EP1178993A1 - Thiazoloderiatives and pharmaceutical compositions containing them - Google Patents

Thiazoloderiatives and pharmaceutical compositions containing them

Info

Publication number
EP1178993A1
EP1178993A1 EP00935009A EP00935009A EP1178993A1 EP 1178993 A1 EP1178993 A1 EP 1178993A1 EP 00935009 A EP00935009 A EP 00935009A EP 00935009 A EP00935009 A EP 00935009A EP 1178993 A1 EP1178993 A1 EP 1178993A1
Authority
EP
European Patent Office
Prior art keywords
benzo
group
formula
carbon atoms
thιophen
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.)
Withdrawn
Application number
EP00935009A
Other languages
German (de)
English (en)
French (fr)
Inventor
Paul Andrew Brough
Sharon Crawford Cheetham
Frank Kerrigan
John Paul Watts
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.)
Abbott GmbH and Co KG
Original Assignee
Knoll GmbH
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 Knoll GmbH filed Critical Knoll GmbH
Publication of EP1178993A1 publication Critical patent/EP1178993A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/16—Central respiratory analeptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • 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
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • 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
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to certain novel substituted dihydroimidazo[2,1- £>]thiazole and dihydro-5H-thiazolo[3,2-a]pyrimidine compounds which have affinity for 5-HT 1A receptors and which inhibit neuronal reuptake of 5-hydroxytryptamine and/or noradrenaline, to processes for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of depression, anxiety, psychoses (for example schizophrenia), tardive dyskinesia, obesity, drug addiction, drug abuse, cognitive disorders, Alzheimer's disease, obsessive- compulsive behaviour, panic attacks, social phobias, eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, stress, as an aid to smoking cessation and in the treatment and/or prophylaxis of seizures, neurological disorders such as epilepsy and/or conditions in which there is neurological damage such as stroke, brain trauma, cerebral ischaemia
  • Ar is phenyl, naphthyl or benzo[ ⁇ ]thiophenyl, each of which may be optionally substituted by one or more substituents selected from a) halo, b) an alkyl group containing 1 to 3 carbon atoms optionally substituted by one or more halo, c) an alkoxy group containing 1 to 3 carbon atoms optionally substituted by one or more halo, d) an alkylthio group containing 1 to 3 carbon atoms optionally substituted by one or more halo, e) a phenoxy group optionally substituted by one or more halo or f) phenyl optionally substituted by one or more halo;
  • Ri and R 2 which may be the same or different, independently are a) H, b) an alkyl group containing 1 to 6 carbon atoms, c) an alkenyl group containing 3 to 6 carbon atoms, d) a cycloalkyl group containing 3 to 7 carbon atoms, e) a cycloalkylmethyl group in which the ring contains 3 to 7 carbon atoms, f) an aryl or heteroaryl group optionally substituted by one or more substituents selected from i) halo, ii) an alkyl group containing 1 to 3 carbon atoms optionally substituted by one or more halo, iii) an alkoxy group containing 1 to 3 carbon atoms optionally substituted by one or more halo, iv) an alkylthio group containing 1 to 3 carbon atoms optionally substituted by one or more halo, g) an arylalkyl or heteroarylalkyl group in which the alkyl
  • R 3 is a) H, b) an aryl or heteroaryl group optionally substituted by one or more substituents selected from i) halo, ii) an alkyl group containing 1 to 3 carbon atoms optionally substituted by one or more halo, iii) an alkoxy group containing 1 to 3 carbon atoms optionally substituted by one or more halo, iv) an alkylthio group containing 1 to 3 carbon atoms optionally substituted by one or more halo, c) an arylmethyl group in which the aryl is optionally substituted by one or more substituents selected from i) halo, ii) an alkyl group containing 1 to 3 carbon atoms optionally substituted by one or more halo, iii) an alkoxy group containing 1 to 3 carbon atoms optionally substituted by one or more halo, iv) an alkylthio group containing 1 to 3 carbon atoms optionally substituted
  • R and R 5 which may be the same or different, independently are an alkyl group containing 1 to 3 carbon atoms, or R 4 and R 5 together with the atom to which they are attached form a cycloalkyl ring containing 3 to 6 carbon atoms;
  • A is S(O) p or O; p is 0, 1 or 2; g is O, 1 , 2, 3, or 4; n is 2 or 3; is a) halo, b) an alkyl group containing 1 to 3 carbon atoms optionally substituted by one or more halo, c) an alkoxy group containing 1 to 3 carbon atoms optionally substituted by one or more halo, d) an alkylthio group, an alkylsulphinyl group or an alkylsulphonyl group each containing 1 to 3 carbon atoms optionally substituted by one or more halo, e) hydroxy, f) an acyloxy group containing 1 to 3 carbon atoms, g) a hydroxyalkyl group containing 1 to 3 carbon atoms, h) cyano, i) an alkanoyl group containing 1 to 6 carbon atoms, j) an alkoxycarbonyl group containing 2 to 6 carbon atoms,
  • R 5 is a) halo, b) an alkyl group containing 1 to 3 carbon atoms optionally substituted by one or more halo, c) an alkoxy group containing 1 to 3 carbon atoms optionally substituted by one or more halo, d) an alkylthio group, an alkylsulphinyl group or an alkylsulphonyl group each containing 1 to 3 carbon atoms optionally substituted by one or more halo, e) hydroxy, f) an acyloxy group containing 1 to 3 carbon atoms, g) a hydroxyalkyl group containing 1 to 3 carbon atoms, h) cyano, i) an alkanoyl group containing 1 to 6 carbon atoms, j) an alkoxycarbonyl group containing 2 to 6 carbon atoms, k) a carbamoyl group or a carbamoylmethyl group each optionally ⁇ /-substituted by one or two al
  • the present invention provides compounds with unexpectedly superior selectivity and efficacy.
  • the compounds of the present invention are not disclosed or suggested in WO 97/02269 .
  • the present invention provides compounds of Formula I
  • A is S or O
  • g is O, 1 , 2, 3 or 4;
  • n 2 or 3;
  • R-i is a) halo, b) an alkyl group containing 1 to 3 carbon atoms optionally substituted by one or more halo, c) an alkoxy group containing 1 to 3 carbon atoms optionally substituted by one or more halo, d) an alkylthio group, an alkylsulphinyl group or an alkylsulphonyl group each containing 1 to 3 carbon atoms optionally substituted by one or more halo, e) hydroxy, f) an acyloxy group containing 1 to 3 carbon atoms, g) a hydroxyalkyl group containing 1 to 3 carbon atoms, h) cyano, i) an alkanoyl group containing 1 to 6 carbon atoms, j) an alkoxycarbonyl group containing 2 to 6 carbon atoms, k) a carbamoyl group or a carbamoylmethyl group each optionally ⁇ /-substituted by one or two
  • R 2 and R 3 are each H ;
  • R 4 represents a hydroxyalkyl group containing 1 to 6 carbon atoms, an ⁇ -hydroxy(2- C ⁇ _ 3 alkoxyphenyl)methyl group, a hydroxyalkenyl group containing 3 to 6 carbon atoms in which hydroxy is not attached directly to either carbon of the double bond, a hydroxyalkynyl group containing 3 to 6 carbon atoms in which hydroxy is not attached directly to either carbon of the triple bond, a hydroxycycloalkyl group containing 3 to 6 carbon atoms, an alkenyl group containing 2 to 8 carbon atoms, an arylalkenyl group containing 8 to 10 carbon atoms, a cycloalkyl group containing 3 to 6 carbon atoms, a Ca ⁇ al ynyialkoxyC L salkyl group, a C 4 .
  • R 5 is H or halo.
  • A is S or O
  • g is O, 1 , 2, 3, or 4;
  • n 2 or 3;
  • Ri is a) halo, b) an alkyl group containing 1 to 3 carbon atoms optionally substituted by one or more halo, c) an alkoxy group containing 1 to 3 carbon atoms optionally substituted by one or more halo, d) an alkylthio group, an alkylsulphinyl group or an alkylsulphonyl group each containing 1 to 3 carbon atoms optionally substituted by one or more halo, e) hydroxy, f) an acyloxy group containing 1 to 3 carbon atoms, g) a hydroxyalkyl group containing 1 to 3 carbon atoms, h) cyano, i) an alkanoyl group containing 1 to 6 carbon atoms, j) an alkoxycarbonyl group containing 2 to 6 carbon atoms, k) a carbamoyl group or a carbamoylmethyl group each optionally ⁇ /-substituted by one or two alky
  • R 2 and R 3 are each H ;
  • R represents a hydroxyalkyl group containing 1 to 6 carbon atoms, a hydroxyalkenyl group containing 3 to 6 carbon atoms in which hydroxy is not attached directly to either carbon of the double bond, a hydroxyalkynyl group containing 3 to 6 carbon atoms in which hydroxy is not attached directly to either carbon of the triple bond, a hydroxycycloalkyl group containing 3 to 6 carbon atoms, an alkenyl group containing 2 to 8 carbon atoms, a cycloalkyl group containing 3 to 6 carbon atoms, a C ⁇ . 3 alkoxyC-
  • R 5 is H or halo.
  • halo when used herein, includes fluoro, chloro, bromo and iodo. It will be understood that in alkyl groups, alkenyl groups, alkynyl groups, alkylthio groups and alkoxy groups containing more than two carbon atoms the alkyl group may be straight or branched.
  • Aryl is used to indicate phenyl optionally substituted by one or more of the following: a C ⁇ alkyl group, a C ⁇ . 3 alkoxy group or halo.
  • A is S.
  • A is O.
  • g is 0 or 1 and R ⁇ is a) halo, b) an alkyl group containing 1 to 3 carbon atoms optionally substituted by one or more halo, or c) an alkoxy group containing 1 to 3 carbon atoms optionally substituted by one or more halo.
  • R ⁇ is in the 5-position of the benzo[b]thiophene ring. More preferably g is 0 or 1 and Ri is halo or an alkoxy group containing 1 to 3 carbon atoms. Most preferably g is 0 or 1 and Ri is chloro or methoxy.
  • n is 2.
  • R 2 and R 3 are each H.
