WO2000049017A1 - Dioxydes de 1-((indoly azacycloalkyl) alkyl)-2,1, 3-benzothiadiazole 2,2 faisant montre d'une activite de recepteur 5-ht2a - Google Patents

Dioxydes de 1-((indoly azacycloalkyl) alkyl)-2,1, 3-benzothiadiazole 2,2 faisant montre d'une activite de recepteur 5-ht2a Download PDF

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Publication number
WO2000049017A1
WO2000049017A1 PCT/GB2000/000469 GB0000469W WO0049017A1 WO 2000049017 A1 WO2000049017 A1 WO 2000049017A1 GB 0000469 W GB0000469 W GB 0000469W WO 0049017 A1 WO0049017 A1 WO 0049017A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
hydrogen
optionally substituted
substituted phenyl
halo
Prior art date
Application number
PCT/GB2000/000469
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English (en)
Inventor
John Fairhurst
Original Assignee
Eli Lilly And Company Limited
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 Eli Lilly And Company Limited filed Critical Eli Lilly And Company Limited
Priority to AU24539/00A priority Critical patent/AU2453900A/en
Publication of WO2000049017A1 publication Critical patent/WO2000049017A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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

Definitions

  • This invention relates to novel compounds with pharmaceutical properties .
  • the compounds of the invention are of the following formula:
  • n is 0, 1 or 2
  • p is 1 or 2
  • q is 1 to 6
  • r is 0 or 1 to 3
  • R is halo, C ⁇ _4 alkyl, nitrile, trifluoromethyl or C ⁇ __4
  • R ⁇ and R ⁇ are each hydrogen or C]__4 alkyl
  • R ⁇ is hydrogen, C ⁇ __4 alkyl, optionally substituted
  • R5 is C ⁇ _4 alkyl, C ⁇ __4 alkoxy, carboxy, hydroxy, cyano,
  • the dotted line represents an optional double bond
  • the compounds of the invention and their pharmaceutically acceptable salts and esters are indicated for use in the treatment of disorders of the central nervous system.
  • a Cj__4 alkyl group can be methyl, ethyl or propyl and
  • a C ⁇ __4 alkoxy group is one such C]__4 alkyl
  • An optionally substituted phenyl-C ⁇ _4 alkyl group is an
  • a halo substituent is preferably fluoro, chloro or bromo .
  • An optionally substituted phenyl group is optionally substituted with one or more, preferably one to three, substitutents selected from, for example C ⁇ _4 alkyl,
  • a preferred group of compounds is one of formula (I) above, in which the dotted line represents a double
  • Substituent (R ⁇ ) m preferably represents 6-fluoro
  • Preferred compounds are those of the following formula (II) :
  • R ⁇ is C ⁇ _4 alkyl, especially isopropyl
  • r is 0 or 1, and preferably 0 (unsubstituted)
  • R5 is C _4 alkoxy, hydroxy, halo or amino (-NH2)
  • a particularly preferred group of compounds is of the formula:
  • R ⁇ is C ⁇ _4 alkyl and especially._is equally distributed.
  • Acid addition salts are preferably the pharmaceutically acceptable, non-toxic addition salts with suitable acids, such as those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids, or with organic acids, such as organic carboxylic acids, for example, glycollic, maleic, hydroxymaleic, fumaric, malic, tartaric, citric, salicyclic, o-acetoxybenzoic, or organic sulphonic, 2-hydroxyethane sulphonic, toluene-p-sulphonic, or naphthalene-2-sulphonic acid.
  • suitable acids such as those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids
  • organic acids such as organic carboxylic acids, for example, glycollic, maleic, hydroxymaleic, fumaric, malic, tartaric, citric, salicyclic, o-acetoxybenzoic, or
  • salts are included in the invention. They may serve as intermediates in the purification of compounds or in the preparation of other, for example pharmaceutically acceptable, acid addition salts, or are useful for identification, characterisation or purification.
  • esters can be aliphatic or aromatic, being preferably alkyl esters derived from C _4 alkanols, especially methyl and ethyl esters.
  • ester substituent is -COOR' where R' is C ⁇ _4 alkyl.
  • Some of the compounds of the invention contain one or more asymmetric carbon atoms which gives rise to isomers. These compounds are normally prepared as racemic mixtures and can conveniently be used as such, but individual isomers can be isolated by conventional techniques, if so desired. Such racemic mixtures and individual optical isomers form part of the present invention. It is preferred to use an enantiomerically pure form.
  • the invention also includes a process for producing a compound of formula (I) above, which comprises reacting a compound of the formula:
  • X is a leaving group such as, for example, a halo atom, or a mesylate or tosylate.
  • the reaction is preferably carried out in a polar solvent such as, for example, acetonitrile or water, at a temperature of from 50 a C. to 150 s C, and in the presence of sodium iodide and a base such as, for example, sodium carbonate
