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WO2018153546A1 - Dérivés de méthanone tétrahydropyrane et tétrahydrothiopyrane ayant une activité multimodale contre la douleur - Google Patents

Dérivés de méthanone tétrahydropyrane et tétrahydrothiopyrane ayant une activité multimodale contre la douleur Download PDF

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Publication number
WO2018153546A1
WO2018153546A1 PCT/EP2018/000079 EP2018000079W WO2018153546A1 WO 2018153546 A1 WO2018153546 A1 WO 2018153546A1 EP 2018000079 W EP2018000079 W EP 2018000079W WO 2018153546 A1 WO2018153546 A1 WO 2018153546A1
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WO
WIPO (PCT)
Prior art keywords
unsubstituted
substituted
alkyl
compound
alkenyl
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.)
Ceased
Application number
PCT/EP2018/000079
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English (en)
Inventor
Carmen ALMANSA-ROSALES
Monica Garcia-Lopez
Sergio Rodriguez Escrich
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.)
Esteve Pharmaceuticals SA
Original Assignee
Laboratorios del Dr Esteve SA
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 Laboratorios del Dr Esteve SA filed Critical Laboratorios del Dr Esteve SA
Publication of WO2018153546A1 publication Critical patent/WO2018153546A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero 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

Definitions

  • X is a bond or -0-
  • the compound according to the invention of general Formula (I) is a compound of general Formula (I 5 ')
  • diastereomers a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof.
  • Rs and R5' are independently selected from halogen, -Rn, -ORn, -NO2, - NRnR ', -NRnC(0)Rir, -NRnS(0) 2 Rir, -S(0) 2 NRnRir, -NRnC(0)NRirR i , -SR11 , -S(0)Rii, -S(0) 2 Rii, -CN, haloalkyl, haloalkoxy, -C(0)ORn, - C(0)NRiiRir, -OCH 2 CH 2 ORn, -NRnS(0) 2 NRn R i r and -C(CH 3 ) 2 ORn; and R 1 1 , Ru and Rn- are independently selected from hydrogen, unsubstituted C1-6 alkyl, unsubstituted C 2 -6 alkenyl and unsubstituted C 2 -e alkynyl. optionally in form of one of the stereoisomers, preferably
  • diastereomers a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof.
  • cycloalkyi is understood as meaning saturated and unsaturated (but not aromatic) cyclic hydrocarbons (without a heteroatom in the ring), which can be unsubstituted or once or several times substituted.
  • C3-4- cycloalkyl represents C3- or C4-cycloalkyl
  • C3-5-cycloalkyl represents C3-, C4- or C5- cycloalkyl
  • C 3 - 6 -cycloalkyl represents C3-, C4-, C5- or C6-cycloalkyl
  • C 3 -7-cycloalkyl represents C3-, C4-, C5-, C6- or C7-cycloalkyl
  • C 3 -8-cycloalkyl represents C3-, C4-, C5- , C6-, C7- or C8-cycloalkyl
  • C 4 -5-cycloalkyl represents C4- or C5-cycloalkyl
  • physiologically acceptable salt means in the context of this invention any salt that is physiologically tolerated (most of the time meaning not being toxic- especially not caused by the counter-ion) if used appropriately for a treatment especially if used on or applied to humans and/or mammals.
  • physiologically acceptable salts can be formed with cations or bases and in the context of this invention is understood as meaning salts of at least one of the compounds used according to the invention - usually a (deprotonated) acid - as an anion with at least one, preferably inorganic, cation which is physiologically tolerated - especially if used on humans and/or mammals.
  • W is -C(RwRw)- or -N(R W )-; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the invention of general Formula (I) is a compound wherein
  • Rw is hydrogen; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • Ri 3 and R13' are independently selected from hydrogen, unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl, and unsubstituted C 2 -& alkynyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • Ri4, Ri 4 ' and Ri 4 - are independently selected from hydrogen, unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl, unsubstituted C2-6 alkynyl, unsubstituted aryl, unsubstituted cycloalkyl and unsubstituted heterocyclyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • m is 0, 1 or 2; and/or
  • q is 1 , 2 or 3;
  • R5 and R5' are independently selected from halogen, -Rn, -ORn, -NO2, -NRnRir, - NRiiC(0)Rir, -NRnS(0) 2 ir, -S(0) 2 NRnRir, -NRnC(0)NRirRir, -SRn , -S(0)Rn, - S(0) 2 Rii, -CN, haloalkyl, haloalkoxy, -C(0)ORn, -C(0)NRnRir, -OCH 2 CH 2 ORn, - NRnS(0) 2 NRii Rir and -C(CH 3 ) 2 ORn; wherein the alkyl is Ci-6 alkyl like methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, or 2-methylpropyl; more preferably the alkyl is methyl; and/or Ri i , Ri i and
  • Ri 4 , Ri 4 ' and Ri 4 - are independently selected from hydrogen, unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl, unsubstituted C2-6 alkynyl, unsubstituted aryl, unsubstituted cycloalkyl and unsubstituted heterocyclyl; wherein the C1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, or 2-methylpropyl; and/or the C2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyn
  • the compound is a compound, wherein p is 1 , 2 or 3; preferably p is 1 or 2; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • R2 is selected from hydrogen, substituted or unsubstituted Ci-e alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2 . 6 alkynyl, substituted or unsubstituted cycloalkyi, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl,
  • R3 is selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C 2 . 6 alkenyl, substituted or unsubstituted C 2 . 6 alkynyl, substituted or unsubstituted cycloalkyi, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted alkylaryl and substituted or unsubstituted alkylheterocyclyl;
  • Ri 2 , Ri 2 and Ri 2 - are independently selected from hydrogen, unsubstituted C1-6 alkyl, unsubstituted C 2 -6 alkenyl and unsubstituted C 2 -e alkynyl ;
  • R 1 2, Rib and Ri 2 are independently selected from hydrogen, unsubstituted C 1 -6 alkyl, unsubstituted C2-6 alkenyl and unsubstituted C 2 -e alkynyl ;
  • R 4 " and R 4 - are both hydrogen, while R 4 and R 4 are both substituted or unsubstituted methyl; more preferably while R 4 and R 4 ' are both unsubstituted methyl.

