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WO2009030270A1 - Dérivés dhydroindoles utilisés pour traiter la maladie de parkinson - Google Patents

Dérivés dhydroindoles utilisés pour traiter la maladie de parkinson Download PDF

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Publication number
WO2009030270A1
WO2009030270A1 PCT/EP2007/059194 EP2007059194W WO2009030270A1 WO 2009030270 A1 WO2009030270 A1 WO 2009030270A1 EP 2007059194 W EP2007059194 W EP 2007059194W WO 2009030270 A1 WO2009030270 A1 WO 2009030270A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
alkylamino
formula
alkoxy
aminocarbonyl
Prior art date
Application number
PCT/EP2007/059194
Other languages
English (en)
Inventor
Tewis Bouwmeester
Paulette Greenidge
Jens M. Rick
Giorgio Rovelli
Thomas J. Troxler
Kaspar Zimmermann
Original Assignee
Novartis Ag
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 Novartis Ag filed Critical Novartis Ag
Priority to PCT/EP2007/059194 priority Critical patent/WO2009030270A1/fr
Publication of WO2009030270A1 publication Critical patent/WO2009030270A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • 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
    • 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
    • C07D403/06—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 carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to novel heterocyclic compounds, to their preparation, to their use as medicaments and to medicaments comprising them.
  • the invention relates to a compound of the formula
  • R 1 is hydrogen; halogen; amino; N-(C 1-8 )alkylamino; N,N-di-(Ci. 8 )alkylamino, in which the two (C ⁇ sjalkyl groups are the same or different; N-(Ci -8 )alkylcarbonylamino; hydroxy; (Ci -8 )alkoxy; aminocarbonyl-(C 1-8 )alkoxy; aminocarbonyloxy; mercapto; (C 1-8 )alkyl- thio; aminosulfonyl; N,N-di-(C 1 .
  • R 2 is hydrogen; halogen; amino; N-(C 1-8 )alkylamino; N,N-di-(Ci. 8 )alkylamino, in which the two (C 1-8 )alkyl groups are the same or different; N-(C 1-8 )alkylcarbonylamino; hydroxy; (d.s)alkoxy; aminocarbonyl-(C 1-8 )alkoxy; aminocarbonyloxy; mercapto; (C 1-8 )alkylthio; aminosulfonyl; N-(Ci_ 8 )alkylaminosulfonyl; N,N-di-(C 1-8 )alkylaminosulfonyl, in which the two (C 1-8 )alkyl groups are the same or different; nitro; cyano; (C-i-aJalkyl; hydroxy-(C 1-8 )alkyl; (Ci.
  • R 1 and R 2 together form, together with the carbon atoms, to which they are attached, an optionally substituted 5-, 6- or 7-membered carbocyclic or heterocyclic ring;
  • R 3 is hydrogen; halogen; hydroxy; (C 1-8 )alkoxy; aminosulfonyl; N-(C 1-8 )alkylamino- sulfonyl; N,N-di-(C 1 . 8 )alkylaminosulfonyl, in which the two (C 1 .
  • R 4 is hydrogen; halogen; hydroxy; (Ci -8 )alkoxy; aminosulfonyl; N-(C 1-8 )alkylamino- sulfonyl; N.N-dKC ⁇ alkylaminosulfonyl, in which the two (C 1-8 )alkyl groups are the same or different; (d. 8 )alkyl; or (C 3 . 8 )cycloalkyl; either R 5 is hydrogen; or (Ci -8 )alkyl; and
  • R 6 is hydrogen; carboxy; (Ci -8 )alkoxycarbonyl; (Ci -8 )alkyl; amino-(C 1 . 8 )alkyl; N-(C 1-8 )- alkylamino-(Ci -8 )alkyl; N,N-di-(C 1 .
  • R 7 is hydrogen; (C 1 . 8 )alkyl; amino-(C 1-8 )alkyl; aminocarbonyl-(C 1-8 )alkyl; or aminocarbonyl, in free form or in salt form.
  • a corresponding compound of the formula I may exist in pure optically active form or in the form of a mixture of optical isomers, e. g. in the form of a race- mic mixture. All of such pure optical isomers and all of their mixtures, including the racemic mixtures, are part of the present invention.
  • a compound of the formula I may exist in free form or in salt form, e. g. a basic compound in acid addition salt form or an acidic compound in the form of a salt with a base. All of such free compounds and salts are part of the present invention.
  • a compound of the formula I may exist in tautomeric form. All of such tautomers are part of the present invention.