  • the coupling can also be effected by reacting the compound of formula (IV) with an aldehyde equivalent of the compound of formula (V) .
  • aldehydes can be prepared from the appropriate terminal alkene by oxidation employing, for example, ozone or osmium tetroxide, followed by reductive amination using, for example, sodium cyanoborohydride, borane in pyridine or sodium triacetoxy borohydride, and the compound of formula (IV) .
  • This reaction is preferably carried out at a temperature of from -20 2 C. to 50 2 C, in a solvent such as, for example, dic loromethane .
  • X is a leaving group
  • Y is halo, preferably bromo, with a compound of formula:
  • Preferred alkane reactants are dihalo-alkanes , for instance bromo chloroethane, and the reaction is preferably carried out in an organic solvent such as, for example, dimethylformamide, with a strong base such as sodium hydride, at a temperature of from 0 2 C. to 100 2 C, for instance at room temperature.
  • organic solvent such as, for example, dimethylformamide
  • a strong base such as sodium hydride
  • the compounds of the invention and their pharmaceutically acceptable salts have useful central nervous system activity.
  • the compounds are active at the serotonin, 5-HT2A, receptor- _ Their binding activity has been demonstrated in a test described by Nelson, D. L. et al, J. Pharmacol. Exp. Ther., 265, 1272-1279, in which the affinity of the compound for the human 2A receptor is measured by its
  • the compounds of the invention in the following Examples had a Ki of less than 15 nM.
  • the compounds of the invention are also active serotonin reuptake inhibitors as measured by their displacement of
  • the compounds of the present invention are indicated for use in treating a variety of conditions such as depression, obesity, bulimia, alcoholism, pain, hypertension, ageing, memory loss, sexual dysfunction, anxiety, schizophrenia, gastrointestinal disorders, headache, cardiovascular disorders, smoking cessation, drug addiction, emesis, Alzheimer's and sleep disorders.
  • the compounds of the invention are effective over a wide dosage range, the actual dose administered being dependent on such factors as the particular compound being used, the condition being treated and the type and size of mammal being treated.
  • the dosage required will normally fall within the range of 0.01 to 20 mg/kg per day, for example in the treatment of adult humans, dosages of from 0.5 to 100 mg per day may be used.
  • compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • the invention includes a pharmaceutical composition
  • a pharmaceutical composition comprising as active ingredient a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof, associated with a pharmaceutically acceptable excipient.
  • the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container.
  • the excipient may be a solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient.
  • compositions of the invention may, if desired, be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient.
  • the foregoing compositions may be formulated as tablets, capsules or suspensions for oral use and injection solutions or suspensions for parenteral use or as suppositories.
  • the compositions are formulated in a dosage unit form, each dosage containing from 0.5 to 100 mg, more usually 1 to 100 mg, of the active ingredient.
  • 6-Fluoroindole l-Dimethylamino-2- (4-fluoro-2-nitro) phenylethene A mixture of 4-fluoro-2-nitrotoluene (50 g, 0.32 mol) , dimethylformamide dimethylacetal (76.77 g) and dimethylformamide (910 ml) were heated under reflux under nitrogen with stirring for 7 hours, cooled, allowed to stand for 16 hours, poured into ice-water (2000 ml) , stirred for 15 minutes and the resultant precipitate isolated by filtration, washed with water (500 ml), dried to give a red solid. 6-Fluoroindole
  • the compound was converted into its hydrochloride salt using ethereal HC1 in ethanol with M.P. 246-8 2 C.
  • Tablets each containing 10 mg of active ingredient are made up as follows:
  • Microcrystalline cellulose 100 mg Polyvinylpyrrolidone (as 10% solution in water) 13 mg Sodium carboxymethyl starch 14 mg
  • the active ingredient, starch and cellulose are mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders and passed through a sieve.
  • the granules so produced are dried and re-passed through a sieve.
  • the sodium carboxymethyl starch and magnesium stearate are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 300 mg.
  • Capsules each containing 20 mg of medicament are made as follows :
  • the active ingredient, starch and magnesium stearate are passed through a sieve and filled into hard gelatine capsules in 200 mg quantities.