  • R 4 represents a hydroxyalkyl group containing 1 to 6 carbon atoms, a hydroxyalkenyl group containing 3 to 6 carbon atoms in which hydroxy is not attached directly to either carbon of the double bond, a hydroxyalkynyl group containing 3 to 6 carbon atoms in which hydroxy is not attached directly to either carbon of the triple bond, an alkenyl group containing 2 carbon atoms optionally substituted by one or more C-
  • R 4 represents a hydroxyalkyl group containing 1 to 5 carbon atoms, a hydroxyalkenyl group containing 3 to 5 carbon atoms in which hydroxy is not attached directly to either carbon of the double bond, a hydroxyalkynyl group containing 3 to 4 carbon atoms in which hydroxy is not attached directly to either carbon of the triple bond or an alkenyl group containing 2 carbon atoms optionally substituted by one or more methyl groups.
  • R 4 represents hydroxymethyl or vinyl. Hydroxymethyl is especially preferred for R 4 .
  • R are hydroxymethyl, 1-hydroxyethyl, 1-hydroxy-1- methylethyl; 1-hydroxypropyl, 1-hydroxy-2-methylpropyl, 1-hydroxybutyl, 1-hydroxy- 3-methylbutyl, 1-hydroxypentyl, 1-hydroxypropenyl, 1-hydroxybut-3-enyl, 1-hydroxy- 2-methylpropenyl, 1-hydroxy-2-methylbut-3-enyi, 1 -hydroxy pent-4-enyl, 1- hydroxypropynyl, 1-hydroxybut-2-ynyl, methoxymethyl, ethoxymethyl, methylthio, bromo, chloro, vinyl, allyl, 1-methylvinyi, formyl, acetyl, ⁇ /-(1-methylethyl)iminomethyl, and hydroxyiminomethyl.
  • R is hydroxymethyl, 1-hydroxyethyl, 1- hydroxy-1-methylethyl; 1-hydroxypropyl, 1-hydroxy-2-methylpropyl, 1-hydroxybutyl, 1-hydroxy-3-methylbutyl, 1-hydroxypentyl, 1-hydroxypropenyl, 1-hydroxybut-3-enyl, 1-hydroxy-2-methylpropenyl, 1-hydroxy-2-methylbut-3-enyl, 1-hydroxypent-4-enyl, 1 - hydroxypropynyl, 1-hydroxybut-2-ynyl, vinyl, 1-methylvinyl, acetyl, ⁇ /-(1- methylethyl)imi ⁇ omethyl, and hydroxyiminomethyl.
  • R 4 is hydroxymethyl or vinyl. Hydroxymethyl is especially preferred.
  • R 5 is H.
  • n is 2.
  • A is S, g is 0 or 1 ; n is 2; R-, is halo or an alkoxy group containing 1 to 3 carbon atoms; R 2 and R 3 are each H; R represents a hydroxyalkyl group containing 1 to 5 carbon atoms, a hydroxyalkenyl group containing 3 to 5 carbon atoms in which hydroxy is not attached directly to either carbon of the double bond, a hydroxyalkynyl group containing 3 to 4 carbon atoms in which hydroxy is not attached directly to either carbon of the triple bond or an alkenyl group containing 2 carbon atoms optionally substituted by one or more methyl groups; and R 5 is H.
  • g is 0 or 1 and Ri is chloro or methoxy. More preferably Ri is in the 5-position of the benzo[5]thiophene ring.
  • A is S or O
  • g is O, 1 , 2, 3 or 4;
  • n 2 or 3;
  • Ri is a) halo, b) an alkyl group containing 1 to 3 carbon atoms optionally substituted by one or more halo, c) an alkoxy group containing 1 to 3 carbon atoms optionally substituted by one or more halo, d) an alkylthio group, an alkylsulphinyl group or an alkylsulphonyl group each containing 1 to 3 carbon atoms optionally substituted by one or more halo, e) hydroxy, f) an acyloxy group containing 1 to 3 carbon atoms, g) a hydroxyalkyl group containing 1 to 3 carbon atoms, h) cyano, i) an alkanoyl group containing 1 to 6 carbon atoms, j) an alkoxycarbonyl group containing 2 to 6 carbon atoms, k) a carbamoyl group or a carbamoylmethyl group each optionally A/-substituted by one or two alkyl
  • A is S.
  • n is 2 in this group of compounds.
  • g is 0 or 1 in this group of compounds.
  • R-i is halo, an alkoxy group containing 1 to 3 carbon atoms, or an alkylthio group containing 1 to 3 carbon atoms.
  • A is O.
  • n is 2 in this group of compounds.
  • g is 0 or 1 in this group of compounds.
  • R ⁇ is halo, an alkoxy group containing 1 to 3 carbon atoms, or an alkylthio group containing 1 to 3 carbon atoms.
  • R- ⁇ are methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy, bromo, chloro, fluoro, iodo, trifluoromethyl, trifluoromethoxy, methylthio, methylsulphinyl, methylsulphonyl, hydroxy, formyloxy, acetoxy, hydroxymethyl, 1-hydroxyethyl, 1- hydroxy-1-methylethyl, 1-hydroxypropyl, cyano, formyl, acetyl, methoxycarbonyl, ethoxycarbonyl, carbamoyl, carbamoylmethyl, sulphamoyl, sulphamoylmethyl, amino, methylamino, dimethylamino, ethylamino or diethylamino. More preferably R- ⁇ is methoxy, chloro or methylthio
  • R 4 are cyclopropyl, methoxy, ethoxy, bromo, chloro, fluoro, iodo, trifluoromethyl, trifluoromethoxy, hydroxymethyl, 1-hydroxyethyl, 1-hydroxy-1-methylethyl; 1- hydroxypropyl, 1-hydroxy-2-methylpropyl, 1-hydroxybutyl, 1-hydroxy-3-methylbutyl, 1-hydroxypentyl, 1-hydroxypropenyl, 1-hydroxybut-3-enyl, 1-hydroxy-2- methylpropenyl, 1-hydroxy-2-methylbut-3-enyl, 1-hydroxypent-4-enyl, 3-hydroxybut- 1-enyl, 1-hydroxypropynyl, 1 -hydroxy but-2-yny I, -hydroxy-2-methoxybenzyl, methoxymethyl, ethoxymethyl, isopropoxymethyl, cyclopropylmethoxymethyl, cyclobutylmethoxymethyl, prop-2-ynyl
  • A is S or O; g is 0 or 1 , n is 2; Ri represents halo, an alkoxy group containing 1 to 3 carbon atoms or an alkylthio group containing 1 to 3 carbon atoms; and R 4 represents a hydroxyalkyl group containing 1 to 4 carbon atoms, an ⁇ -hydroxy(2-C-
  • Compounds of Formula I may exist as salts with pharmaceutically acceptable acids.
  • the present invention includes all such salts.
  • Examples of such salts include hydrochlorides, hydrobromides, sulphates, methanesulphonates, nitrates, maleates, formates, acetates, citrates, fumarates, tartrates [eg (+)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures], succinates, oxalates, benzoates and salts with amino acids such as glutamic acid.
  • Such salts are prepared by methods known to those skilled in the art as illustrated in the Examples.
  • Certain compounds of Formula I may exist in different tautome ⁇ c forms or as different geometric isomers, and the present invention includes each tautomer and/or geometric isomer of compounds of Formula I and mixtures thereof
  • Certain compounds of Formula I may exist in different stable conformational forms which may be separable For example, if a bulky group is present there may be restricted rotation about one or more single bond or bonds due to ste ⁇ c hindrance Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of ste ⁇ c hindrance or ring strain, may permit separation of different conformers
  • the present invention includes each conformational isomer of compounds of Formula I and mixtures thereof
  • Certain compounds of Formula I and their salts may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof Certain compounds of Formula I and their salts may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof
  • Certain compounds of Formula I contain one or more chiral centres, and exist in different optically active forms
  • the compounds exist in two enantiomenc forms and the present invention includes both enantiomers and mixtures of enantiomers
  • the enantiomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomenc salts which may be separated, for example, by crystallisation, formation of diastereoisomenc derivatives or complexes which may be separated, for example, by crystallisation, gas-liquid or liquid chromatography, or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent
  • a further step is required to liberate the desired enantiomenc form
  • the term "active compound” denotes a compound of Formula I or a salt thereof
  • the active compound may be administered orally, rectally, parenterally or topically, preferably orally
  • the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for oral, rectal, parenteral or topical administration
  • Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art of pharmacy
  • the compositions of the invention may contain 0 1-99% by weight of active compound
  • the compositions of the invention are generally prepared in unit dosage form Preferably the unit dosage of active ingredient is 1-500 mg
  • the excipients used in the preparation of these compositions are the excipients known in the pharmacist's art
  • compositions for oral administration are the preferred compositions of the invention and these are the known pharmaceutical forms for such administration, for example tablets, capsules, syrups and aqueous or oil suspensions
  • the excipients used in the preparation of these compositions are the excipients known in the pharmacist's art Tablets may be prepared by mixing the active compound with an inert diluent such as calcium phosphate in the presence of disintegrating agents, for example maize starch, and lubricating agents, for example magnesium stearate, and tableting the mixture by known methods
  • the tablets may be formulated in a manner known to those skilled in the art so as to give a sustained release of the compounds of the present invention
  • Such tablets may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate
  • capsules, for example hard or soft gelatin capsules, containing the active compound with or without added excipients may be prepared by conventional means and, if desired, provided with enteric coatings in a known manner
  • compositions of the invention are administered orally in the known pharmaceutical forms for such administration
  • Dosage forms suitable for oral administration may comprise tablets, pills, capsules, caplets, multiparticulates including granules, beads, pellets and micro-encapsulated particles, powders, elixirs, syrups, suspensions and solutions
