt thereof
Figure imgf000011_0002
(II)
4. A pharmaceutical composition for use in the treatment of Parkinson's
Disease which comprises a compound described in any one of claims 1 - 3 and a pharmaceutically acceptable carrier.
PCT/EP1999/006219 1998-08-28 1999-08-25 Use of 5-th receptor antagonists for the treatment of parkinson's disease WO2000012623A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU59706/99A AU5970699A (en) 1998-08-28 1999-08-25 Use

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9818914.5 1998-08-28
GBGB9818914.5A GB9818914D0 (en) 1998-08-28 1998-08-28 Use

Publications (2)

Publication Number Publication Date
WO2000012623A2 true WO2000012623A2 (en) 2000-03-09
WO2000012623A3 WO2000012623A3 (en) 2000-08-24

Family

ID=10838073

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1999/006219 WO2000012623A2 (en) 1998-08-28 1999-08-25 Use of 5-th receptor antagonists for the treatment of parkinson's disease

Country Status (3)

Country Link
AU (1) AU5970699A (en)
GB (1) GB9818914D0 (en)
WO (1) WO2000012623A2 (en)

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001098279A2 (en) * 2000-06-20 2001-12-27 Pharmacia & Upjohn Company Bis-arylsulfones
WO2002022595A1 (en) * 2000-09-18 2002-03-21 Toa Eiyo Ltd. N-substituted benzothiophenesulfonamide derivatives
WO2002092585A1 (en) * 2001-05-11 2002-11-21 Biovitrum Ab Novel, arylsusfonamide compounds for the treatment of obesity, type ii diabetes and cns-disorders
US6586592B2 (en) 2000-06-20 2003-07-01 Pharmacia & Upjohn Company Bis-arylsulfones
WO2003078419A1 (en) * 2002-03-15 2003-09-25 Toa Eiyo Ltd. N-substituted benzothiophenesulfonamide derivative
US6812225B2 (en) 2001-01-16 2004-11-02 Astrazeneca Ab Therapeutic heterocyclic compounds
US6825202B2 (en) 2001-08-10 2004-11-30 Syntex (U.S.A.) Llc Arylsulfonyl derivatives with 5-HT6 receptor affinity
US7026314B2 (en) 2001-01-16 2006-04-11 Astrazeneca Ab Therapeutic chromone compounds
US7041691B1 (en) 1999-06-30 2006-05-09 Amgen Inc. Compounds for the modulation of PPARγ activity
US7071220B2 (en) 2000-09-18 2006-07-04 Toa Eiyo Ltd. N-substituted benzothiophenesulfonamide derivatives
WO2009056632A1 (en) * 2007-11-02 2009-05-07 Abbott Gmbh & Co. Kg Benzenesulfonanilide compounds suitable for treating disorders that respond to modulation of the serotonin 5-ht6 receptor
US7718650B2 (en) 2001-05-11 2010-05-18 Biovitrum Ab Aryl sulfonamide compounds for treating obesity
US8076326B2 (en) 2009-04-30 2011-12-13 Abbott Gmbh & Co. Kg N-phenyl- (piperazinyl or homopiperazinyl)-benzenesulfonamide or benzenesulfonyl-phenl-(piperazine or homopiperazine) compounds suitable for treating disorders that respond to modulation of the serotonin 5-HT6 receptor
WO2012059431A1 (en) 2010-11-01 2012-05-10 Abbott Gmbh & Co. Kg Benzenesulfonyl or sulfonamide compounds suitable for treating disorders that respond to the modulation of the serotonin 5-ht6 receptor
WO2012059432A1 (en) 2010-11-01 2012-05-10 Abbott Gmbh & Co. Kg N-phenyl-(homo)piperazinyl-benzenesulfonyl or benzenesulfonamide compounds suitable for treating disorders that respond to the modulation of the 5-ht6 receptor
CN102459200A (en) * 2009-04-30 2012-05-16 雅培股份有限两合公司 Benzenesulfonanilide compounds suitable for treating disorders that respond to modulation of the serotonin 5-ht6 receptor
US8343959B2 (en) 2009-04-30 2013-01-01 Abbott Gmbh & Co. Kg N-phenyl-(piperazinyl or homopiperazinyl)-benzenesulfonamide or benzenesulfonyl-phenyl-(piperazine or homopiperazine) compounds suitable for treating disorders that respond to modulation of the serotonin 5-HT6 receptor
US8362010B2 (en) 2009-04-30 2013-01-29 Abbott Gmbh & Co. Kg Benzenesulfonanilide compounds suitable for treating disorders that respond to modulation of the serotonin 5-HT6 receptor
US8513282B2 (en) 2008-10-23 2013-08-20 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
WO2015061515A1 (en) * 2013-10-25 2015-04-30 Glaxosmithkline Llc Novel compounds
WO2017186686A1 (en) * 2016-04-26 2017-11-02 H. Lundbeck A/S Use of an acetylcholinesterase inhibitor and idalopirdine for reducing falls in parkinson's disease patients