Abstract

Cette invention a trait à un composé à usage pharmaceutique, correspondant à la formule (I), ainsi qu'à ses sels et esters. Dans cette formule, la valeur de m est égale à 0, 1 ou 2, celle de n à 1 ou à 2, celle de p à 1 ou à 2, celle de q va de 1 à 6 et celle de o étant de 0 ou allant de 1 à 3 ; dans cette même formule, R1 représente un halo, un alkyle portant de 1 à 4 atomes de carbone, un nitrile, un trifluorométhyle ou un alcoxy portant de 1 à 4 atomes de carbone, R2 et R3 représentent, chacun, un hydrogène ou un alkyle portant de 1 à 4 atomes de carbone, R4 représente un hydrogène, un alkyle portant de 1 à 4 atomes de carbone, un phényle éventuellement substitué ou un phényle-alkyle C¿1-4? éventuellement substitué, R?5¿ représente un alkyle portant de 1 à 4 atomes de carbone, un alcoxy portant de 1 à 4 atomes de carbone, un carboxy, un hydroxy, un cyano, un halo, un trifluorométhyle, un nitro ou un amino, la ligne en pointillés représentant une double liaison facultative.
PCT/GB2000/000469 1999-02-18 2000-02-11 Dioxydes de 1-((indoly azacycloalkyl) alkyl)-2,1, 3-benzothiadiazole 2,2 faisant montre d'une activite de recepteur 5-ht2a WO2000049017A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU24539/00A AU2453900A (en) 1999-02-18 2000-02-11 1-((indoly azacycloalkyl) alkyl)-2,1, 3-benzothiadiazole 2,2-dioxides exhibiting5-ht2a receptor activity

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9903784.8A GB9903784D0 (en) 1999-02-18 1999-02-18 Pharmaceutical compounds
GB9903784.8 1999-02-18

Publications (1)

Publication Number Publication Date
WO2000049017A1 true WO2000049017A1 (fr) 2000-08-24

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001087881A1 (fr) * 2000-05-18 2001-11-22 Eli Lilly And Company Piperidyindoles comme ligands du recepteur de la serotonine
WO2004052886A1 (fr) * 2002-12-10 2004-06-24 Merck Patent Gmbh Derives d'indol et leur utilisation comme ligands 5-ht
US6777437B2 (en) 2001-03-29 2004-08-17 Bristol-Myers Squibb Company Cyclopropylindole derivatives as selective serotonin reuptake inhibitors
US6844338B2 (en) 2000-05-18 2005-01-18 Eli Lilly And Company Piperidyindoles as serotonin receptor ligands
WO2007075717A1 (fr) * 2005-12-19 2007-07-05 Janssen Pharmaceutica N.V. Utilisation de derives de sulfamide heterocyclique benzo-fusionne pour le traitement de l'alcoolisme et/ou des toxicomanies
WO2007095617A1 (fr) * 2006-02-15 2007-08-23 Janssen Pharmaceutica N.V. Utilisation de dérivés de benzo-hétéroarylsulfamide dans le traitement d'un abus et d'une dépendance à une substance
US8853263B2 (en) 2006-05-19 2014-10-07 Janssen Pharmaceutica Nv Co-therapy for the treatment of epilepsy and related disorders
US8937096B2 (en) 2005-12-19 2015-01-20 Janssen Pharmaceutica Nv Use of benzo-fused heterocyle sulfamide derivatives for the treatment of mania and bipolar disorder

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0013612A2 (fr) * 1979-01-08 1980-07-23 Janssen Pharmaceutica N.V. Dérivés de (pipéridinylalcoyl)quinazoline, procédé pour leur préparation et compositions pharmaceutiques les contenant
EP0058975A1 (fr) * 1981-02-25 1982-09-01 Boehringer Ingelheim Pharmaceuticals Inc. N-(4-Indolyl-pipéridino-alkyl)-benzimidazolones substituées, procédés pour leur préparation et leur utilisation en thérapeutique
EP0184258A2 (fr) * 1984-12-05 1986-06-11 Janssen Pharmaceutica N.V. Dérivés de pipéridinylalkylquinazolines hydroxy ou amino-substituées
FR2621588A1 (fr) * 1987-10-08 1989-04-14 Roussel Uclaf Nouveaux derives de la 1,1-dioxo 1,2-benzoisothiazol 3-one, leur procede de preparation et leur application comme medicaments
EP0433149A2 (fr) * 1989-12-13 1991-06-19 Rhone-Poulenc Sante Antagonistes de la sérotonine, leur préparation et les médicaments les contenant
EP0854146A1 (fr) * 1997-01-17 1998-07-22 Eli Lilly And Company Limited 4-(6-fluoro-[1H]-indole-3-yl)1,2,3,6-tetrahydropyridine substituées pour le traitement des troubles du SNC
EP0897921A1 (fr) * 1997-08-22 1999-02-24 Eli Lilly And Company Limited Dérivés de benzothiadiazinyl-indole et leur utilisation comme ligands des récepteurs de la sérotonine
WO1999014203A1 (fr) * 1997-09-16 1999-03-25 Takeda Chemical Industries, Ltd. Composes azotes a cycles condenses, procede de preparation de ces composes et medicaments