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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

La présente invention concerne des dérivés de méthanone tétrahydropyrane et tétrahydrothiopyrane ayant une double activité pharmacologique à la fois envers le récepteur sigma (σ) et le récepteur µ-opioïde. L'invention concerne également des procédés de préparation de ces composés, des compositions pharmaceutiques les comprenant, ainsi que leur utilisation thérapeutique, en particulier pour le traitement de la douleur.
PCT/EP2018/000079 2017-02-27 2018-02-27 Dérivés de méthanone tétrahydropyrane et tétrahydrothiopyrane ayant une activité multimodale contre la douleur Ceased WO2018153546A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP17382093.7 2017-02-27
EP17382093 2017-02-27

Publications (1)

Publication Number Publication Date
WO2018153546A1 true WO2018153546A1 (fr) 2018-08-30

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2018/000079 Ceased WO2018153546A1 (fr) 2017-02-27 2018-02-27 Dérivés de méthanone tétrahydropyrane et tétrahydrothiopyrane ayant une activité multimodale contre la douleur

Country Status (1)

Country Link
WO (1) WO2018153546A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110071179A1 (en) * 2009-09-21 2011-03-24 Alam Jahangir Macrocyclic inhibitors of jak
WO2017016669A1 (fr) * 2015-07-29 2017-02-02 Laboratorios Del Dr. Esteve, S.A. Dérivés d'amide substitués ayant une activité multimodale contre la douleur

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110071179A1 (en) * 2009-09-21 2011-03-24 Alam Jahangir Macrocyclic inhibitors of jak
WO2017016669A1 (fr) * 2015-07-29 2017-02-02 Laboratorios Del Dr. Esteve, S.A. Dérivés d'amide substitués ayant une activité multimodale contre la douleur

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
"Progress in Pain Research and Management", vol. 25, 2003, IASP PRESS, article "Opioids and Pain Relief: A Historical Perspective"
BORNOT A; BAUER U; BROWN A; FIRTH M; HELLAWELL C; ENGKVIST O: "Systematic Exploration of Dual-Acting Modulators from a Combined Medicinal Chemistry and Biology Perspective", J. MED. CHEM, vol. 56, 2013, pages 1197 - 1210
CHIEN CC; PASTERNAK GW: "Sigma antagonists potentiate opioid analgesia in rats", NEUROSCI. LETT., vol. 190, 1995, pages 137 - 9, XP002498085, DOI: doi:10.1016/0304-3940(95)11504-P
DICKENSON, A.H.; SUZUKI, R.: "Opioids in neuropathic pain: Clues from animal studies", EUR J PAIN, vol. 9, 2005, pages 113 - 6, XP004767581, DOI: doi:10.1016/j.ejpain.2004.05.004
GOLDBERG DS; MCGEE SJ: "Pain as a global public health priority", BMC PUBLIC HEALTH., vol. 11, 2011, pages 770, XP021110362, DOI: doi:10.1186/1471-2458-11-770
KROGSGAARD-LARSEN ET AL.: "Textbook of Drug design and Discovery", April 2002, TAYLOR & FRANCIS
MAO J; GOLD MS; BACKONJA M: "Combination drug therapy for chronic pain: a call for more clinical studies", J. PAIN, vol. 12, 2011, pages 157 - 166, XP028136366, DOI: doi:10.1016/j.jpain.2010.07.006
PANDEY RISHI RANJAN ET AL: "Design and synthesis of [gamma]-butyrolactone derivatives as potential spermicidal ag", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 24, no. 16, 26 June 2014 (2014-06-26), pages 3903 - 3906, XP029041713, ISSN: 0960-894X, DOI: 10.1016/J.BMCL.2014.06.045 *
TURK DC; WILSON HD; CAHANA A: "Treatment of chronic non-cancer pain", LANCET, vol. 377, 2011, pages 2226 - 2235, XP055117246, DOI: doi:10.1016/S0140-6736(11)60402-9
ZAMANILLO D; ROMERO L; MERLOS M; VELA JM: "Sigma 1 receptor: A new therapeutic target for pain", EUR. J. PHARMACOL, vol. 716, 2013, pages 78 - 93, XP028739249, DOI: doi:10.1016/j.ejphar.2013.01.068

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