  • Halogen denotes fluorine, bromine, chlorine or iodine. Any non-cyclic carbon containing group or moiety with more than 1 carbon atom is straight- chain or branched.
  • carbon containing groups, moieties or molecules contain 1 to 8, preferably 1 to 6, more preferably 1 to 4, most preferably 1 or 2, carbon atoms.
  • the invention relates to a compound of the formula I, in free form or in salt form, in which
  • R 1 is hydrogen; halogen; amino; N-(C 1 . 8 )alkylamino; N,N-di-(C 1-8 )alkylamino, in which the two (d ⁇ alkyl groups are the same or different; N-(C 1 . 8 )alkylcarbonylamino; hydroxy; (C 1-8 )alkoxy; aminocarbonyl-(C 1 .
  • R 2 is hydrogen; halogen; amino; N,N-di-(C 1-8 )alkylamino, in which the two (C 1-8 )alkyl groups are the same or different; N-(C 1-8 )alkylcarbonylamino; hydroxy; (C 1-8 )- alkoxy; aminocarbonyl-(C 1 . 8 )alkoxy; aminocarbonyloxy; mercapto; (C 1-8 )alkylthio; aminosulfonyl; N-(Ci -8 )alkylaminosulfonyl; N.N-di ⁇ C ⁇ alkylaminosulfonyl, in which the two (C-
  • R 1 and R 2 together form, together with the carbon atoms, to which they are attached, an optionally substituted 5-, 6- or 7-membered carbocyclic or heterocyclic ring; preferably either R 1 is hydrogen; halogen; amino; N-(C 1-8 )alkylamino; N,N-di-(C 1-8 )alkylamino, in which the two (C 1-8 )alkyl groups are the same or different; N-(C 1-8 )alkylcarbonylamino; hydroxy; (C 1-8 )alkoxy; aminocarbonyl-(C 1-8 )alkoxy; aminocarbonyloxy; mercapto; (Ci -8 -8
  • R 2 is hydrogen; halogen; amino; N-(C 1-8 )alkylamino; N,N-di-(C- ⁇ - 8 )alkylamino, in which the two (C 1-8 )alkyl groups are the same or different; N-(C 1-8 )alkylcarbonylamino; hydroxy; (C 1-8 )- alkoxy; aminocarbonyl-(C 1 .
  • (Ci -8 )alkyl groups are the same or different; (C 1-8 )alkyl; MyCIrOXy-(C 1-8 )alkyl; (C 1-8 )alkoxy-(C 1-8 )- alkyl; or (C 3 . 8 )cycloalkyl; or R 1 and R 2 together form, together with the carbon atoms, to which they are attached, an optionally substituted 5-, 6- or 7-membered carbocyclic or heterocyclic ring; preferably R 1 is hydrogen; carboxy; or (C 1-8 )alkoxycarbonyl; and
  • R 2 is hydrogen; (C 1-8 )alkoxy; or N,N-di-(C 1-8 )alkylaminosulfonyl, in which the two (C 1-8 )alkyl groups are the same or different; preferably R 1 is hydrogen; carboxy; or (C 1-4 )alkoxycarbonyl; and
  • R 2 is hydrogen; (C 1-4 )alkoxy; or N,N-di-(C 1-4 )alkylaminosulfonyl, in which the two (C 1-4 )alkyl groups are the same or different; preferably R-i is hydrogen; hydroxy; aminocarbonyl; N-(C 1-8 )alkylaminocarbonyl, the alkyl group of which can be substituted by hydroxy or by aminocarbonyl; carboxy; or (C 1-8 )- alkoxycarbonyl; and
  • R 2 is hydrogen; halogen; amino; hydroxy; (C 1-8 )alkoxy; N,N-di-(C 1-8 )alkylaminosulfonyl, in which the two (C ⁇ alkyl groups are the same or different; nitro; or cyano;
  • R 3 is hydrogen; halogen; hydroxy; (C 1-8 JaIkOXy; aminosulfonyl; N-(Ci -8 )alkylaminosulfonyl; N,N-di-(C 1-8 )alkylaminosulfonyl, in which the two (C 1-8 )alkyl groups are the same or different; (C 1-8 )alkyl; or (C 3-8 )cycloalkyl; preferably hydrogen; or (Ci -8 )alkoxy; more preferably hydrogen; or (C 1-4 )alkoxy;
  • R 4 is hydrogen; halogen; hydroxy; (C 1-8 )alkoxy; aminosulfonyl; N ⁇ C ⁇ alkylaminosulfonyl; N,N-di-(C 1-8 )alkylaminosulfonyl, in which the two (C 1-8 )alkyl groups are the same or different; (C-,. 8 )alkyl; or (C 3-8 )cycloalkyl; preferably hydrogen; or (C 1-a )alkoxy; more preferably hydrogen; or (C 1-4 )alkoxy;
  • R 5 is hydrogen; or (C 1-8 )alkyl
  • R 6 is hydrogen; carboxy; (C 1-8 )alkoxycarbonyl; (d. 8 )alkyl; amino-(C-i. 8 )alkyl; N-(C 1-8 )- N,N-di-(C 1 . 8 )alkylamino-(C 1-8 )alkyl, in which the two N-(C 1-8 )alkyl groups are the same or different; carboxy-(C 1-8 )alkyl; aminocarbonyl; N,N-di-(C 1 .
