EP1181287A1 - Composes sulfonamide a activite pharmaceutique - Google Patents

Composes sulfonamide a activite pharmaceutique

Info

Publication number
EP1181287A1
EP1181287A1 EP00935141A EP00935141A EP1181287A1 EP 1181287 A1 EP1181287 A1 EP 1181287A1 EP 00935141 A EP00935141 A EP 00935141A EP 00935141 A EP00935141 A EP 00935141A EP 1181287 A1 EP1181287 A1 EP 1181287A1
Authority
EP
European Patent Office
Prior art keywords
toluene
sulfonyl
piperidin
ylmethyl
pyrrolidin
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Withdrawn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
EP00935141A
Other languages
German (de)
English (en)
Inventor
Peter John SmithKline Beecham Pharm. LOVELL
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.)
SmithKline Beecham Ltd
Original Assignee
SmithKline Beecham Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP1181287A1 publication Critical patent/EP1181287A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/48—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to compounds having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of CNS and other disorders.
  • WO 97/29097, WO 97/48681 and WO 97/49695 all disclose a series of sulphonamide derivatives that are 5-HT ⁇ receptor antagonists and are said to be useful in the treatment of various CNS diseases.
  • a structurally novel class of compounds have now been found that also possess 5-HT7 receptor activity.
  • the present invention therefore provides, in a first aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • R.1, R2 and R ⁇ are independently hydrogen, halogen, hydroxy, C galkyl or C ⁇ . galkoxy; m is 1 or 2,
  • X is nitrogen, carbon or CH, is a single bond when X is nitrogen or a CH; or is a double bond when X is carbon;
  • P is phenyl, naphthyl, a 5 or 6 membered heteroaryl ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, or a benzofused heteroaryl ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur;
  • R 4 is C ⁇ _6alkyl optionally substituted by NR 5 R 6 , aryl, arylC ⁇ .g alkyl, Cj.galkoxy, C ⁇ 6alkylthio, cyano, hydroxy, nitro, halogen, CF3, C2F5, NR 5 R 6 , CONR 5 R 6 ,
  • Ci .galkyl groups whether alone or as part of another group may be straight chain or branched.
  • the term 'halogen' is used herein to describe, unless otherwise stated, a group selected from fluorine, chlorine, bromine or iodine.
  • the term 'aryl' is used herein to describe, unless otherwise stated, a group such as phenyl or naphthyl. Such aryl groups may be optionally substituted by one or more C ⁇ _ galkyl or halogen.
  • the groups R , R ⁇ and R ⁇ are independently hydrogen, halogen such as fluorine, chlorine or bromine or C ⁇ _ galkyl such as methyl.
  • D is a single bond.
  • P is naphthyl this is intended to denote both naphthalen-1-yl and naphthalen-2-yl groups.
  • P is a 5 or 6 membered heteroaryl ring
  • suitable examples include thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyrrolidinyl and pyrazinyl.
  • P is a benzofused heteroaryl ring suitable examples include indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl and isoquinolinyl.
  • P is phenyl, naphthyl, benzimidazol-2-yl, 2-oxo-2,3 -dihydrobenzimidazol-1-yl, indol-3-yl, benzoxazol-2-yl and benzothiazol-2- yi-
  • R 4 groups include halogen such as fluorine or chlorine, Ci .galkyl optionally substituted by NR ⁇ R6 such as methyl, hydroxy, CF3, C ⁇ _ galkoxy such as methoxy or groups COR 7 or CO2R 7 in which R 7 is methyl.
  • n 2 or more the groups R 4 can be the same or different.
  • n is 0 or 1.
  • Particularly preferred compounds of the invention include: (R)-2-( 1 -( 1 -(Toluene-3-sulfony l)-pyrrolidin-2-ylmethyl)-piperidin-4-yl)- 1 H- benzimidazole, (S)-2-( 1 -( 1 -(Toluene-3 -sulfonyl)-pyrrolidin-2-ylmethyl)-piperidin-4-y 1)- 1 H- benzimidazole,
  • the compounds of the formula (I) can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulphonic.