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0013612A2 (fr) * 1979-01-08 1980-07-23 Janssen Pharmaceutica N.V. Dérivés de (pipéridinylalcoyl)quinazoline, procédé pour leur préparation et compositions pharmaceutiques les contenant
EP0058975A1 (fr) * 1981-02-25 1982-09-01 Boehringer Ingelheim Pharmaceuticals Inc. N-(4-Indolyl-pipéridino-alkyl)-benzimidazolones substituées, procédés pour leur préparation et leur utilisation en thérapeutique
EP0184258A2 (fr) * 1984-12-05 1986-06-11 Janssen Pharmaceutica N.V. Dérivés de pipéridinylalkylquinazolines hydroxy ou amino-substituées
FR2621588A1 (fr) * 1987-10-08 1989-04-14 Roussel Uclaf Nouveaux derives de la 1,1-dioxo 1,2-benzoisothiazol 3-one, leur procede de preparation et leur application comme medicaments
EP0433149A2 (fr) * 1989-12-13 1991-06-19 Rhone-Poulenc Sante Antagonistes de la sérotonine, leur préparation et les médicaments les contenant
EP0854146A1 (fr) * 1997-01-17 1998-07-22 Eli Lilly And Company Limited 4-(6-fluoro-[1H]-indole-3-yl)1,2,3,6-tetrahydropyridine substituées pour le traitement des troubles du SNC
EP0897921A1 (fr) * 1997-08-22 1999-02-24 Eli Lilly And Company Limited Dérivés de benzothiadiazinyl-indole et leur utilisation comme ligands des récepteurs de la sérotonine
WO1999014203A1 (fr) * 1997-09-16 1999-03-25 Takeda Chemical Industries, Ltd. Composes azotes a cycles condenses, procede de preparation de ces composes et medicaments

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001087881A1 (fr) * 2000-05-18 2001-11-22 Eli Lilly And Company Piperidyindoles comme ligands du recepteur de la serotonine
US6844338B2 (en) 2000-05-18 2005-01-18 Eli Lilly And Company Piperidyindoles as serotonin receptor ligands
US6777437B2 (en) 2001-03-29 2004-08-17 Bristol-Myers Squibb Company Cyclopropylindole derivatives as selective serotonin reuptake inhibitors
US6822100B2 (en) 2001-03-29 2004-11-23 Bristol-Myers Squibb Company Cyclopropylindole derivatives as selective serotonin reuptake inhibitors
WO2004052886A1 (fr) * 2002-12-10 2004-06-24 Merck Patent Gmbh Derives d'indol et leur utilisation comme ligands 5-ht
US7482465B2 (en) 2002-12-10 2009-01-27 Merck Patent Gmbh Indol derivatives and their use as 5-HT ligands
WO2007075717A1 (fr) * 2005-12-19 2007-07-05 Janssen Pharmaceutica N.V. Utilisation de derives de sulfamide heterocyclique benzo-fusionne pour le traitement de l'alcoolisme et/ou des toxicomanies
EA015962B1 (ru) * 2005-12-19 2012-01-30 Янссен Фармацевтика Н.В. Способ лечения злоупотребления алкоголем и аддикции
US8691867B2 (en) 2005-12-19 2014-04-08 Janssen Pharmaceutica Nv Use of benzo-fused heterocycle sulfamide derivatives for the treatment of substance abuse and addiction
US8937096B2 (en) 2005-12-19 2015-01-20 Janssen Pharmaceutica Nv Use of benzo-fused heterocyle sulfamide derivatives for the treatment of mania and bipolar disorder
WO2007095617A1 (fr) * 2006-02-15 2007-08-23 Janssen Pharmaceutica N.V. Utilisation de dérivés de benzo-hétéroarylsulfamide dans le traitement d'un abus et d'une dépendance à une substance
US8853263B2 (en) 2006-05-19 2014-10-07 Janssen Pharmaceutica Nv Co-therapy for the treatment of epilepsy and related disorders

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AU2453900A (en) 2000-09-04
GB9903784D0 (en) 1999-04-14

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