  • R 5 and R 6 together form, together with the carbon atoms, to which they are attached, an optionally substituted 5- or 6-membered carbocyclic ring; preferably either R 5 is hydrogen; or (d. 8 )alkyl; and
  • R 6 is hydrogen; (Ci. 8 )alkyl; amino-(C 1-8 )alkyl; N-(C 1 . 8 )alkylamino-(Ci. 8 )alkyl; N,N-di-(Ci -8 )- alkylamino-(Ci -8 )alkyl, in which the two N-(C 1-8 )alkyl groups are the same or different; carboxy-(C 1 .
  • R 6 is hydrogen; N-[amino-(C 1-8 )alkyl]aminocarbonyl; N- ⁇ [N-(C 1-8 )alkylamino]-(C 1-8 )alkyl ⁇ - aminocarbonyl; or N- ⁇ [N, N-di-(Ci. 8 )alkylamino]-(C 1-8 )alkyl ⁇ aminocarbonyl, in which the two
  • R 6 is hydrogen; carboxy; (C 1-8 )alkoxycarbonyl; carboxy-(C 1 . 8 )alkyl; aminocarbonyl; N,N-di-
  • (C 1-8 )alkylaminocarbonyl in which the two (C 1-8 )alkyl groups are the same or different and can, independently, be substituted by N-(C 1-8 )alkylamino; morpholinocarbonyl; piperidino- carbonyl; piperazinocarbonyl, which can be substituted by (C 1-8 )alkyl; pyrrolidinocarbonyl, which can be substituted by (C 1-8 )alkoxy-(C 1-8 )alkyl; N-(C 1-8 )alkylaminocarbonyl, the alkyl group of which can be substituted by (C 1-8 )alkoxy or by hydroxy-(d.
  • the preferred embodiments (1 ) to (5) are preferred independently, collectively or in any combination or sub-combination.
  • the invention relates to one or more than one of the compounds of the formula I mentioned in the Examples hereinafter, in free form or in salt form.
  • the invention relates to a process for the preparation of a compound of the formula I, in free form or in salt form, comprising the steps of
  • the reactions can be effected according to conventional methods, for example as described in the Examples.
  • the working-up of the reaction mixtures and the purification of the compounds thus obtainable may be carried out in accordance with known procedures.
  • Salts may be prepared from free compounds in known manner, and vice-versa.
  • agents of the invention exhibit valuable pharmacological properties, when tested in vitro or in vivo, and are, therefore, useful in medicaments.
  • agents of the invention are modulators, e. g. inhibitors, of leucine-rich repeat kinase 2 (LRRK2).
  • LRRK2 leucine-rich repeat kinase 2
  • Their pharmacological properties can be evaluated, for example, in Drug Pull- Down experiments, e. g. as described in WO-2006/134056 A1 , the corresponding disclosure therein being herewith incorporated hereinto by reference.
  • Agents of the invention can, therefore, be used in the treatment or prevention of a condition, disease or disorder, in which LRRK2 plays a role.
  • agents of the invention show activity at concentrations below 20 ⁇ M.
  • the agent of the invention described in Example 3 shows an IC 50 value of 1.2 ⁇ M.