  • Solid oral dosage forms for example tablets, may be prepared by mixing the pharmaceutical composition of the present invention with one or more of the following ingredients or mixtures thereof inert diluents, for example calcium carbonate, calcium sulphate, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, glyceryl palmitostearate, hydrogenated vegetable oil, kaolin, lactose, magnesium carbonate, magnesium oxide, maltodext ⁇ n, mannitol, microcrystalline cellulose, polymethacrylates, potassium chloride, powdered cellulose, pregelatinized starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc and tnbasic calcium phosphate, disintegrating agents, for example alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, methylcellulose
  • Solid oral dosage forms may be formulated in a manner known to those skilled in the art so as to give a sustained release of the active compound Film coated, solid oral dosage forms comprising compositions of the present invention may be advantageous, depending on the nature of the active compound Various materials, for example shellac and/or sugar, may be present as coatings, or to otherwise modify the physical form of the oral dosage form
  • Various materials for example shellac and/or sugar, may be present as coatings, or to otherwise modify the physical form of the oral dosage form
  • tablets or pills may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate and/or hydroxy propyl methylcellulose phthalate
  • Capsules and/or caplets for example hard or soft gelatin capsules comprising the active compound (with or without added excipients such as a fatty oil), may be prepared by conventional means and, if desired, provided with enteric coatings in a known manner
  • the contents of the capsule and/or caplet may
  • Liquid oral dosage forms comprising compositions of the present invention may be an elixir, suspension and/or syrup (for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non- toxic suspending agent [such as sodium carboxymethylcellulose] and/or oily suspensions containing the active compound in a suitable vegetable oil [such as arachis oil and/or sunflower oil])
  • a non- toxic suspending agent such as sodium carboxymethylcellulose
  • suitable vegetable oil such as arachis oil and/or sunflower oil
  • Liquid oral dosage forms may also comprise one or more sweetening agent, flavouring agent, preservatives and/or mixtures thereof
  • the active compound may be formulated into granules with or without additional excipients
  • the granules may be ingested directly by the patient or they may be added to a suitable liquid carrier (for example water) before ingestion
  • a suitable liquid carrier for example water
  • the granules may contain disintegrants (for example a pharmaceutically acceptable effervescent couple formed from an acid and a carbonate or bicarbonate salt) to facilitate dispersion in the liquid medium
  • each of the above oral dosage forms may contain from about 1 mg to about 1000 mg, more preferably from about 5 mg to about 500 mg (for example 10 mg, 50 mg, 100 mg, 200 mg, or 400 mg) of the active compound
  • compositions of the invention suitable for rectal administration are the known pharmaceutical forms for such administration, for example, suppositories with hard fat, semi-synthetic glyce de, cocoa butter and/or polyethylene glycol bases
  • compositions may also be administered parenterally (for example subcutaneously, intramuscularly, intradermally and/or intravenously [such as by injection and/or infusion] in the known pharmaceutical dosage forms for parenteral administration (for example sterile suspensions in aqueous and/or oily media and/or sterile solutions in suitable solvents, preferably isotonic with the blood of the intended patient)
  • Parenteral dosage forms may be sterilised (for example by micro-filtration and/or using suitable sterilising agents [such as ethylene oxide])
  • suitable sterilising agents such as ethylene oxide
  • Parenteral dosage forms may be stored in suitable sterile sealed containers (for example ampoules and/or vials) until use
  • fluid for example water
  • compositions may be administered nasally in known pharmaceutical forms for such administration (for example sprays, aerosols, nebulised solutions and/or powders) Metered dose systems known to those skilled in the art (for example aerosols and/or inhalers) may be used
  • compositions may be administered to the buccal cavity (for example sub-lingually) in known pharmaceutical forms for such administration (for example slow dissolving tablets, chewing gums, troches, lozenges, pastilles, gels, pastes, mouthwashes, rinses and/or powders)
  • known pharmaceutical forms for such administration for example slow dissolving tablets, chewing gums, troches, lozenges, pastilles, gels, pastes, mouthwashes, rinses and/or powders
  • compositions for topical administration may comprise a matrix in which the pharmacologically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally
  • a suitable transdermal composition may be prepared by mixing the pharmaceutically active compound with a topical vehicle, such as a mineral oil, petrolatum and/or a wax, for example paraffin wax or beeswax, together with a potential transdermal accelerant such as dimethyl sulphoxide or propylene glycol
  • the active compounds may be dispersed in a pharmaceutically acceptable cream or ointment base
  • the amount of active compound contained in a topical formulation should be such that a therapeutically effective amount of the compound is delivered during the period of time for which the topical formulation is intended to be on the skin
  • the compounds of the present invention may also be administered by continuous infusion either from an external source, for example by intravenous infusion or from a source of the compound placed within the body
  • Internal sources include implanted reservoirs containing the compound to be infused which is continuously released for example by osmosis and implants which may be (a) liquid such as a suspension or solution in a pharmaceutically acceptable oil of the compound to be infused for example in the form of a very sparingly water-soluble derivative such as a dodecanoate salt or (b) solid in the form of an implanted support, for example of a synthetic resin or waxy material, for the compound to be infused
  • the support may be a single body containing all the compound or a series of several bodies each containing part of the compound to be delivered
  • the amount of active compound present in an internal source should be such that a therapeutically effective amount of the compound is delivered over a long period of
  • the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling
  • the active compound may, if desired, be associated with other compatible pharmacologically active ingredients
  • the present invention also comprises a compound of Formula I for use as a medicament
  • compositions containing a therapeutically effective amount of a compound of Formula I may be used to treat depression, anxiety, psychoses (for example schizophrenia), tardive dyskinesia, obesity, drug addiction, drug abuse, cognitive disorders, Alzheimer's disease, obsessive-compulsive behaviour, panic attacks, social phobias, eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, stress in mammals particularly humans, and as an aid to smoking cessation in human beings
  • compositions may be used in the treatment and/or prophylaxis of seizures, neurological disorders such as epilepsy and/or conditions in which there is neurological damage such as stroke, brain trauma, cerebral ischaemia, head injuries and haemorrhage Whilst the precise amount of active compound administered in such treatment will depend on a number of factors, for example the age of the patient, the severity of the condition and the past medical history, and always lies within the sound discretion of the administering physician, the
  • the present invention provides the use of a compound of Formula I in the manufacture of a medicament for use in the treatment of depression, anxiety, psychoses (for example schizophrenia), tardive dyskinesia, obesity, drug addiction, drug abuse, cognitive disorders, Alzheimer's disease, obsessive-compulsive behaviour, panic attacks, social phobias, eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, stress, as an aid to smoking cessation and in the treatment and/or prophylaxis of seizures, neurological disorders such as epilepsy and/or conditions in which there is neurological damage such as stroke, brain trauma, cerebral ischaemia, head injuries and haemorrhage
  • the present invention also provides a method of treating depression, anxiety, psychoses (for example schizophrenia), tardive dyskinesia, obesity, drug addiction, drug abuse, cognitive disorders, Alzheimer's disease, obsessive-compulsive behaviour, panic attacks, social phobias, eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, stress and seizures, neurological disorders such as epilepsy and/or conditions in which there is neurological damage such as stroke, brain trauma, cerebral ischaemia, head injuries and haemorrhage which comprises the administration of a therapeutically effective amount of a compound of Formula I to a patient in need thereof
  • the compounds of the present invention may be useful in the treatment or prevention of metabolic diseases and conditions arising therefrom, for example non exercise activity thermogenesis and increased metabolic rate, sexual dysfunction, sleep apnoea, premenstrual syndrome, urinary incontinence hyperactivity disorders, hiatial hernia and reflux esophagitis, pain, especially neuropathic pain, weight gain associated with drug treatment, chronic fatigue syndrome, osteoarth ⁇ tis and gout, cancers associated with weight gain, menstrual dysfunction, gallstones, orthostatic hypotension and pulmonary hypertension