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0533267A1 (en) * 1991-09-18 1993-03-24 Glaxo Group Limited Benzanilide derivatives as 5-HT1D antagonists
EP0815861A1 (en) * 1996-06-28 1998-01-07 F. Hoffmann-La Roche Ag Sulphonamides and their use
WO1998027081A1 (en) * 1996-12-19 1998-06-25 Smithkline Beecham Plc Sulphonamide derivatives, process for their preparation, and their use as medicaments
WO1999002502A2 (en) * 1997-07-11 1999-01-21 Smithkline Beecham Plc Sulphonamide derivatives being 5-ht6 receptor antagonists and process for their preparation
WO1999037623A2 (en) * 1998-01-22 1999-07-29 Smithkline Beecham Plc Sulphonamide derivatives for treatment of cns disorders

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0533267A1 (en) * 1991-09-18 1993-03-24 Glaxo Group Limited Benzanilide derivatives as 5-HT1D antagonists
EP0815861A1 (en) * 1996-06-28 1998-01-07 F. Hoffmann-La Roche Ag Sulphonamides and their use
WO1998027081A1 (en) * 1996-12-19 1998-06-25 Smithkline Beecham Plc Sulphonamide derivatives, process for their preparation, and their use as medicaments
WO1999002502A2 (en) * 1997-07-11 1999-01-21 Smithkline Beecham Plc Sulphonamide derivatives being 5-ht6 receptor antagonists and process for their preparation
WO1999037623A2 (en) * 1998-01-22 1999-07-29 Smithkline Beecham Plc Sulphonamide derivatives for treatment of cns disorders

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BOURSON, ANNE ET AL: "Involvement of 5-HT6 receptors in nigro-striatal function in rodents" BR. J. PHARMACOL. (1998), 125(7), 1562-1566,1998, XP000900090 *
BROMIDGE ET AL: "5-Chloro-N-(4-methoxy-3-piperazin-1-yl-ph enyl)-3-methyl-2-benzothioph enesulfonamide(SB-271046): A Potent, Selective, and Orally Bioavailable5-HT6 Receptor Antagonist" JOURNAL OF MEDICINAL CHEMISTRY,US,AMERICAN CHEMICAL SOCIETY. WASHINGTON, vol. 42, no. 2, 28 January 1999 (1999-01-28), pages 202-205-205, XP002109186 ISSN: 0022-2623 *
DATABASE EMBASE [Online] ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL GUPTA Y.K. ET AL: "Therapeutic potentials of 5-HT receptor modulators." retrieved from STN Database accession no. 94205555 XP002133179 & INDIAN JOURNAL OF PHARMACOLOGY, (1994) 26/2 (94-107)., *
SLEIGHT ET AL: "The 5-hydroxytryptamine-6 receptor: localisation and function" EXPERT OPINION ON THERAPEUTIC PATENTS,GB,ASHLEY PUBLICATIONS, vol. 8, no. 10, 1 October 1998 (1998-10-01), pages 1217-1224, XP002093843 ISSN: 1354-3776 *