  • Agents of the invention are therefore useful, e. g., in the treatment or prevention of a condition, disease or disorder of the central nervous system, such as a neurodegenerative condition, disease or disorder, for example a Lewy bodies disease, an alpha-synucleino- pathy, Parkinson's disease, familial parkinsonism, multiple system atrophy, dementia with Lewy bodies, Parkinson's disease with dementia, Alzheimer's disease, mild cognitive impairment (MCI), a tauopathy, a poly-glutamine (polyQ) disease, Huntington's disease, a spinocerebellar ataxia disease, or amyotrophic lateral sclerosis (ALS), such as an inherited metabolic condition, disease or disorder of the nervous system, for example a sphingo- lipidose, a neuronal ceroid lipofuscinose, a glycoproteinose, a mucolipdose, a neonatal metabolic disease, or a mitochondrial disorder, such as a peripheral neuropathy, for example Char
  • Niemann-Pick type C disease g. Niemann-Pick type C disease, Pelizaeus-Merzbacher Disease, Pick's disease, primary lateral sclerosis, Refsum's disease, Sandhoff disease, Schilders disease, Steele-Richardson-Olszewski disease, Tabes dorsalis, and the like.
  • the agents of the invention are especially useful in the treatment and/or prevention of Parkinson's disease.
  • the appropriate dosage will vary depending on, e. g., the compound employed as active pharmaceutical ingredient, the host, the mode of administration, the nature and severity of the condition, disease or disorder or the effect desired.
  • a daily dosage of from about 0.1 to about 100, preferably from about 1 to about 50, mg/kg of animal body weight.
  • an indicated daily dosage is in the range of from about 0.5 to about 2000, preferably from about 2 to about 200, mg of an agent of the invention conveniently administered, for example, in divided doses up to four times a day or in sustained release form.
  • An agent of the invention may be administered by any conventional route, in particular en- terally, preferably orally, e. g. in the form of a tablet or capsule, or parenterally, e. g. in the form of an injectable solution or suspension.
  • the invention in a further aspect, relates to an agent of the invention for use as a medicament, e. g. in the treatment or prevention of a condition, disease or disorder, in which LRRK2 plays a role.
  • the invention in a further aspect, relates to the use of an agent of the invention as active pharmaceutical ingredient in a medicament, e. g. in the treatment or prevention of a condition, disease or disorder, in which LRRK2 plays a role.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an agent of the invention as active pharmaceutical ingredient in association with at least one pharmaceutically acceptable carrier or diluent.
  • Such a composition may be manufactured in conventional manner, e. g. by mixing its components.
  • Unit dosage forms contain, e. g., from about 0.1 to about 1000, preferably from about 1 to about 500, mg of an agent of the invention.
  • An agent of the invention can be administered as sole active pharmaceutical ingredient or as a combination with at least one other active pharmaceutical ingredient effective, e. g., in the treatment or prevention of a condition, disease or disorder, in which LRRK2 plays a role.
  • a pharmaceutical combination may be in the form of a unit dosage form, which unit dosage form comprises a predetermined quantity of each of the at least two active components in association with at least one pharmaceutically acceptable carrier or diluent.
  • the pharmaceutical combination may be in the form of a package comprising the at least two active components separately, e. g. a pack or dispenser-device adapted for the concomitant or separate administration of the at least two active components, in which these active components are separately arranged.
  • the invention relates to such pharmaceutical combinations.
  • the invention relates to the use of an agent of the invention for the manufacture of a medicament for the treatment or prevention of a condition, disease or disorder, in which LRRK2 plays a role.
  • the invention relates to a method for the treatment or prevention of a condition, disease or disorder, in which LRRK2 plays a role, in a subject in need of such treatment or prevention, which method comprises administering to such subject an effective amount of an agent of the invention.
  • Example 2 5-r5-Methoxv-2-oxo-1,2-dihvdro-indol-(3Z)-vlidenemethyll-2,4-dimethvl-1H- pyrrole-3-carboxylic acid (3-amino-propyl)-amide a) [3-( ⁇ 5-[5-Methoxy-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H- pyrrole-3-carbonyl ⁇ -amino)-propyl]-carbamic acid tert-butyl ester
  • Examples 4 to 50 can be prepared in a manner analogous to those described hereinbefore.
  • Example 52 3-[1 -[4-(2-Diethylamino-ethylcarbamoyl)-3,5-dimethyl-1 H-pyrrol-2-yl]- meth-(Z)-ylidene]-5-methoxy-2-oxo-2,3-dihydro-1 H-indole-4-carboxylic acid methyl ester
  • Example 53 3-[1 -[4-(2-Diethylamino-ethylcarbamoyl)-3,5-dimethyl-1 H-pyrrol-2-yl]- meth-(Z)-ylidene]-5-methoxy-2-oxo-2,3-dihydro-1H-indole-4-carboxylic acid
  • Example 54 3-[1 -[4-(2-Diethylamino-ethylcarbamoyl)-3,5-dimethyl-1 H-pyrrol-2-yl]- meth-(Z)-ylidene]-5-methoxy-2-oxo-2,3-dihydro-1 H-indole-4-carboxylic acid (2-hydroxy- ethyl)-amide
  • Examples 55 and 56 can be prepared in a manner analogous to those described hereinbefore (LC system 2).