  • metabolic diseases and conditions for example non exercise activity thermogenesis and increased metabolic rate, sexual dysfunction, sleep apnoea, premenstrual syndrome, urinary incontinence hyperactivity disorders, hiatial hernia and reflux esophagitis, pain, especially neuropathic pain, weight gain associated with drug treatment, chronic fatigue syndrome, osteoarth ⁇ tis and gout, cancers associated with weight gain, menstrual dysfunction, gallstones, orthostatic hypotension and pulmonary hypertension
  • the compounds of the present invention may be useful in preventing cardiovascular disease, and in reducing platelet adhesiveness, in aiding weight loss after pregnancy and in aiding weight loss after smoking cessation
  • the compounds of the present invention are particularly useful in treating obesity and related co-morbid conditions, for example, diabetes, hyperglycaemia and hyperlipidaemia
  • monoamine reuptake inhibitors which are used to treat obesity are often associated with cardiovascular side effects, for example, increased heart rate and increased blood pressure
  • the compounds of the present invention reduce the cardiovascular side effects which might be expected to occur from the administration of a monoamine reuptake inhibitor particularly a noradrenaline reuptake inhibitor Whilst not wishing to be bound by theory it is likely that the combination of 5-HT A agonism in the compounds of the present invention reduces the cardiovascular side effects which might have arisen from their monoamine reuptake inhibition particularly their noradrenaline reuptake inhibition
  • the present invention provides a method of reducing the cardiovascular side effects of an anti-obesity drug comprising incorporating into the compound 5-HT 1A agonism
  • the present invention provides the use of a compound which is a 5-HT-
  • the 5-HT-i A agonism of especially preferred compounds of the present invention may be determined by electrophysiology by methods known to those skilled in the art
  • Processes for the preparation of compounds of Formula I will now be described
  • the processes may be performed on an individual basis, or by multiple parallel synthesis, also known as High Speed Analoguing
  • the processes are preferably carried out at atmospheric pressure
  • A, R ⁇ R 2 , R 3 , R 4 , R 5 , g and n are as hereinbefore defined, optionally in the presence of an acid, for example acetic or sulphuric acid, at a temperature in the range 0-200°C, preferably in the range 20-150°C
  • Z is a leaving group, for example a halo such as bromo, and A, R-i, R , R 5 and g are as hereinbefore defined, at a temperature in the range 0-200°C, in the presence of a solvent, for example ethanol and optionally in the presence of an acid, for example acetic acid; preferably by heating at a temperature in the range 20°C to the boiling point of the solvent used.
  • a solvent for example ethanol
  • an acid for example acetic acid
  • Compounds of Formula I may also be prepared directly by reacting a compound of Formula III with a compound of Formula IV at a temperature in the range of 0-200°C, optionally in the presence of an acid, for example acetic acid, and optionally in the presence of a solvent, for example ethanol, without isolation of the intermediate of Formula II; preferably by heating at a temperature in the range 20-150°C.
  • halogenating agent for example bromine, phenyltrimethylammonium tribromide, iodine raonochloride or benzyltrimethylammonium tetrachloroiodate at a temperature in the range -50-200°C optionally in the presence of a solvent, for example dichloromethane, tetrahydrofuran or acetone
  • R 4 represents a group of Formula -CH(OH)R x in which R x is a d. 5 alkyl group, an alkenyl group containing 2-5 carbon atoms, an alkynyl group containing 2-5 carbon atoms or (2-C 1 . 3 alkoxyphenyl) may be prepared by reacting a compound of Formula VI
  • R y is H with an organometallic reagent, for example a compound of formula R x MgX or R x L ⁇ in which R x is as hereinbefore defined and X is halo, for example bromo, in the presence of a solvent, for example tetrahydrofuran or ether, at a temperature in the range of -50°C to the boiling point of the solvent used
  • organometallic reagent for example a compound of formula R x MgX or R x L ⁇ in which R x is as hereinbefore defined and X is halo, for example bromo, in the presence of a solvent, for example tetrahydrofuran or ether, at a temperature in the range of -50°C to the boiling point of the solvent used
  • R 4 represents a group of Formula -CH(OH)R y in which R y is a d 5 alkyl group, an alkenyl group containing 2-5 carbon atoms, an alkynyl group containing 2-5 carbon atoms or (2-C 1 .
  • 3 alkoxyphenyl may be prepared by reacting a compound of Formula VI in which A, R-i, R 2 , R 3 , F%, g and n are as hereinbefore defined and R y is a Ci 5 alkyl group, an alkenyl group containing 2-5 carbon atoms, an alkynyl group containing 2-5 carbon atoms or (2-C- ⁇ 3 alkoxyphenyl) with a reducing agent, for example sodium borohydride, in the presence of a solvent, for example ethanol, at a temperature in the range of 0°C to the boiling point of the solvent used
  • a reducing agent for example sodium borohydride
  • Compounds of Formula I in which R 4 is hydroxymethyl may be prepared by reacting a compound of Formula VI in which A, R-i, R ⁇ R 3 , R 4 , R 5 , g and are as hereinbefore defined and R y is H with a reducing agent, for example sodium borohydride, in a solvent, for example methanol, at a temperature in the range of -50°C to the boiling point of the solvent used
  • a reducing agent for example sodium borohydride
  • a solvent for example methanol
  • Compounds of Formula I in which R is cyano may be prepared by reacting a compound of Formula VI in which A, R-i, R 2 , R 3 , R 5 , n and g are as hereinbefore defined and R y is H with hydroxylamine or a salt thereof in the presence of formic acid at a temperature in the range of 0-250°C.
  • R represents a d ⁇ alkyliminomethylene group
  • R y represents H
  • R a represents a C ⁇ alkyl group optionally in the presence of a solvent, for example ethanol, optionally in the presence of an acid catalyst, for example acetic acid, at a temperature in the range 0-250°C.
  • Compounds of Formula I in which R represents a C 1 - 4 alkylaminomethylene group may be prepared by reacting a compound of Formula I in which R 4 represents a group, and A, R-i, R 2 , R 3 , R 5 , n and g are as hereinbefore defined, with a reducing agent, for example sodium borohydride, in the presence of a solvent, for example an alcohol e.g. ethanol, at a temperature in the range 0°C to the boiling point of the solvent used.
  • a reducing agent for example sodium borohydride
  • R represents a C 1 - 4 alkylaminomethylene group
  • R y represents hydrogen by reaction with an amine of formula R a NH 2 wherein R a represents a C ⁇ alkyl group and a reducing agent, for example sodium triacetoxyborohydride, in the presence of a solvent, for example tetrahydrofuran, at a temperature in the range 0°C to the boiling point of the solvent used.
  • a solvent for example tetrahydrofuran
  • R-i, R , R 3 , R 5 , n and g are as previously defined, with an organometallic reagent, for example a compound of formula R x MgX or R x L ⁇ in which R x is as hereinbefore defined and X is halo, for example bromo, in the presence of a solvent, for example tetrahydrofuran or ether, at a temperature in the range of -50°C to the boiling point of the solvent used
  • R 4 represents a group of formula -C(OH)R x R y in which R x and R y are the same d 2 alkyl group
  • R y is OR z in which R z is a d 6 alkyl group
  • an organometallic reagent for example a compound of formula R x MgX or R x L ⁇ in which R x is as hereinbefore defined and X is halo, for example bromo, in the presence of a solvent, for example tetrahydrofuran or ether, at a temperature in the range of -50°C to the boiling point of the solvent used
  • R 4 represents a C 2 . 6 alkenyl group in which the double bond is attached to the carbon alpha to the thiazole ring or a styryl group
  • R y represents hydrogen or a C 1-4 alkyl group
  • A, R 1 f R 2 , R 3 , R 5 , n and g are as previously defined, with a phosphonium salt of formula R z Ph 3 P + Br- in which R z represents a d- 5 alkyl group or a benzyl group in the presence of a base for example n- butyllithium, in a solvent for example, an ether, e g tetrahydrofuran, at a temperature in the range -78°C to the boiling point of the solvent used
  • Compounds of Formula I in which R represents a C 2 _ 6 alkanoyl group may be prepared by reacting a compound of Formula I in which R 4 represents halo, for example bromo or chloro, and A, R-,, R 2 , R 3 , R 5 , n and g are as previously defined, or a compound of Formula V with a compound of formula R MgX or R b L ⁇ in which R is a C 1 - 6 alkyl group and X is halo, for example bromo or chloro, in the presence of a solvent for example an ether, eg diethyl ether or tetrahydrofuran, at a temperature in the range -78°C to the boiling point of the solvent used, and then reacting the product obtained with an acylating agent for example a compound of Formula R c CON(CH 3 )OCH 3 in which R c represents a C- 1 . 5 alkyl group in a solvent, for example an ether e
  • Compounds of Formula I in which R represents a C 1-3 alkoxyd- 3 alkyl group may be prepared by reacting a compound of Formula I in which R 4 represents a hydroxyd- 3 alkyl group, and A, R ⁇ R 2 , R 3 , R 5 , n and g are as previously defined, with a C- ⁇ - 3 alkylating agent, for example a _ 3 alkyl halide e g. a C 1-3 alkyl iodide in the presence of a base, for example sodium hydride, in a solvent, for example/V, ⁇ /- dimethylformamide, at a temperature in the range of -50 to 150°C
  • a C- ⁇ - 3 alkylating agent for example a _ 3 alkyl halide e g. a C 1-3 alkyl iodide in the presence of a base, for example sodium hydride, in a solvent, for example/V, ⁇ /- dimethylformamide, at a