  • acids such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulphonic.
  • Certain compounds of formula (I) are capable of existing in stereoisomeric forms including diastereomers and enantiomers and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates.
  • the different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis.
  • the invention also extends to any tautomeric forms and mixtures thereof.
  • the present invention also provides, in a further aspect, a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises coupling a compound of formula (II):
  • Suitable leaving groups Y include halogen (particularly chloro) and OSO2Nr groups such as tosylate.
  • the reaction of a compounds of formulae (II) and (III) is preferably carried out in a solvent such as dichloromethane or acetonitrile optionally in the presence of sodium iodide and a base such as potassium carbonate.
  • Compounds of formula (I) and their pharmaceutically acceptable salts have 5-HT7 receptor antagonist activity and are believed to be of potential use for the treatment or prophylaxis of certain CNS disorders such as anxiety, depression, sleep disorders (including disturbances of Circadian rhythms), migraine, Parkinson's disease, schizophrenia, pain, appetite disorders and other indications such as inflammation, spastic colon, renal disorders, hypotension, cardiovascular shock, disorders associated with neuronal degeneration resulting from ischaemic events such as stroke, septic shock and gastrointestinal diseases such as IBS (irritable bowel syndrome).
  • CNS disorders such as anxiety, depression, sleep disorders (including disturbances of Circadian rhythms), migraine, Parkinson's disease, schizophrenia, pain, appetite disorders and other indications such as inflammation, spastic colon, renal disorders, hypotension, cardiovascular shock, disorders associated with neuronal degeneration resulting from ischaemic events such as stroke, septic shock and gastrointestinal diseases such as IBS (irritable bowel syndrome).
  • IBS irritable bowel syndrome
  • the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance, in particular in the treatment or prophylaxis of the above disorders, particularly depression and/or sleep disorders.
  • the invention further provides a method of treatment or prophylaxis of the above disorders, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof or a solvate thereof for use in the treatment or prophylaxis of depression and/or sleep disorders.
  • the present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutical composition of the invention which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusable solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.
  • Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colourants.
  • fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
  • suitable unit doses may be 0.05 to 1000 mg, more suitably 0.05 to 20.0 mg, for example 0.2 to 5 mg; and such unit doses may be administered more than once a day, for example two or three a day, so that the total daily dosage is in the range of about 0.5 to 100 mg; and such therapy may extend for a number of weeks or months.
  • the title compound can be prepared according to procedures described in J. Med.
  • the title compound can be prepared according to procedures described in J. Med. Chem., 1992, 35(26), 4813.
  • Examples El 3 - El 8 shown in Table 2 were prepared using the procedure described in Example 1 using D3 and a 4-substituted piperidine or piperazine. Such reagents are either commercially available or can be prepared by methods described above.
  • the affinity of the compounds of this invention for the 5-HT7 receptor binding site can be determined by methods described in WO 97/29097.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Anesthesiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrrole Compounds (AREA)

