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WO2018069210A1 - Tétrahydrofuro [3,4-c] isoquinolines en tant qu'inhibiteurs de pde4 - Google Patents

Tétrahydrofuro [3,4-c] isoquinolines en tant qu'inhibiteurs de pde4 Download PDF

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Publication number
WO2018069210A1
WO2018069210A1 PCT/EP2017/075602 EP2017075602W WO2018069210A1 WO 2018069210 A1 WO2018069210 A1 WO 2018069210A1 EP 2017075602 W EP2017075602 W EP 2017075602W WO 2018069210 A1 WO2018069210 A1 WO 2018069210A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
disease
formula
ethoxy
methoxy
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/EP2017/075602
Other languages
English (en)
Inventor
Beate Schmidt
Guido Hanauer
Stefanie Vollert
Ewald Benediktus
Christof Zitt
Michaela SCHÄFER
Ragna Hussong
Daniela SMIEJA
Yo MURAKI
Mitsugi OOKAWARA
Yasunori NIO
Yuichiro Amano
Shuntarou TSUCHIYA
Osamu Isono
Hiroshi Nagabukuro
Hiroko Yamakawa
Naoya Kikuchi
Yuichiro AKAO
Yoshinori Satomi
Tatsuya Ando
Sham Nikam
Masatoshi Hazama
Takanori Matsuo
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.)
Takeda GmbH
Original Assignee
Takeda 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 Takeda GmbH filed Critical Takeda GmbH
Publication of WO2018069210A1 publication Critical patent/WO2018069210A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • 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
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • 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

Definitions

  • R4 and R5 are methyl, and R6 and R7, together with the nitrogen atom to which both are bonded form a pyrrolidin-1-yl, piperidin-1-yl, azepan-1-yl, morpholin-4-yl,
  • the invention relates to a compound of formula 1 , wherein
  • the compounds of formula 4 are saponified to give the benzoic acid derivatives of formula 3, which then can be activated prior to the reaction with compounds of formula R3-H for example by forming an acid halide or acid anhydride.
  • Compounds of formula 1 finally then can be obtained from the activated compounds of formula 2 by reaction with compounds of formula R3-H, in which R3 has the meanings given above.
  • the compounds according to the invention are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as column chromatography on a suitable support material.
  • the invention preferably relates to a method of treating or preventing dermatological diseases, such as, but not limited to, psoriasis or atopic dermatitis (eczema) comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
  • dermatological diseases such as, but not limited to, psoriasis or atopic dermatitis (eczema) comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
  • the invention furthermore relates to a pharmaceutical composition according to the invention inhibiting the type 4 phosphodiesterase, especially for the treatment or prophylaxis of diseases alleviated by inhibition of type 4 phosphodiesterase, in particular for the treatment or prophylaxis of the diseases exemplified above.
  • a pharmaceutical composition for oral administration being a tablet may comprise one or more pharmaceutically acceptable auxiliaries (for example, carriers and/or excipients) suitable for preparing tablet formulations.
  • the carrier may, for example, be or include lactose, cellulose or mannitol.
  • the tablet may also or instead contain one or more pharmaceutically acceptable excipients, for example, a binding agent, a lubricant and/or a tablet disintegrant.
  • compositions according to the invention can be administered such that the dose of the compound of the invention is in the range customary for type 4 phosphodiesterase inhibitors.
  • This amphiphilic lipid sub-layer layer includes (O-acyl)-omega-hydroxy fatty acids (OAHFAs) and free fatty acids (VLC-FFAs, longer than C28) which are synthesized by elongation of very long chain fatty acids-4 (ELOVL4) enzyme [5].
  • OAHFAs O-acyl-omega-hydroxy fatty acids
  • VLC-FFAs free fatty acids
  • the OAHFAs and the VLC-FFAs are recently found as major amphiphilic lipids in meibum of human and animals [6].
  • the ratio of OAHFA in meibum is lower in dry eye patients than that of normal subjects.
  • the extent of OAHFA reduction depends on the severi- ty of dry eye [7].

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Diabetes (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés de formule 1, dans laquelle, R1, R2 et R3 ont les significations indiquées dans la description, ces composés sont de nouveaux inhibiteurs efficaces de phosphodiestérase de type 4.
PCT/EP2017/075602 2016-10-10 2017-10-09 Tétrahydrofuro [3,4-c] isoquinolines en tant qu'inhibiteurs de pde4 Ceased WO2018069210A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201662406172P 2016-10-10 2016-10-10
US62/406,172 2016-10-10

Publications (1)

Publication Number Publication Date
WO2018069210A1 true WO2018069210A1 (fr) 2018-04-19

Family

ID=60043199

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2017/075602 Ceased WO2018069210A1 (fr) 2016-10-10 2017-10-09 Tétrahydrofuro [3,4-c] isoquinolines en tant qu'inhibiteurs de pde4

Country Status (1)

Country Link
WO (1) WO2018069210A1 (fr)

Citations (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0372777A2 (fr) 1988-12-06 1990-06-13 Riker Laboratories, Inc. Formulations d'aérosols à usage médical
EP0407028A2 (fr) 1989-05-31 1991-01-09 FISONS plc Formule médicamenteuse et appareil d'inhalation
WO1991004011A1 (fr) 1989-09-20 1991-04-04 Riker Laboratories, Inc. Formulations aerosols medicinales
WO1991011495A1 (fr) 1990-02-03 1991-08-08 Boehringer Ingelheim Kg Nouveaux melanges de gaz propulseurs et leur utilisation dans des preparations medicamenteuses
WO1991011173A1 (fr) 1990-02-02 1991-08-08 Fisons Plc Compositions d'agents propulseurs
WO1991014422A1 (fr) 1990-03-23 1991-10-03 Minnesota Mining And Manufacturing Company Emploi de fluorotensioactifs solubles dans la preparation de formulations d'aerosols doseurs
EP0505321A2 (fr) 1991-03-21 1992-09-23 Ciba-Geigy Ag Inhalateur
WO1993011743A1 (fr) 1991-12-12 1993-06-24 Glaxo Group Limited Medicaments
EP0553298A1 (fr) 1990-10-18 1993-08-04 Minnesota Mining & Mfg Formulation d'aerosol contenant du beclomethasone 17,21 dipropionate.
EP0650410A1 (fr) 1992-06-30 1995-05-03 FISONS plc Procede de production de compositions pour medicaments
EP0691865A1 (fr) 1993-03-31 1996-01-17 Fisons Plc Dispositif d'inhalation
EP0725725A1 (fr) 1993-10-08 1996-08-14 Fisons Plc Procede de production de formulations medicamenteuses
WO2000007567A1 (fr) 1998-08-04 2000-02-17 Jago Research Ag Formulations d'aerosol a usage medical
US6302331B1 (en) 1999-04-23 2001-10-16 Battelle Pulmonary Therapeutics, Inc. Directionally controlled EHD aerosol sprayer
WO2002030394A2 (fr) 2000-10-09 2002-04-18 3M Innovative Properties Company Formulations medicinales en aerosol
US6397838B1 (en) 1998-12-23 2002-06-04 Battelle Pulmonary Therapeutics, Inc. Pulmonary aerosol delivery device and method
WO2002066476A1 (fr) 2001-02-21 2002-08-29 Altana Pharma Ag 6-phenylbenzonaphtyridines
US6454193B1 (en) 1999-04-23 2002-09-24 Battellepharma, Inc. High mass transfer electrosprayer
WO2004018431A2 (fr) 2002-08-17 2004-03-04 Altana Pharma Ag Nouvelles phenanthridines
WO2004018465A2 (fr) 2002-08-17 2004-03-04 Altana Pharma Ag Nouvelles benzonaphtyridines
WO2005077906A1 (fr) 2004-02-18 2005-08-25 Altana Pharma Ag Nouveaux hydroxy-6-phenylphenenthridines a substitution guanidinyle efficaces en tant qu'inhibiteurs de la phosphodiesterase (pde) 4
WO2006027345A2 (fr) * 2004-09-08 2006-03-16 Altana Pharma Ag Nouveaux derives 3-thia-10-aza-phenanthrene

Patent Citations (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0372777A2 (fr) 1988-12-06 1990-06-13 Riker Laboratories, Inc. Formulations d'aérosols à usage médical
EP0407028A2 (fr) 1989-05-31 1991-01-09 FISONS plc Formule médicamenteuse et appareil d'inhalation
WO1991004011A1 (fr) 1989-09-20 1991-04-04 Riker Laboratories, Inc. Formulations aerosols medicinales
WO1991011173A1 (fr) 1990-02-02 1991-08-08 Fisons Plc Compositions d'agents propulseurs
WO1991011495A1 (fr) 1990-02-03 1991-08-08 Boehringer Ingelheim Kg Nouveaux melanges de gaz propulseurs et leur utilisation dans des preparations medicamenteuses
WO1991014422A1 (fr) 1990-03-23 1991-10-03 Minnesota Mining And Manufacturing Company Emploi de fluorotensioactifs solubles dans la preparation de formulations d'aerosols doseurs
EP0553298A1 (fr) 1990-10-18 1993-08-04 Minnesota Mining & Mfg Formulation d'aerosol contenant du beclomethasone 17,21 dipropionate.
EP0505321A2 (fr) 1991-03-21 1992-09-23 Ciba-Geigy Ag Inhalateur
WO1993011743A1 (fr) 1991-12-12 1993-06-24 Glaxo Group Limited Medicaments
EP0650410A1 (fr) 1992-06-30 1995-05-03 FISONS plc Procede de production de compositions pour medicaments
EP0691865A1 (fr) 1993-03-31 1996-01-17 Fisons Plc Dispositif d'inhalation
EP0725725A1 (fr) 1993-10-08 1996-08-14 Fisons Plc Procede de production de formulations medicamenteuses
WO2000007567A1 (fr) 1998-08-04 2000-02-17 Jago Research Ag Formulations d'aerosol a usage medical
US6397838B1 (en) 1998-12-23 2002-06-04 Battelle Pulmonary Therapeutics, Inc. Pulmonary aerosol delivery device and method
US6302331B1 (en) 1999-04-23 2001-10-16 Battelle Pulmonary Therapeutics, Inc. Directionally controlled EHD aerosol sprayer
US6454193B1 (en) 1999-04-23 2002-09-24 Battellepharma, Inc. High mass transfer electrosprayer
WO2002030394A2 (fr) 2000-10-09 2002-04-18 3M Innovative Properties Company Formulations medicinales en aerosol
WO2002066476A1 (fr) 2001-02-21 2002-08-29 Altana Pharma Ag 6-phenylbenzonaphtyridines
WO2004018431A2 (fr) 2002-08-17 2004-03-04 Altana Pharma Ag Nouvelles phenanthridines
WO2004018465A2 (fr) 2002-08-17 2004-03-04 Altana Pharma Ag Nouvelles benzonaphtyridines
WO2005077906A1 (fr) 2004-02-18 2005-08-25 Altana Pharma Ag Nouveaux hydroxy-6-phenylphenenthridines a substitution guanidinyle efficaces en tant qu'inhibiteurs de la phosphodiesterase (pde) 4
WO2006027345A2 (fr) * 2004-09-08 2006-03-16 Altana Pharma Ag Nouveaux derives 3-thia-10-aza-phenanthrene

Non-Patent Citations (26)

* Cited by examiner, † Cited by third party
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A HATZELMANN ET AL., BRIT J PHARMACOL, vol. 114, 1995, pages 821 - 831
AGBAGA, M.P. ET AL.: "Role of Stargardt-3 macular dystrophy protein (ELOVL4) in the biosynthesis of very long chain fatty acids", PROC NATL ACAD SCI USA, vol. 105, no. 35, 2008, pages 12843 - 12488
ARZNEIMITTEL-FORSCHUNG, vol. 25, no. 10, 1975, pages 1477 - 1482
BARABINO S ET AL., INVEST OPTHALMOL VIS SCI, vol. 46, 2005, pages 2766 - 2771
BIOORG. MED. CHEM. LETT., 1999, pages 227 - 232
BIORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 11, no. 24, 2001, pages 3151 - 3155
BUTOVICH, I.A., TEAR FILM LIPIDS. EXP EYE RES, vol. 117, 2013, pages 4 - 27
BUTOVICH, I.A.; J.C. WOJTOWICZ; M. MOLAI: "Human tear film and meibum. Very long chain wax esters and (O-acyl)-omega-hydroxy fatty acids of meibum", J LIPID RES, vol. 50, no. 12, 2009, pages 2471 - 2485, XP055157215, DOI: doi:10.1194/jlr.M900252-JLR200
C SCHUDT ET AL., ARCH PHARMACOL, vol. 344, 1991, pages 682 - 690
DM ESSAYAN, BIOCHEM PHARMACOL, vol. 57, 1999, pages 965 - 973
GANTNER ET AL., BRIT J PHARMACOL, vol. 121, 1997, pages 221 - 231
GEERLING, G. ET AL.: "The international workshop on meibomian gland dysfunction: report of the subcommittee on management and treatment of meibomian gland dysfunction", INVEST OPHTHALMOL VIS SCI, vol. 52, no. 4, 2011, pages 2050 - 2064
H TENOR; C SCHUDT: "The Handbook of Immunopharmacology", vol. 21-40, 1996, ACADEMIC PRESS, article "Phosphodiesterase Inhibitors"
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LAM, S.M. ET AL.: "Meibum lipid composition in Asians with dry eye disease", PLOS ONE, vol. 6, no. 10, 2011, pages e24339, XP055013727, DOI: doi:10.1371/journal.pone.0024339
MCMAHON, A.; H. LU; I.A. BUTOVICH: "A role for ELOVL4 in the mouse meibomian gland and sebocyte cell biology", INVEST OPHTHALMOL VIS SCI, vol. 55, no. 5, 2014, pages 2832 - 2840
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