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

Abstract

Cette invention concerne des nouveaux composés hétérocycliques représentés par la formule (I) dans laquelle toutes les variables sont telles que définies dans la spécification, sous une forme libre ou sous une forme saline. Cette invention concerne également un procédé permettant de préparer et d'utiliser ces composés en tant que médicaments ainsi que des médicaments les contenant.
PCT/EP2007/059194 2007-09-03 2007-09-03 Dérivés dhydroindoles utilisés pour traiter la maladie de parkinson WO2009030270A1 (fr)

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Cited By (19)

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WO2011038572A1 (fr) 2009-09-29 2011-04-07 Glaxo Group Limited Composés inédits
WO2011141756A1 (fr) * 2010-05-14 2011-11-17 Medical Research Council Technology Pyrazolopyridines en tant qu'inhibiteurs de la kinase lrrk2
WO2012038743A1 (fr) * 2010-09-22 2012-03-29 Medical Research Council Technology Pyrazolopyridines comme inhibiteurs de la kinase lrrk2
WO2012118679A1 (fr) 2011-02-28 2012-09-07 Merck Sharp & Dohme Corp. Composés inhibant l'activité enzymatique de la kinase à motifs répétés riches en leucine
WO2012162254A1 (fr) 2011-05-23 2012-11-29 Elan Pharmaceuticals, Inc. Inhibiteurs de l'activité lrrk2 kinase
WO2012178015A2 (fr) * 2011-06-24 2012-12-27 Zenobia Therapeutics, Inc. Inhibiteurs de lrrk2
JP2014515745A (ja) * 2011-04-08 2014-07-03 ベータ・ファーマ・インコーポレイテッド 新規なインドリノンタンパク質キナーゼインヒビター
US8846953B2 (en) 2010-11-01 2014-09-30 Scinopharm Taiwan, Ltd. Processes for the preparation of 3-(pyrrol-2-yl)methylene)-2-pyrrolones using 2-silyloxy-pyrroles
CN104292154A (zh) * 2009-09-29 2015-01-21 葛兰素集团有限公司 新化合物
EP2632260A4 (fr) * 2010-10-29 2015-06-17 Merck Sharp & Dohme Activité de l'enzyme kinase à répétition riche en leucine
US9156845B2 (en) 2012-06-29 2015-10-13 Pfizer Inc. 4-(substituted amino)-7H-pyrrolo[2,3-d] pyrimidines as LRRK2 inhibitors
WO2017072335A1 (fr) * 2015-10-28 2017-05-04 Ab Science Utilisation de masitinib et d'autres inhibiteurs de mastocyte pour le traitement de la maladie de parkinson
US9695171B2 (en) 2013-12-17 2017-07-04 Pfizer Inc. 3,4-disubstituted-1 H-pyrrolo[2,3-b]pyridines and 4,5-disubstituted-7H-pyrrolo[2,3-c]pyridazines as LRRK2 inhibitors
US9956302B2 (en) 2015-09-22 2018-05-01 Graybug Vision, Inc. Compounds and compositions for the treatment of ocular disorders
US10039753B2 (en) 2015-09-14 2018-08-07 Pfizer Inc. Imidazo[4,5-c]quinoline and imidazo[4,5-c][1,5]naphthyridine derivatives as LRRK2 inhibitors
US11160870B2 (en) 2017-05-10 2021-11-02 Graybug Vision, Inc. Extended release microparticles and suspensions thereof for medical therapy
US11548861B2 (en) 2017-03-23 2023-01-10 Graybug Vision, Inc. Drugs and compositions for the treatment of ocular disorders
WO2023076404A1 (fr) 2021-10-27 2023-05-04 Aria Pharmaceuticals, Inc. Méthodes de traitement de lupus érythémateux disséminé
WO2023104170A1 (fr) * 2021-12-08 2023-06-15 Hangzhou Jijing Pharmaceutical Technology Limited Composés pour le traitement de troubles neurodégénératifs associés à la polyq

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EP2483254A1 (fr) * 2009-09-29 2012-08-08 Glaxo Group Limited Composés inédits
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