  • Compounds of Formula I in which R represents a C . 7 cycloalkylalkoxyC ⁇ . 3 alkyl group may be prepared by reacting a compound of Formula I in which R represents a hydroxyC ⁇ - 3 alkyl group, and A, R-
  • Compounds of Formula I in which R represents a C 3 _ 7 alkynylalkoxyd. 3 alkyl group may be prepared by reacting a compound of Formula I in which R represents a hydroxyC- ⁇ . 3 alkyl group, and A, R ⁇ R 2 , R 3 , R 5 , n and g are as previously defined, with a C 3 7 alkynylalkylating agent, for example a C 3 7 alkynylalkyl halide e g a C 3 7 alkynylalkyl iodide in the presence of a base, for example sodium hydride, in a solvent, for example ⁇ /, ⁇ /-d ⁇ methylformam ⁇ de, at a temperature in the range of -50 to 150°C
  • a base for example sodium hydride
  • Compounds of Formula I in which R 4 represents a . 3 alkylth ⁇ oC 1 . 3 alkyl group may be prepared by reacting a compound of Formula I in which R 4 represents a mercaptoC ⁇ _ 3 alkyl group, and A, R-i, R 2 , R 3 , R 5 , n and g are as previously defined, with a C- ⁇ - 3 alkylating agent, for example a . 3 alkyl halide e g a .
  • Compounds of Formula I in which R represents a d_ 3 alkoxy group and A, R-i , R 2 , R 3 , R 5 , n and g are as previously defined may be prepared by reacting a compound of Formula I in which R 4 represents halo, for example bromo or iodo, with an - 3 alkoxide salt, for example a sodium or potassium salt, optionally in the presence of a solvent, for example a - 3 alcohol or dimethylformamide, optionally in the presence of a catalyst, for example a copper (I) salt, at a temperature in the range of 0-350°C
  • Compounds of Formula I in which R represents a C 3 . 6 alkenyl group in which the double bond is not attached to the carbon alpha to the thiazole ring may be prepared by reacting a compound of Formula I in which R represents halo, for example bromo or chloro, and A, R-i, R 2 , R 3 , R 5 , n and g are as previously defined, or a compound of Formula V with a compound of formula R MgX or R b L ⁇ in which R b is a C 1 - 6 alkyl group and X is halo, for example bromo or chloro, in the presence of a solvent for example an ether, eg diethyl ether or tetrahydrofuran, at a temperature in the range -78°C to the boiling point of the solvent used, and then reacting the product obtained with an alkenylating agent, for example a C 3 .
  • Compounds of Formula I in which R 4 is a C . 6 hydroxyalkenyl group in which the double bond is attached to the carbon alpha to the thiazole ring may be prepared by reacting compounds of Formula VI, in which R y represents hydrogen and A, R ⁇ F 2> R 3 . R 5 .
  • n an d 9 are as previously defined, with a compound of Formula (R z O) 2 POCH2COR c in which R z represents a C ⁇ alkyl group and R c represents a d- 3 alkyl group in the presence of a base, for example sodium hydride, in a solvent for example an ether, e g tetrahydrofuran, at a temperature in the range -78°C to the boiling point of the solvent used, then subjecting the resulting intermediate product to reaction with a reducing agent, for example sodium borohydride, in a solvent, for example ethanol, at a temperature in the range -20°C to the boiling point of the solvent used
  • a base for example sodium hydride
  • a solvent for example an ether, e g tetrahydrofuran
  • Membranes 400 ⁇ l, equivalent to 2 5 mg wet weight of tissue/tube were incubated with 50 ⁇ l of [ 3 H]8-hydroxy-2-(d ⁇ propylam ⁇ no)tetral ⁇ n ([ 3 H]8-OH-DPAT) at a single concentration of 1 nM and 50 ⁇ l of distilled water (total binding) or 50 ⁇ l of test compound (at a single concentration of 10 6 M or at 10 concentrations ranging from 10 11 -10 3 M) or 50 ⁇ l of 5-HT (10 ⁇ M, non-specific binding) at 25°C for 30 minutes The incubation was terminated by rapid filtration under vacuum through Skatron 11734 filters using a Skatron Cell Harvester Filters were washed with ice-cold 50 mM Tris-HCl buffer, pH 7 7 (at 25°C, wash setting 9,9,0) The scored filter paper discs were punched out into vials, scintillation fluid added and radioactivity determined by liquid scintillation counting
  • Frontal cortical tissue from the brains of male Charles River rats weighing 150-250 g was homogenised in ice-cold 50 mM Tris-HCl, pH 7 4 (when measured at 25°C) containing 120 mM sodium chloride and 5 mM potassium chloride (T ⁇ s buffer, 1 30 w/v) and centrifuged at 40,000 g for 10 minutes The supernatant was discarded and the pellet rehomogenised in Tris buffer, 1 60 w/v, and centrifuged at 40,000 g for 10 minutes This step was repeated a further time The final pellet was resuspended in 50 mM Tris-HCl, pH 7 4 containing 120 mM sodium chloride and 5 mM potassium chloride (equivalent to 3 125 mg wet weight of tissue/ml) and used immediately in the binding assay All centnfugations were performed at 4°C
  • Membranes 400 ⁇ l, equivalent to 1 25 mg wet weight of tissue/tube were incubated with 50 ⁇ l [ 3 H]c ⁇ talopram at a single concentration of 1 3 nM and 50 ⁇ l of distilled water (total binding) or 50 ⁇ l of test compound (at a single concentration of 10 6 M or at 10 concentrations ranging from 10 11 -10 3 M) or 50 ⁇ l of paroxetine (0 5 ⁇ M, non-specific binding) for 1 h at 27°C Membrane bound radioactivity was recovered by filtration under vacuum through Skatron 11734 filters presoaked in 0 5% PEI using a Skatron Cell Harvester Filters were then washed in ice-cold 50 mM Tns-HCI buffer, pH 7 4 (at 25°C, wash setting 9,9,0) The scored filter paper discs were punched out into vials, scintillation fluid added and radioactivity determined by liquid scintillation counting
  • Frontal cortical tissue from the brains of male Charles River rats weighing 150-250 g was homogenised in ice-cold 50 mM Tns-HCI, pH 7 4 (at 25°C) containing 120 mM sodium chloride and 5 mM potassium chloride (T ⁇ s buffer, 1 60 w/v) using a Kinematic polytron (speed setting 6 for 10 seconds) and centrifuged at 40,000 g for 10 minutes The supernatant was discarded and the pellet rehomogenised in Tris buffer, 1 60 w/v, and centrifuged at 40,000 g for 10 minutes This step was repeated twice more so that, in total, the brain tissue was homogenised and centrifuged four times The final pellet was resuspended in 50 mM Tns-HCI, pH 7 4 containing 300 mM sodium chloride and 5 mM potassium chloride (equivalent to 18 75 mg wet weight of tissue/ml) and used immediately in the binding assay All centnfugations were performed at 4
  • Membranes 400 ⁇ l, equivalent to 7 5 mg wet weight of tissue/tube were incubated with 50 ⁇ l [ 3 H]n ⁇ soxet ⁇ ne at a single concentration of 0 6 nM and 50 ⁇ l of distilled water (total binding) or 50 ⁇ l of test compound (at a single concentration 10 6 M or at 10 concentrations ranging from 10 11 -10 3 M) or 50 ⁇ l of mazindol (1 ⁇ M, non-specific binding) for 4 h at 4°C Membrane bound radioactivity was recovered by filtration under vacuum through Skatron 11734 filters using a Skatron cell harvester Filters were rapidly washed with ice-cold 50 mM Tns-HCI, pH 7 4 containing 120 mM sodium chloride and 5 mM potassium chloride (wash setting 9,9,0) The scored filter paper discs were punched out into vials, scintillation fluid added and radioactivity determined by liquid scintillation counting The ability of compounds of Formula 1
  • Frontal cortical tissue from the brains of male Charles River rats weighing 150-250 g was homogenised in ice-cold 20 mM HEPES buffer, pH 7.5 (measured at 25°C) containing 100 mM sodium chloride and 10 mM magnesium chloride (1 :10 w/v) using a Polytron PT3100 (speed setting 21 ,700rpm, 3 x 5 seconds) and centrifuged at 49,500 g for 30 minutes at 4°C. The supernatant was discarded and the pellet rehomogenised in 20 mM HEPES buffer, pH 7.5 containing 100 mM sodium chloride and 10 mM magnesium chloride (equivalent to 12.5 mg wet weight of tissue/ml). Membranes were stored at -80°C until required.
  • Membranes were thawed, diluted 1 :10 in ice-cold 20 mM HEPES buffer, pH
  • Membrane bound radioactivity was recovered by filtration under vacuum through Skatron 1 1734 filters using a Skatron cell harvester. Filters were rapidly washed with ice-cold 20 mM HEPES buffer, pH 7.5 (wash 1 ,2 at setting 5,5). The scored filter paper discs were punched out into vials, scintillation fluid added and radioactivity determined by liquid scintillation counting.
  • a (dpm) Total binding (dpm) - Non-specific binding (dpm)
  • displacement curves were then produced for compounds which displaced >50% of specific binding of the tritiated ligand at 10 "6 M using a range of concentrations of the compound.
  • B is the concentration of bound ligand-receptor complex This is calculated for each observation as B .
  • [L] tot is the concentration of the tritiated ligand used, calculated as r ⁇ _ Mean DPM for Total DPM added samples x Dilution Specific activity x Volume of incubation
  • Krj is the equilibrium dissociation constant for the ligand
  • F T and F 2 are the concentrations of free ligand and free compound respectively
  • N is the non-specific binding constant
  • the assay was performed using the following general procedure in which the tissue source was human placenta
  • Especially preferred compounds of Formula la have surprisingly lower affinity for muscarinic receptors compared to the Examples of WO97/02269 and/or have significantly reduced MAO A inhibitory activity compared to compounds exemplified in WO97/02269
  • Example 1 of WO97/02269 has a muscarinic receptor binding K
  • Particularly preferred compounds of the present invention have superior activity in acute feeding studies compared to the compounds exemplified in WO 97/02269