Cited By (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7968567B2 (en) 1999-06-30 2011-06-28 Amgen Inc. Compounds for the modulation of PPARγ activity
US7041691B1 (en) 1999-06-30 2006-05-09 Amgen Inc. Compounds for the modulation of PPARγ activity
WO2001098279A3 (en) * 2000-06-20 2002-08-01 Upjohn Co Bis-arylsulfones
WO2001098279A2 (en) * 2000-06-20 2001-12-27 Pharmacia & Upjohn Company Bis-arylsulfones
US6579870B2 (en) 2000-06-20 2003-06-17 Pharmacia & Upjohn Company Bis-arylsulfones
US6586592B2 (en) 2000-06-20 2003-07-01 Pharmacia & Upjohn Company Bis-arylsulfones
US7399781B2 (en) 2000-09-18 2008-07-15 Toa Eiyo Ltd. N-substituted benzothiophenesulfonamide derivatives
US7071220B2 (en) 2000-09-18 2006-07-04 Toa Eiyo Ltd. N-substituted benzothiophenesulfonamide derivatives
WO2002022595A1 (en) * 2000-09-18 2002-03-21 Toa Eiyo Ltd. N-substituted benzothiophenesulfonamide derivatives
US6812225B2 (en) 2001-01-16 2004-11-02 Astrazeneca Ab Therapeutic heterocyclic compounds
US7285662B2 (en) 2001-01-16 2007-10-23 Astrazeneca Ab Therapeutic heterocyclic compounds
US7045514B2 (en) 2001-01-16 2006-05-16 Astrazeneca Ab Therapeutic heterocyclic compounds
US7026314B2 (en) 2001-01-16 2006-04-11 Astrazeneca Ab Therapeutic chromone compounds
US6969710B2 (en) 2001-05-11 2005-11-29 Biovitrum Ab Compounds
US7173035B2 (en) 2001-05-11 2007-02-06 Biovitrum Ab Arylsulfonamide compounds
JP2004534755A (en) * 2001-05-11 2004-11-18 ビオヴィトルム・アクチボラゲット Novel arylsulfonamide compounds for the treatment of obesity, type II diabetes and CNS disease
US7319097B2 (en) 2001-05-11 2008-01-15 Biovitrum Ab Compounds
EA009647B1 (en) * 2001-05-11 2008-02-28 Биовитрум Аб Arylsylfonamide compounds and use thereof for the treatment of obesity and type ii diabetes
WO2002092585A1 (en) * 2001-05-11 2002-11-21 Biovitrum Ab Novel, arylsusfonamide compounds for the treatment of obesity, type ii diabetes and cns-disorders
US7566715B2 (en) 2001-05-11 2009-07-28 Biovitrum Ab Substituted sulfonamide compounds useful for the prophylaxis and treatment of conditions relating to obesity, type II diabetes and/or disorders of the central nervous system
US7718650B2 (en) 2001-05-11 2010-05-18 Biovitrum Ab Aryl sulfonamide compounds for treating obesity
US6825202B2 (en) 2001-08-10 2004-11-30 Syntex (U.S.A.) Llc Arylsulfonyl derivatives with 5-HT6 receptor affinity
WO2003078419A1 (en) * 2002-03-15 2003-09-25 Toa Eiyo Ltd. N-substituted benzothiophenesulfonamide derivative
WO2009056632A1 (en) * 2007-11-02 2009-05-07 Abbott Gmbh & Co. Kg Benzenesulfonanilide compounds suitable for treating disorders that respond to modulation of the serotonin 5-ht6 receptor
US7790727B2 (en) 2007-11-02 2010-09-07 Abbott Gmbh & Co. Kg Benzenesulfonanilide compounds suitable for treating disorders that respond to modulation of the serotonin 5-HT6 receptor
JP2011502973A (en) * 2007-11-02 2011-01-27 アボット ゲーエムベーハー ウント カンパニー カーゲー Benzenesulfonanilide compounds suitable for the treatment of disorders responsive to modulation of serotonin 5-HT6 receptors
US8598205B2 (en) 2008-10-23 2013-12-03 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US8785640B2 (en) 2008-10-23 2014-07-22 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US8513282B2 (en) 2008-10-23 2013-08-20 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US8076326B2 (en) 2009-04-30 2011-12-13 Abbott Gmbh & Co. Kg N-phenyl- (piperazinyl or homopiperazinyl)-benzenesulfonamide or benzenesulfonyl-phenl-(piperazine or homopiperazine) compounds suitable for treating disorders that respond to modulation of the serotonin 5-HT6 receptor
CN102459200A (en) * 2009-04-30 2012-05-16 雅培股份有限两合公司 Benzenesulfonanilide compounds suitable for treating disorders that respond to modulation of the serotonin 5-ht6 receptor
US8183237B2 (en) 2009-04-30 2012-05-22 Abbott Laboratories Benzenesulfonanilide compounds suitable for treating disorders that respond to modulation of the serotonin 5-HT6 receptor
US8343959B2 (en) 2009-04-30 2013-01-01 Abbott Gmbh & Co. Kg N-phenyl-(piperazinyl or homopiperazinyl)-benzenesulfonamide or benzenesulfonyl-phenyl-(piperazine or homopiperazine) compounds suitable for treating disorders that respond to modulation of the serotonin 5-HT6 receptor
US8362010B2 (en) 2009-04-30 2013-01-29 Abbott Gmbh & Co. Kg Benzenesulfonanilide compounds suitable for treating disorders that respond to modulation of the serotonin 5-HT6 receptor
WO2012059432A1 (en) 2010-11-01 2012-05-10 Abbott Gmbh & Co. Kg N-phenyl-(homo)piperazinyl-benzenesulfonyl or benzenesulfonamide compounds suitable for treating disorders that respond to the modulation of the 5-ht6 receptor
WO2012059431A1 (en) 2010-11-01 2012-05-10 Abbott Gmbh & Co. Kg Benzenesulfonyl or sulfonamide compounds suitable for treating disorders that respond to the modulation of the serotonin 5-ht6 receptor
WO2015061515A1 (en) * 2013-10-25 2015-04-30 Glaxosmithkline Llc Novel compounds
WO2017186686A1 (en) * 2016-04-26 2017-11-02 H. Lundbeck A/S Use of an acetylcholinesterase inhibitor and idalopirdine for reducing falls in parkinson's disease patients
CN109069650A (en) * 2016-04-26 2018-12-21 H.隆德贝克有限公司 Acetylcholinesterase inhibitor and Ida Shandong pyridine are used to reduce the purposes of parkinsonian's tumble
US10383849B2 (en) 2016-04-26 2019-08-20 H. Lundbeck A/S Use of an acetylcholinesterase inhibitor and idalopirdine for reducing falls in Parkinson's disease patients
RU2742173C2 (en) * 2016-04-26 2021-02-02 Х. Лундбекк А/C Using the acetylcholinesterase and idalopirdine inhibitor to reduce the risk of falls in the patients with parkinson's disease