Abstract

L'invention concerne de nouveaux composés sulfonamide présentant une activité antagoniste du récepteur 5-HT7, ainsi que des procédés de préparation associés, des compositions contenant ces composés et leur utilisation dans le traitement de troubles du système nerveux central et d'autres troubles.
EP00935141A 1999-06-01 2000-05-25 Composes sulfonamide a activite pharmaceutique Withdrawn EP1181287A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB9912701.1A GB9912701D0 (en) 1999-06-01 1999-06-01 Novel compounds
GB9912701 1999-06-01
PCT/EP2000/004893 WO2000073299A1 (fr) 1999-06-01 2000-05-25 Composes sulfonamide a activite pharmaceutique

Publications (1)

Publication Number Publication Date
EP1181287A1 true EP1181287A1 (fr) 2002-02-27

Family

ID=10854529

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00935141A Withdrawn EP1181287A1 (fr) 1999-06-01 2000-05-25 Composes sulfonamide a activite pharmaceutique

Country Status (5)

Country Link
EP (1) EP1181287A1 (fr)
JP (1) JP2003500488A (fr)
AU (1) AU5073400A (fr)
GB (1) GB9912701D0 (fr)
WO (1) WO2000073299A1 (fr)

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040267010A1 (en) * 2001-02-02 2004-12-30 Forbes Ian Thomson Sulfonamide compounds, their preparation and use
JP4399862B2 (ja) * 2002-08-09 2010-01-20 味の素株式会社 腸疾患および内臓痛の治療薬
JPWO2004069828A1 (ja) * 2003-02-04 2006-05-25 三菱ウェルファーマ株式会社 ピペリジン化合物およびその医薬用途
GB0311201D0 (en) 2003-05-15 2003-06-18 Merck Sharp & Dohme Therapeutic agents
AU2004283196B2 (en) 2003-09-17 2011-08-25 Janssen Pharmaceutica, N.V. Fused heterocyclic compounds
BRPI0613597A2 (pt) 2005-06-28 2011-01-18 Sanofi Aventis derivado de isoquinolina como inibidores de rho-quinase
PT1910333E (pt) 2005-07-26 2013-08-01 Sanofi Sa Derivados de isoquinolona substituída com piperidinilo como inibidores da rho-cinase
US7598255B2 (en) 2005-08-04 2009-10-06 Janssen Pharmaceutica Nv Pyrimidine compounds as serotonin receptor modulators
JP5313919B2 (ja) 2006-12-27 2013-10-09 サノフイ 新規な置換イソキノリン及びイソキノリノン誘導体
CN101595094B (zh) 2006-12-27 2013-02-20 塞诺菲-安万特股份有限公司 环烷基胺取代的异喹诺酮衍生物
MX2009006517A (es) 2006-12-27 2009-06-26 Sanofi Aventis Nuevos derivados de isoquinolina e isoquinolinona sustituidos.
MY150746A (en) 2006-12-27 2014-02-28 Sanofi Aventis Substituted isoquinoline and isoquinolinone derivatives as inhibitors of rho-kinase
KR20090092303A (ko) 2006-12-27 2009-08-31 사노피-아벤티스 사이클로알킬아민 치환된 이소퀴놀린 유도체
ATE490243T1 (de) 2006-12-27 2010-12-15 Sanofi Aventis Cycloalkylaminsubstituierte isochinolin- und isochinolinonderivate
MY157330A (en) 2008-06-24 2016-05-31 Sanofi Aventis Substituted isoquinolinones as rho kinase inhibitors
SI2303845T1 (sl) 2008-06-24 2013-12-31 Sanofi Bi- in policiklični substituirani izokinolin in izokinolinski derivati kot inhibitorji rho-kinaze
JP5714485B2 (ja) 2008-06-24 2015-05-07 サノフイ ６−置換イソキノリン類及びイソキノリノン類
JP5641436B2 (ja) * 2011-03-28 2014-12-17 国立大学法人 鹿児島大学 抗ｈｉｖ薬
KR20210020182A (ko) * 2018-05-11 2021-02-23 템플 유니버시티-오브 더 커먼웰쓰 시스템 오브 하이어 에듀케이션 5-히드록시트립타민 수용체 7의 조절자로서의 신규한 기능화된 락탐 및 이의 사용 방법

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997029097A1 (fr) * 1996-02-09 1997-08-14 Smithkline Beecham Plc Derives de sulfonamide en tant qu'antagonistes du recepteur de 5ht¿7?
WO1997049695A1 (fr) * 1996-06-25 1997-12-31 Smithkline Beecham P.L.C. Derives de sulfonamide utilises comme antagonistes du recepteur 5ht7

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9612884D0 (en) * 1996-06-20 1996-08-21 Smithkline Beecham Plc Novel compounds
AU9206798A (en) * 1997-08-28 1999-03-16 Merck & Co., Inc. Pyrrolidine and piperidine modulators of chemokine receptor activity

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997029097A1 (fr) * 1996-02-09 1997-08-14 Smithkline Beecham Plc Derives de sulfonamide en tant qu'antagonistes du recepteur de 5ht¿7?
WO1997049695A1 (fr) * 1996-06-25 1997-12-31 Smithkline Beecham P.L.C. Derives de sulfonamide utilises comme antagonistes du recepteur 5ht7

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO0073299A1 *

Also Published As

Publication number Publication date
WO2000073299A1 (fr) 2000-12-07
GB9912701D0 (en) 1999-08-04
AU5073400A (en) 2000-12-18
JP2003500488A (ja) 2003-01-07

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