  • Triethylamine (75 ml) was added dropwise at ⁇ 10 °C to a stirred suspension of 3-(benzo[jb]th ⁇ ophen-3-yl)-5,6-d ⁇ hydro ⁇ m ⁇ dazo[2,1-b]th ⁇ azole hydrobromide (50 g prepared in a manner similar to that described in WO 97/02269) in dichloromethane (400 ml), then the mixture was stirred at ambient temperature for 1 hour.
  • n-Butyllithium (2.5 M solution in hexanes; 17.5 ml) was added dropwise under nitrogen at -70 °C to a stirred solution of 3-(benzo[5]thiophen-3-yl)-5,6-dihydro- imidazo[2,1-/b]thiazole (10.14 g) in tetrahydrofuran (260 ml), then the mixture was stirred at -70 °C for 20 minutes, allowed to warm to 0 °C, and stirred at 0 °C for 30 minutes. Dimethylformamide (2.86 ml) was added, and the mixture was stirred at ambient temperature for 20 minutes.
  • Triethylamine (3 ml) was added, then the resulting solution was washed with water (20 ml) and saturated aqueous sodium chloride solution (20 ml), dried (MgSO 4 ), and the solvent was removed in vacuo to leave 3-(benzo[b]thiophen-3-yl)-5,6-dihydro- imidazo[2,1- ⁇ ]thiazole-2-carboxaldehyde oxime as a white solid (0.07 g), m.p. 226-228°C.
  • Methylmagnesium bromide (3 M solution in ether; 1.2 ml) was added dropwise at 0°C under nitrogen to a stirred solution of 3-(benzo[b]thiophen-3-yl)-5,6- dihydroimidazo[2,1-b]thiazole-2-carboxaldehyde (0.286 g) in tetrahydrofuran (30 ml), then the mixture was stirred at ambient temperature for 15 minutes.
  • the resulting solid was collected by filtration, washed with ice-cold methanol (200 ml), and dried in vacuo at 60°C for 3 hours and at 80°C for 2 hours to give a white solid which was shown by nmr spectroscopy to be solvated by 1 equivalent of methanol.
  • Phenyltrimethylammonium tribromide (3.0 g) was added in portions under nitrogen at 0°C to a stirred suspension of 3-(benzo[ ⁇ ]thiophen-3-yl)-5,6-dihydro- imidazo[2,1-(b]thiazole (2.0 g) in tetrahydrofuran (50 ml), then the mixture was stirred at 0°C for 1 hour and at ambient temperature for 18 hours. Water (50 ml) and triethylamine (50 ml) were added, and the organic phase was separated, washed with saturated aqueous sodium chloride solution (50 ml), dried (MgSO 4 ), and the solvents were removed in vacuo.
  • Phenyltrimethylammonium tribromide (0.75 g) was added in portions under nitrogen at 0°C to a stirred suspension of 3-(benzo[b]thiophen-3-yl)-6,7-dihydro-5/-/- thiazolo[3,2-a]pyrimidine (0.5 g; prepared in a manner similar to that described in WO 97/02269)) in tetrahydrofuran (15 ml), then the mixture was stirred at 0°C for 4 hours and allowed to warm to ambient temperature.
  • Phenyltrimethylammonium tribromide (2 15 g) was added in portions at 0°C under nitrogen to a stirred solution of ethyl 3-(benzo[ ⁇ ]th ⁇ ophen-3-yl)-3-oxo- propanoate (1 5 g) in tetrahydrofuran (30 ml), then the mixture was stirred at 0°C for 30 minutes and at ambient temperature for 1 5 hours The resulting solid was removed by filtration and washed with tetrahydrofuran (30 ml) The filtrate and washings were combined and the solvent was removed in vacuo The residue was purified by flash chromatography over silica in Biotage Flash 40 ⁇ ⁇ equipment using a 9 1 mixture of petroleum ether (b p 60-80 °C) and ethyl acetate as eluant Appropriate fractions were combined and the solvents were removed in vacuo to leave ethyl 3-(benzo[6]-th ⁇ ophen-3-yl
  • Triethylamine (50 ml) was added dropwise at ambient temperature to a stirred suspension of 3-(5-methoxybenzo[b]th ⁇ ophen-3-yI)-5,6-d ⁇ hydro ⁇ m ⁇ dazo[2,1-b]- thiazole hydrobromide (1 g, prepared in a manner similar to that described in WO 97/02269) in dichloromethane (25 ml), then the mixture was stirred at ambient temperature for 10 minutes Water (25 ml) was added, then the organic phase was separated, washed with water (25 ml), dried (Na 2 SO 4 ), and the solvents were removed in vacuo to leave 3-(5-methoxybenzo[b]th ⁇ ophen-3-yl)-5,6-d ⁇ hydro- ⁇ m ⁇ dazo[2,1-Jb]th ⁇ azole as a brown solid (0 65 g) which was used without further purification
  • Phenyltrimethylammonium tribromide (1 5 g) was added in portions at 0°C under nitrogen to a stirred solution of 3-(5-methoxybenzo[ ⁇ ]th ⁇ ophen-3-yl)-5,6- d ⁇ hydro ⁇ m ⁇ dazo[2,1-6]th ⁇ azole (0 65 g) in tetrahydrofuran (25 ml), the mixture was stirred at 0°C for 16 hours, then it was allowed to warm to ambient temperature Triethylamine (50 ml) and water (50 ml) were added, then the organic phase was separated, dried (Na 2 SO 4 ), and the solvents were removed in vacuo The residue was purified by flash chromatography over silica using a 99 1 0 1 mixture of ethyl acetate, methanol and triethylamine as eluant Appropriate fractions were combined and the solvents were removed in vacuo The residue was crystallised from methanol and the resulting solid was
  • Phenyltrimethylammonium tribromide (1.0 g) was added in portions at 0 - 5°C under nitrogen over 15 minutes to a stirred solution of 3-(5- chlorobenzo[Jb]thiophen-3-yl)-5,6-dihydroimidazo[2,1- ⁇ ]thiazole (0.8 g; prepared in a manner similar to that described in WO 97/02269) in tetrahydrofuran (20 ml), then the mixture was stirred at ambient temperature for 18 hours.
  • Phenyltrimethylammonium tribromide (0 4 g) was added in portions under nitrogen to a stirred solution of 1-(benzo[b]th ⁇ ophen-3-yl)-3-benzyloxypropan-1-one (0 43 g) in tetrahydrofuran (5 ml), the mixture was stirred at ambient temperature for 18 hours then it was filtered and the solvent was removed in vacuo to leave 1-(benzo[6]th ⁇ ophen-3-yl)-3-benzyloxy-2-bromopropan-1 -one as a yellow oil (0 56 g) which was used without further purification
  • Benzylt ⁇ methylammonium chloride (8 g) was added in portions at ambient temperature to a stirred solution of iodine trichloride (10 g) in dichloromethane (120 ml), then the mixture was stirred at ambient temperature for 2 5 hours The resulting solid was collected by filtration and dried in vacuo at ambient temperature to give benzylt ⁇ methylammonium tetrachloroiodate as a yellow solid (16 2 g) which was used without further purification
  • Examples 25 - 33 were prepared as part of a High Speed Analogue library using the following general method :
  • n-Butyllithium (2 5M solution in hexanes, 73 8 ml) was added dropwise over 45 minutes at 0 - 4 °C under nitrogen to a stirred mixture of methylt ⁇ phenylphosphonium bromide (65 7 g) and tetrahydrofuran (680 ml), then the mixture was stirred at 4 °C for 10 minutes and at ambient temperature for 30 minutes 3-(Benzo[6]th ⁇ ophen-3-yl)-5,6-d ⁇ hydro ⁇ m ⁇ dazo[2,1-6]th ⁇ azole-2- carboxaldehyde (48 g, prepared in a manner similar to that described in Example 6) was added in portions at ambient temperature, then the mixture was heated under reflux for 3 hours, cooled to ambient temperature, and added to water (500 ml) The product was extracted into ethyl acetate (3 x 400 ml), then the combined extracts were washed with water (400 ml), d ⁇ ed (MgSO ),
  • Phenyltrimethylammonium tribromide (1.74 g) was added under nitrogen to a stirred solution of 1-(benzo[b]thiophen-3-yl)-2-cyclopropylethan-1-one (1 g) in tetrahydrofuran (15 ml), the mixture was stirred at ambient temperature for 18 hours, then it was filtered and the solvent was removed in vacuo. The residue was dissolved in ethanol (12 ml), 2-imidazolidinethione (0.47 g) and acetic acid (4 ml) were added, the mixture was heated under reflux under nitrogen for 18 hours, then the solvents were removed in vacuo.
  • the product was extracted into ether (3 x 150 ml), then the combined extracts were washed with 2M hydrochloric acid (200 ml) and saturated aqueous sodium chloride solution (200 ml), dried (Na 2 SO 4 ), and the solvents were removed in vacuo.
  • the mixture was basified by the addition of an excess of 1 M aqueous sodium hydroxide solution and concentrated in vacuo to remove ethanol, then the product was extracted into dichloromethane (3 x 30 ml).
  • the combined extracts were dried (MgSO ), the solvent was removed in vacuo, and the residue was purified by Biotage flash chromatography over silica using a 34:3:3 mixture of ethyl acetate, industrial methylated spirit and triethylamine as eluant. Appropriate fractions were combined and the solvents were removed in vacuo, then the residue was triturated with ether (10 ml).
  • Phenyltrimethylammonium tribromide (2 55 g) was added in portions at ambient temperature under nitrogen over 20 minutes to a stirred solution of 1-(7-methoxybenzo[b]th ⁇ ophen-3-yl)ethan-1-one (1 4 g) in tetrahydrofuran (40 ml), the mixture was stirred at ambient temperature for 1 hour, then it was filtered and the solvent was removed in vacuo The residue was dissolved in ethanol (30 ml), 2- ⁇ m ⁇ dazol ⁇ d ⁇ neth ⁇ one (0 69 g) and acetic acid (20 ml) were added, the mixture was heated under reflux for 18 hours, then it was cooled to ambient temperature The resulting solid was collected by filtration, washed with ether (20 ml) and dried in vacuo at 60 °C to give 3-(7-methoxybenzo[b]th ⁇ ophen-3-yl)-5,6-d ⁇ hydro ⁇ m ⁇ dazo[2,1- ]th ⁇ azole hydrobromid
  • Tablets are prepared from the following ingredients
  • the active compound, the lactose and some of the starch are de-aggregated, blended and the resulting mixture is granulated with a solution of the polyvinyl- pyrrolidone in ethanol
  • the dry granulate is blended with the magnesium stearate and the rest of the starch
  • the mixture is then compressed in a tabletting machine to give tablets each containing a unit dose or a part of a unit dose of active compound
  • Tablets are prepared by the method described in (b) above
  • the tablets are enteric coated in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol dichloromethane (1 1 )
  • suppositories 100 parts by weight of active compound is incorporated in 1300 parts by weight of t ⁇ glyce ⁇ de suppository base and the mixture formed into suppositories each containing a therapeutically effective amount of active ingredient