Also Published As

Publication number Publication date
GB9818914D0 (en) 1998-10-21
WO2000012623A3 (en) 2000-08-24
AU5970699A (en) 2000-03-21

Similar Documents

Publication Publication Date Title
WO2000012623A2 (en) Use of 5-th receptor antagonists for the treatment of parkinson's disease
EP1107745A1 (en) Use of 5ht-6 antagonists
TW541178B (en) Pharmaceutical combination for treatment of psychoses
US3636219A (en) Anticholinergic compositions containing certain thiazolines or imidazolines
MY132565A (en) Substituted phenylpropionic acid derivatives as agonists to human peroxisome proliferator-activated receptor alpha (ppar)
BRPI0609952A2 (en) Methods to Modulate Bladder Function
IL195511A (en) 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl] piperazine which compound is crystalline and use thereof for the preparation of a medicament for treatment of cognitive impairment
JP2003522724A (en) Antioxidant-stabilizer system for pharmaceutical formulations
RU2005116254A (en) Pyridopyrrolizine derivatives and pyridoindolizine
EP1988898A2 (en) Pharmaceutical compositions for the treatment of attention deficit hyperactivity disorder comprising flibanserin
RU2057120C1 (en) N-alkyl-3-phenyl-3-(2-substituted phenoxy) propylamine or pharmaceutically acceptable acid addition salt thereof, process for preparation thereof, pharmaceutical composition having norminephrine absortion inhibitory activity
EP0285278A2 (en) The use of tetrahydrobenz[C,D]indole-6-carboxamides for the preparation of a medicament for the treating anxiety
EP1123702A1 (en) Analgesics
KR20010032009A (en) Use of mirtazapine for treating sllep apneas
EP0760665B1 (en) Compositions containing 5htia and 5htid antagonists
UA81640C2 (en) Antimycobacterial compounds, process for the preparation thererof, pharmaceutical composition based thereon
CA1291041C (en) Centrally-acting muscle relaxants
PT93680A (en) PROCESS FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS CONTAINING HETEROARIL-3-OXO-PROPANONITRIL DERIVATIVES SUITABLE FOR THE TREATMENT OF ARTHRITIS RHEUMATOIDE AND OTHER AUTO-IMMUNE DISEASES
GB2303303A (en) 5HT-1A and 5HT-2 antagonists for treating side-effects of serotonin re-uptake inhibitors
JPS63253024A (en) Central muscle relaxant containing pyridine derivative
US4259346A (en) Bradycardiac pharmaceutical compositions and method of use
JPS6335547A (en) Substituted 2-aminotetralin and manufacture
JPWO2005007191A1 (en) Pharmaceutical composition
JP3238153B2 (en) Use of piperazine derivatives for treating cognitive impairment
JP2543955B2 (en) Central muscle relaxant containing piperazine derivative

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

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 MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW SD SL SZ 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)
AK Designated states

Kind code of ref document: A3

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 MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): GH GM KE LS MW SD SL SZ 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

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase