WO2020165031A1 - Dérivés isochinolin-pipéridinylméthanone substitués - Google Patents

Dérivés isochinolin-pipéridinylméthanone substitués Download PDF

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Publication number
WO2020165031A1
WO2020165031A1 PCT/EP2020/053080 EP2020053080W WO2020165031A1 WO 2020165031 A1 WO2020165031 A1 WO 2020165031A1 EP 2020053080 W EP2020053080 W EP 2020053080W WO 2020165031 A1 WO2020165031 A1 WO 2020165031A1
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WO
WIPO (PCT)
Prior art keywords
diabetic
diseases
acid
compound
peripheral
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/EP2020/053080
Other languages
German (de)
English (en)
Inventor
Eva Maria BECKER-PELSTER
Philipp BUCHGRABER
Anna ENGELEN
Michael Gerisch
Jorma Hassfeld
Isabel PIEL
Carsten Schmeck
Dietrich Seidel
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.)
Bayer AG
Original Assignee
Bayer 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 Bayer AG filed Critical Bayer AG
Publication of WO2020165031A1 publication Critical patent/WO2020165031A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • 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
    • 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

Definitions

  • R 1 is a group of the formula
  • Glycerophosphoric acid aspartic acid, sulfosalicylic acid or thiocyanic acid.
  • the present invention includes all possible salts of the compounds of the present invention as individual salts or as a mixture of these salts in any proportion.
  • the compounds (I-C-1), (I-A‘-2) and (I-A‘-3) are particularly preferred.
  • the compounds (I-C-1) and (I-A‘-2) are very particularly preferred.
  • the compound (II) is for example base-catalyzed in the presence of an oxidizing agent to compound (III) by known processes in the second step (2)
  • compound (III) is converted to compound (IV) by known processes in the presence of an acid chloride former and an alcohol
  • the compound of the formula (I) and its metabolites are suitable for the treatment and / or prophylaxis of accompanying and / or secondary diseases of diabetes mellitus.
  • accompanying and / or secondary diseases of diabetes mellitus are diabetic heart diseases, such as diabetic coronary heart diseases, diabetic coronary microvascular disease (MVD), diabetic heart failure, diabetic cardiomyopathy and myocardial infarction, high blood pressure, diabetic microangiopathy, diabetic neuropathy, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, diabetic erectile dysfunction, diabetic ulcers on the extremities, and diabetic foot syndrome.
  • the compound of the formula (I) and its metabolites are also suitable for promoting diabetic wound healing, in particular for promoting wound healing of diabetic foot ulcers. The promotion of the wound healing of diabetic foot ulcers is defined, for example, as an improvement in wound closure.
  • the present invention further relates to the use of the compound of the formula (I) and its metabolites for the production of a medicament for the treatment and / or prophylaxis of illnesses, in particular the diseases mentioned above.
  • Active ingredients that change lipid metabolism, for example and preferably from the group of
  • Agonists such as, for example and preferably, niacin, acipimox, acifran or Radecol, and antioxidants / radical scavengers such as, for example and preferably, probucol, succinobucol (AGI-1067), BO-653 or AEOL-10150;
  • HNE human neutrophil elastase
  • compounds which inhibit the signal transduction cascade such as, for example, tyrosine kinase inhibitors and multikinase inhibitors, in particular sorafenib, imatinib, gefitinib and erlotinib; and or
  • fast and / or modified application forms which release the compound of the formula (I) and its metabolites and which contain the compounds according to the invention in crystalline and / or amorphized and / or dissolved form are suitable, e.g. Tablets (uncoated or coated tablets, for example with gastric juice-resistant or delayed dissolving or insoluble coatings that control the release of the compound according to the invention), tablets or films / wafers that disintegrate quickly in the oral cavity, films / fyophylisates, capsules (for example hard or Soft gelatine capsules), coated tablets, granulates, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • Tablets uncoated or coated tablets, for example with gastric juice-resistant or delayed dissolving or insoluble coatings that control the release of the compound according to the invention
  • tablets or films / wafers that disintegrate quickly in the oral cavity
  • films / fyophylisates for example hard or Soft gelatine capsules
  • the present invention also relates to medicaments which contain at least one compound of the formula (I) and its metabolites, preferably together with one or more inert, non-toxic, pharmaceutically suitable auxiliary substances, and their use for the purposes mentioned above.
  • Method 2 Instrument MS: Waters (Micromass) QM; HPLC instrument: Agilent 1100 series; Column: Agient ZORBAX Extend-C18 3.0x50mm 3.5-Micron; Eluent A: 1 1 water + 0.01 mol ammonium carbonate, eluent B: 1 1 acetonitrile; Gradient: 0.0 min 98% A— 0.2 min 98% A—> 3.0 min 5% A— 4.5 min 5% A; Oven: 40 ° C; Flow rate: 1.75 ml / min; UV detection: 210 nm.
  • 1,2,3,4-Tetrahydroisoquinolin-4-ol hydrochloride (0.70 g, 5.12 mmol) was placed in 15 ml of THF.
  • Tert-butyl 4-oxopiperidine-1-carboxylate (1.02 g, 5.12 mmol)
  • acetic acid 0.292 ml, 5.12 mmol
  • Sodium triacetoxyborohydride (1.70 g, 8.02 mmol) was added in portions and the mixture was stirred at room temperature for 2.5 h. After the addition of saturated sodium hydrogen carbonate solution, the mixture was extracted with dichloromethane.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (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

L'invention concerne de nouveaux dérivés isochinolin-pipéridinylméthanone substitués, leur procédé de production, leur utilisation dans un procédé pour le traitement et/ou la prophylaxie de maladies ainsi que leur utilisation pour produire des médicaments destinés au traitement et/ou à la prophylaxie de maladies.
PCT/EP2020/053080 2019-02-15 2020-02-07 Dérivés isochinolin-pipéridinylméthanone substitués Ceased WO2020165031A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP19157388 2019-02-15
EP19157388.0 2019-02-15

Publications (1)

Publication Number Publication Date
WO2020165031A1 true WO2020165031A1 (fr) 2020-08-20

Family

ID=65443722

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2020/053080 Ceased WO2020165031A1 (fr) 2019-02-15 2020-02-07 Dérivés isochinolin-pipéridinylméthanone substitués

Country Status (1)

Country Link
WO (1) WO2020165031A1 (fr)

Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3966781A (en) 1970-12-17 1976-06-29 Merck Sharp & Dohme (I.A.) Corporation Deuteration of functional group-containing hydrocarbons
WO1997026265A1 (fr) 1996-01-17 1997-07-24 Novo Nordisk A/S Derives de 1,2,4-thiadiazine fusionnee et de 1,4-thiazine fusionnee, leur preparation et utilisation
WO1999003861A1 (fr) 1997-07-16 1999-01-28 Novo Nordisk A/S Derives de 1,2,4-thiadiazine fusionnee, leur preparation et utilisation
WO2000006569A1 (fr) 1998-07-29 2000-02-10 Bayer Aktiengesellschaft Derives de pyrazole substitues, condenses avec des noyaux heterocycliques a six chaines
WO2000006568A1 (fr) 1998-07-29 2000-02-10 Bayer Aktiengesellschaft Derives de pyrazole substitues
WO2001019776A2 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Nouveaux derives d'acide dicarboxylique presentant des proprietes pharmaceutiques
WO2001019778A1 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Derives d'acide dicarboxylique a proprietes pharmaceutiques
WO2001019355A2 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Derives d'acide dicarboxylique presentant de nouvelles proprietes pharmaceutiques
WO2001019780A2 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Nouveaux derives d'acide aminodicarboxylique presentant des proprietes pharmaceutiques
WO2002042301A1 (fr) 2000-11-22 2002-05-30 Bayer Aktiengesellschaft Nouveaux derives de pyrazolopyridine a substitution pyridine
WO2002070462A1 (fr) 2001-03-07 2002-09-12 Bayer Aktiengesellschaft Derives d'acide aminodicarboxylique
WO2002070510A2 (fr) 2001-03-07 2002-09-12 Bayer Aktiengesellschaft Nouveaux derives d'acide aminodicarbonique presentant des proprietes pharmaceutiques
WO2003095451A1 (fr) 2002-05-08 2003-11-20 Bayer Healthcare Ag Pyrazolopyridines a substitution carbamate
WO2012112363A1 (fr) 2011-02-14 2012-08-23 Merck Sharp & Dohme Corp. Inhibiteurs de cystéine protéases, les cathepsines
WO2015091417A1 (fr) * 2013-12-19 2015-06-25 Bayer Pharma Aktiengesellschaft Pipéridinyl-tétrahydroquinoléines substituées
WO2015091414A2 (fr) 2013-12-19 2015-06-25 Bayer Pharma Aktiengesellschaft Pipéridinyl-tétrahydrochinolines substituées

Patent Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3966781A (en) 1970-12-17 1976-06-29 Merck Sharp & Dohme (I.A.) Corporation Deuteration of functional group-containing hydrocarbons
WO1997026265A1 (fr) 1996-01-17 1997-07-24 Novo Nordisk A/S Derives de 1,2,4-thiadiazine fusionnee et de 1,4-thiazine fusionnee, leur preparation et utilisation
WO1999003861A1 (fr) 1997-07-16 1999-01-28 Novo Nordisk A/S Derives de 1,2,4-thiadiazine fusionnee, leur preparation et utilisation
WO2000006569A1 (fr) 1998-07-29 2000-02-10 Bayer Aktiengesellschaft Derives de pyrazole substitues, condenses avec des noyaux heterocycliques a six chaines
WO2000006568A1 (fr) 1998-07-29 2000-02-10 Bayer Aktiengesellschaft Derives de pyrazole substitues
WO2001019776A2 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Nouveaux derives d'acide dicarboxylique presentant des proprietes pharmaceutiques
WO2001019778A1 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Derives d'acide dicarboxylique a proprietes pharmaceutiques
WO2001019355A2 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Derives d'acide dicarboxylique presentant de nouvelles proprietes pharmaceutiques
WO2001019780A2 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Nouveaux derives d'acide aminodicarboxylique presentant des proprietes pharmaceutiques
WO2002042301A1 (fr) 2000-11-22 2002-05-30 Bayer Aktiengesellschaft Nouveaux derives de pyrazolopyridine a substitution pyridine
WO2002070462A1 (fr) 2001-03-07 2002-09-12 Bayer Aktiengesellschaft Derives d'acide aminodicarboxylique
WO2002070510A2 (fr) 2001-03-07 2002-09-12 Bayer Aktiengesellschaft Nouveaux derives d'acide aminodicarbonique presentant des proprietes pharmaceutiques
WO2003095451A1 (fr) 2002-05-08 2003-11-20 Bayer Healthcare Ag Pyrazolopyridines a substitution carbamate
WO2012112363A1 (fr) 2011-02-14 2012-08-23 Merck Sharp & Dohme Corp. Inhibiteurs de cystéine protéases, les cathepsines
WO2015091417A1 (fr) * 2013-12-19 2015-06-25 Bayer Pharma Aktiengesellschaft Pipéridinyl-tétrahydroquinoléines substituées
WO2015091414A2 (fr) 2013-12-19 2015-06-25 Bayer Pharma Aktiengesellschaft Pipéridinyl-tétrahydrochinolines substituées

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