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Diabetes (AREA)
  • Psychiatry (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Addiction (AREA)
  • Pain & Pain Management (AREA)
  • Endocrinology (AREA)
  • Urology & Nephrology (AREA)
  • Rheumatology (AREA)
  • Reproductive Health (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Virology (AREA)
  • Molecular Biology (AREA)
  • AIDS & HIV (AREA)
  • Psychology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Hospice & Palliative Care (AREA)
  • Anesthesiology (AREA)
EP00935009A 1999-05-21 2000-05-11 Thiazoloderiatives and pharmaceutical compositions containing them Withdrawn EP1178993A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9911863 1999-05-21
GBGB9911863.0A GB9911863D0 (en) 1999-05-21 1999-05-21 Therapeutic agents
PCT/EP2000/004279 WO2000071549A1 (en) 1999-05-21 2000-05-11 Thiazoloderivatives and pharmaceutical compositions containing them

Publications (1)

Publication Number Publication Date
EP1178993A1 true EP1178993A1 (en) 2002-02-13

Family

ID=10853913

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00935009A Withdrawn EP1178993A1 (en) 1999-05-21 2000-05-11 Thiazoloderiatives and pharmaceutical compositions containing them

Country Status (19)

Country Link
EP (1) EP1178993A1 (cs)
JP (1) JP2003500410A (cs)
KR (1) KR20020033626A (cs)
CN (1) CN1361783A (cs)
AU (1) AU5065700A (cs)
BG (1) BG106227A (cs)
BR (1) BR0010827A (cs)
CA (1) CA2374926A1 (cs)
CZ (1) CZ20014171A3 (cs)
GB (1) GB9911863D0 (cs)
HU (1) HUP0201376A2 (cs)
IL (1) IL146540A0 (cs)
MX (1) MXPA01011895A (cs)
NO (1) NO20015667L (cs)
PL (1) PL352282A1 (cs)
SK (1) SK16852001A3 (cs)
TR (1) TR200200164T2 (cs)
WO (1) WO2000071549A1 (cs)
ZA (1) ZA200110022B (cs)

Families Citing this family (79)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0005789D0 (en) 2000-03-11 2000-05-03 Knoll Ag Therapeutic agents
GB0023610D0 (en) * 2000-09-27 2000-11-08 Knoll Ag Therapeutic agents
UA76130C2 (en) * 2000-11-20 2006-07-17 Merck Patent Gmbh Use of compounds combining properties of selective inhibitors of serotonin re-uptake and agonists of 5-ht1a receptor for treatment of irritable bowel syndrome
PL366851A1 (en) 2001-08-22 2005-02-07 Aventis Pharma Deutschland Gmbh Combined preparations, containing 1,4-benzothiepine-1,1-dioxide derivatives and other active substances, and the use thereof
IL160556A0 (en) 2001-08-31 2004-07-25 Aventis Pharma Gmbh Diaryl cycloalkyl derivatives, method for producing the same and the use thereof as ppar activators
US7399777B2 (en) 2001-08-31 2008-07-15 Sanofi-Aventis Deutschland Gmbh Diarylcycloalkyl derivatives, processes for their preparation and their use as pharmceuticals
US6884812B2 (en) 2001-08-31 2005-04-26 Aventis Pharma Deutschland Gmbh Diarylcycloalkyl derivatives, processes for their preparation and their use as pharmaceuticals
US7078404B2 (en) 2002-04-11 2006-07-18 Sanofi-Aventis Deutschland Gmbh Acyl-3-carboxyphenylurea derivatives, processes for preparing them and their use
US7223796B2 (en) 2002-04-11 2007-05-29 Sanofi-Aventis Deutschland Gmbh Acyl-4-carboxyphenylurea derivatives, processes for preparing them and their use
US7049341B2 (en) 2002-06-07 2006-05-23 Aventis Pharma Deutschland Gmbh N-benzoylureidocinnamic acid derivatives, processes for preparing them and their use
US7262220B2 (en) 2002-07-11 2007-08-28 Sanofi-Aventis Deutschland Gmbh Urea- and urethane-substituted acylureas, process for their preparation and their use
DE10231370B4 (de) 2002-07-11 2006-04-06 Sanofi-Aventis Deutschland Gmbh Thiophenglycosidderivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zur Herstellung dieser Arzneimittel
PL373329A1 (en) 2002-07-12 2005-08-22 Sanofi-Aventis Deutschland Gmbh Heterocyclically substituted benzoylureas, method for their production and their use as medicaments
US20040157922A1 (en) 2002-10-04 2004-08-12 Aventis Pharma Deutschland Gmbh Carboxyalkoxy-substituted acyl-carboxyphenylurea derivatives and their use as medicaments
US7208504B2 (en) 2002-10-12 2007-04-24 Sanofi-Aventis Deutschland Gmbh Bicyclic inhibitors of hormone sensitive lipase
DE10258007B4 (de) 2002-12-12 2006-02-09 Sanofi-Aventis Deutschland Gmbh Aromatische Fluorglycosidderivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zur Herstellung dieser Arzneimittel
US20040242583A1 (en) 2003-01-20 2004-12-02 Aventis Pharma Deutschland Gmbh Pyrimido[5,4-e][1,2,4]triazine-5,7-diones, processes for preparing them and their use
US7179941B2 (en) 2003-01-23 2007-02-20 Sanofi-Aventis Deutschland Gmbh Carbonylamino-substituted acyl phenyl urea derivatives, process for their preparation and their use
DE10306250A1 (de) 2003-02-14 2004-09-09 Aventis Pharma Deutschland Gmbh Substituierte N-Arylheterozyklen, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
US7196114B2 (en) 2003-02-17 2007-03-27 Sanofi-Aventis Deutschland Gmbh Substituted 3-(benzoylureido) thiophene derivatives, processes for preparing them and their use
DE10308351A1 (de) 2003-02-27 2004-11-25 Aventis Pharma Deutschland Gmbh 1,3-substituierte Cycloalkylderivate mit sauren, meist heterocyclischen Gruppen, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
DE10308353A1 (de) 2003-02-27 2004-12-02 Aventis Pharma Deutschland Gmbh Diarylcycloalkylderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
DE10308352A1 (de) 2003-02-27 2004-09-09 Aventis Pharma Deutschland Gmbh Arylcycloalkylderivate mit verzweigten Seitenketten, Verfahren zu ihrer Herstellung und ihre Anwendung als Arzneimittel
DE10308355A1 (de) 2003-02-27 2004-12-23 Aventis Pharma Deutschland Gmbh Aryl-cycloalkyl substituierte Alkansäurederivate, Verfahren zu ihrer Herstellung und ihre Anwendung als Arzneimittel
US7148246B2 (en) 2003-02-27 2006-12-12 Sanofi-Aventis Deutschland Gmbh Cycloalkyl derivatives having bioisosteric carboxylic acid groups, processes for their preparation and their use as pharmaceuticals
US7501440B2 (en) 2003-03-07 2009-03-10 Sanofi-Aventis Deutschland Gmbh Substituted benzoylureidopyridylpiperidine-and-pyrrolidinecarboxylic acid derivatives, processes for preparing them and their use
DE10314610A1 (de) 2003-04-01 2004-11-04 Aventis Pharma Deutschland Gmbh Neues Diphenylazetidinon mit verbesserten physiologischen Eigenschaften, Verfahren zu dessen Herstellung, diese Verbindungen enthaltende Arzneimittel und dessen Verwendung
US7094800B2 (en) 2003-07-25 2006-08-22 Sanofi-Aventis Deutschland Gmbh Cyanopyrrolidides, process for their preparation and their use as medicaments
US7008957B2 (en) 2003-07-25 2006-03-07 Sanofi-Aventis Deutschland Gmbh Bicyclic cyanoheterocycles, process for their preparation and their use as medicaments
US7094794B2 (en) 2003-07-28 2006-08-22 Sanofi-Aventis Deutschland Gmbh Substituted thiazole-benzoisothiazole dioxide derivatives, process for their preparation and their use
DE10335092B3 (de) 2003-08-01 2005-02-03 Aventis Pharma Deutschland Gmbh Substituierte Benzoylureido-o-benzoylamide, Verfahren zu deren Herstellung und deren Verwendung
US7241787B2 (en) 2004-01-25 2007-07-10 Sanofi-Aventis Deutschland Gmbh Substituted N-cycloexylimidazolinones, process for their preparation and their use as medicaments
US7470706B2 (en) 2004-01-31 2008-12-30 Sanofi-Aventis Deutschland Gmbh Cycloalkyl-substituted 7-amino-4-quinolone-3-carboxylic acid derivatives, process for their preparation and their use as medicaments
US7498341B2 (en) 2004-01-31 2009-03-03 Sanofi Aventis Deutschland Gmbh Heterocyclically substituted 7-amino-4-quinolone-3-carboxylic acid derivatives, process for their preparation and their use as medicaments
US7402674B2 (en) 2004-01-31 2008-07-22 Sanofi-Aventis Deutschland Gmbh, 7-Phenylamino-4-quinolone-3-carboxylic acid derivatives, process for their preparation and their use as medicaments
DE102004005172A1 (de) 2004-02-02 2005-08-18 Aventis Pharma Deutschland Gmbh Indazolderivate als Inhibitoren der Hormon Sensitiven Lipase
DE602004004631D1 (de) 2004-04-01 2007-03-22 Sanofi Aventis Deutschland Oxadiazolone, Verfahren zu ihrer Herstellung sowie ihre Verwendung als Pharmazeutika
DE102005026762A1 (de) 2005-06-09 2006-12-21 Sanofi-Aventis Deutschland Gmbh Azolopyridin-2-on-derivate als Inhibitoren von Lipasen und Phospholipasen
EP2013182B1 (en) 2006-03-13 2013-09-04 Kyorin Pharmaceutical Co., Ltd. Aminoquinolones as gsk-3 inhibitors
DE102006028862A1 (de) 2006-06-23 2007-12-27 Merck Patent Gmbh 3-Amino-imidazo[1,2-a]pyridinderivate
AU2007283113A1 (en) 2006-08-08 2008-02-14 Sanofi-Aventis Arylaminoaryl-alkyl-substituted imidazolidine-2,4-diones, processes for preparing them, medicaments comprising these compounds, and their use
DE102007002260A1 (de) 2007-01-16 2008-07-31 Sanofi-Aventis Verwendung von substituierten Pyranonsäurederivaten zur Herstellung von Medikamenten zur Behandlung des Metabolischen Syndroms
DE102007008420A1 (de) 2007-02-21 2008-08-28 Merck Patent Gmbh Benzimidazolderivate
ATE531721T1 (de) 2007-09-11 2011-11-15 Kyorin Seiyaku Kk Cyanoaminochinolone als gsk-3-inhibitoren
US8476261B2 (en) 2007-09-12 2013-07-02 Kyorin Pharmaceutical Co., Ltd. Spirocyclic aminoquinolones as GSK-3 inhibitors
DE102007048716A1 (de) 2007-10-11 2009-04-23 Merck Patent Gmbh Imidazo[1,2-a]pyrimidinderivate
DE102007063671A1 (de) 2007-11-13 2009-06-25 Sanofi-Aventis Deutschland Gmbh Neue kristalline Diphenylazetidinonhydrate, diese Verbindungen enthaltende Arzneimittel und deren Verwendung
US9044235B2 (en) 2008-02-18 2015-06-02 Covidien Lp Magnetic clip for implant deployment device
US8317808B2 (en) 2008-02-18 2012-11-27 Covidien Lp Device and method for rolling and inserting a prosthetic patch into a body cavity
US9301826B2 (en) 2008-02-18 2016-04-05 Covidien Lp Lock bar spring and clip for implant deployment device
US8758373B2 (en) 2008-02-18 2014-06-24 Covidien Lp Means and method for reversibly connecting a patch to a patch deployment device
US9393002B2 (en) 2008-02-18 2016-07-19 Covidien Lp Clip for implant deployment device
US9034002B2 (en) 2008-02-18 2015-05-19 Covidien Lp Lock bar spring and clip for implant deployment device
WO2009104182A2 (en) 2008-02-18 2009-08-27 Polytouch Medical Ltd A device and method for deploying and attaching a patch to a biological tissue
US8808314B2 (en) 2008-02-18 2014-08-19 Covidien Lp Device and method for deploying and attaching an implant to a biological tissue
US9833240B2 (en) 2008-02-18 2017-12-05 Covidien Lp Lock bar spring and clip for implant deployment device
US9393093B2 (en) 2008-02-18 2016-07-19 Covidien Lp Clip for implant deployment device
US9398944B2 (en) 2008-02-18 2016-07-26 Covidien Lp Lock bar spring and clip for implant deployment device
DE102008017590A1 (de) 2008-04-07 2009-10-08 Merck Patent Gmbh Glucopyranosidderivate
RU2011102262A (ru) * 2008-06-21 2012-07-27 КенБер ЛЛСи (US) Нутригеномные способы и композиции
UY31968A (es) 2008-07-09 2010-01-29 Sanofi Aventis Nuevos derivados heterocíclicos, sus procesos para su preparación, y sus usos terapéuticos
CA2730547C (en) 2008-10-20 2013-08-06 Polytouch Medical Ltd. A device for attaching a patch to a biological tissue
WO2010068601A1 (en) 2008-12-08 2010-06-17 Sanofi-Aventis A crystalline heteroaromatic fluoroglycoside hydrate, processes for making, methods of use and pharmaceutical compositions thereof
JP5502889B2 (ja) 2009-03-11 2014-05-28 杏林製薬株式会社 ｇｓｋ−３阻害剤としての７−シクロアルキルアミノキノロン
WO2011021082A1 (en) 2009-08-17 2011-02-24 PolyTouch Medical, Inc. Means and method for reversibly connecting an implant to a deployment device
AU2010286117B9 (en) 2009-08-17 2014-07-10 Covidien Lp Articulating patch deployment device and method of use
EP2470552B1 (en) 2009-08-26 2013-11-13 Sanofi Novel crystalline heteroaromatic fluoroglycoside hydrates, pharmaceuticals comprising these compounds and their use
EP2482823A2 (en) 2009-10-02 2012-08-08 Sanofi Use of compounds with sglt-1/sglt-2 inhibitor activity for producing medicaments for treatment of bone diseases
WO2012120053A1 (de) 2011-03-08 2012-09-13 Sanofi Verzweigte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung
US8710050B2 (en) 2011-03-08 2014-04-29 Sanofi Di and tri- substituted oxathiazine derivatives, method for the production, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
EP2683702B1 (de) 2011-03-08 2014-12-24 Sanofi Neue substituierte phenyl-oxathiazinderivate, verfahren zu deren herstellung, diese verbindungen enthaltende arzneimittel und deren verwendung
US8809325B2 (en) 2011-03-08 2014-08-19 Sanofi Benzyl-oxathiazine derivatives substituted with adamantane and noradamantane, medicaments containing said compounds and use thereof
WO2012120052A1 (de) 2011-03-08 2012-09-13 Sanofi Mit carbozyklen oder heterozyklen substituierte oxathiazinderivate, verfahren zu deren herstellung, diese verbindungen enthaltende arzneimittel und deren verwendung
US8895547B2 (en) 2011-03-08 2014-11-25 Sanofi Substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof
US8828994B2 (en) 2011-03-08 2014-09-09 Sanofi Di- and tri-substituted oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
US8846666B2 (en) 2011-03-08 2014-09-30 Sanofi Oxathiazine derivatives which are substituted with benzyl or heteromethylene groups, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
US8871758B2 (en) 2011-03-08 2014-10-28 Sanofi Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
EP2567959B1 (en) 2011-09-12 2014-04-16 Sanofi 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
CN114113064B (zh) * 2021-12-27 2023-09-08 郑州大学 基于苯并双噻唑的光响应类氧化物酶及其制备方法和在比色检测食品中谷胱甘肽的应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9513467D0 (en) * 1995-07-01 1995-09-06 Knoll Ag Therapeutic agents
GB9705428D0 (en) * 1997-03-15 1997-04-30 Knoll Ag Therapeutic agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0071549A1 *

Also Published As

Publication number Publication date
AU5065700A (en) 2000-12-12
SK16852001A3 (sk) 2002-05-09
TR200200164T2 (tr) 2002-04-22
ZA200110022B (en) 2003-05-28
BR0010827A (pt) 2002-06-04
PL352282A1 (en) 2003-08-11
MXPA01011895A (es) 2004-03-19
HUP0201376A2 (en) 2002-08-28
CA2374926A1 (en) 2000-11-30
JP2003500410A (ja) 2003-01-07
BG106227A (en) 2002-08-30
KR20020033626A (ko) 2002-05-07
GB9911863D0 (en) 1999-07-21
NO20015667L (no) 2002-01-21
NO20015667D0 (no) 2001-11-20
IL146540A0 (en) 2002-07-25
WO2000071549A1 (en) 2000-11-30
CZ20014171A3 (cs) 2002-06-12
CN1361783A (zh) 2002-07-31

Similar Documents

Publication Publication Date Title
WO2000071549A1 (en) Thiazoloderivatives and pharmaceutical compositions containing them
US6900216B2 (en) Dihydroimidazo[2,1-b]thiazole and dihydro-5h-thiazolo[3,2-A]pyrimidines as antidepressant agents
EP0970090B1 (en) Substituted 4-arylmethylene-2-imino-2,3-dihydrothiazoles and derivatives and their pharmaceutical use
KR101855471B1 (ko) 다환형 화합물 및 이의 사용 방법
HU201553B (en) Process for producing tetrahydrofuro- and -thieno(2,3-c)pyridines and pharmaceutical compositions comprising same
WO2000071548A1 (en) Substituted imidazothiazoles as antidepressant agents
WO2002026747A1 (en) Dihydroimidazo[2,1-b]thiazole and dihydro-5h-thiazolo[3,2-a]pyrimidine derivatives with 5-ht receptor affinity
EP0836606B1 (en) Condensed thiazole derivatives, having 5-ht receptor affinity
EP1242419A1 (en) Azabicyclo 3.2.1]octane derivatives
WO2001046186A1 (en) Benzofuran derivatives
CZ9903260A3 (cs) Terapeutická činidla
MXPA97009509A (en) Therapeutic agents

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20011212

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: AL;LT PAYMENT 20011212;LV;MK;RO;SI PAYMENT 20011212

17Q First examination report despatched

Effective date: 20020704

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20021201