WO2008135041A1 - Dérivés d'adamantyloxyamine et composés apparentés en tant que modulateurs de nmda et/ou dpp-4 pour traiter des maladies du snc et le diabète - Google Patents

Dérivés d'adamantyloxyamine et composés apparentés en tant que modulateurs de nmda et/ou dpp-4 pour traiter des maladies du snc et le diabète Download PDF

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Publication number
WO2008135041A1
WO2008135041A1 PCT/DE2008/000835 DE2008000835W WO2008135041A1 WO 2008135041 A1 WO2008135041 A1 WO 2008135041A1 DE 2008000835 W DE2008000835 W DE 2008000835W WO 2008135041 A1 WO2008135041 A1 WO 2008135041A1
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Prior art keywords
group
onr
compound
radicals
medicament
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PCT/DE2008/000835
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German (de)
English (en)
Inventor
Hans Scheefers
Ursula Scheefers-Borchel
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Schebo Biotech 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
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Publication of WO2008135041A1 publication Critical patent/WO2008135041A1/fr

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Classifications

    • 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
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
    • C07C239/08—Hydroxylamino compounds or their ethers or esters
    • C07C239/20—Hydroxylamino compounds or their ethers or esters having oxygen atoms of hydroxylamino groups etherified
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the present patent application relates to novel pharmaceuticals of the general formula I 1 Process for their preparation and their use in the therapy of CNS diseases and diabetes.
  • the application claims the priority of the German patent application DE 10 2007022 007 of May 8, 2007.
  • Adamantane derivatives especially 1-amino-3,5-dimethyl adamantane (also known as memantines) are known as Alzheimer's therapeutics. Their effectiveness is limited, there are a number of known side effects. Further developments, such as Donepezil has been shown to be ineffective in the treatment of Alzheimer's disease. There is therefore a need for other Alzheimer's and other CNS therapeutics.
  • radicals R 1 -R 10 represents a group -ONR 11 R 12 -CH 2 -ONR 11 R 12 , - (CHz) 2 -ONR 11 R 12 ,
  • R 11 and R 12 independently of one another represent a hydrogen atom, a branched or unbranched C 1 -C 10 -alkyl group
  • R 13 is a group - (CH 2 ) n - (CO) m - (CH 2 ) o - (S) p - (CH 2 ) q -
  • R 13 is a group - (CH 2 ) n - (NH) m - (CH 2 ) 0 - (S) p- (CH 2 VR 13 is a group - (CO) n - (NH) m - (CH 2 ) o- (S) p- (CH 2 ) q -R 13 is a group - (CH 2 ) n - (NH) m - (CH 2 ) o - (SO 2 ) p - (CH 2 ) q -R 13 wherein n is 0, 1 or 2 m is 0 or 1 o is 0 or 1 when p is 0 or 1 is q is 0, 1 or 2, R 13 is -CH 3 , -OH or an aryl or heteroaryl radical
  • radicals R 1 -R 10 independently of one another represent a hydrogen atom, a hydroxy group, a methoxy group, a methyl or an ethyl group, and their optical isomers and their salts with physiologically tolerable counterions, surprisingly have outstanding suitability as CNS therapeutics. They are also effective in the treatment of diabetes.
  • the compounds of general formula I are adamantane derivatives.
  • one of the radicals R 1 -R 10 is a group -ONR 11 R 12 or -CH 2 -ONR 11 R 12 or - (CH 2 ) 2 -ONR 11 R 12 and the other radicals are independent each other represents a hydrogen atom, a hydroxy group, a methoxy group, a methyl or an ethyl group.
  • the groups R 5 and R 8 are methyl groups.
  • R 11 and R 12 can be hydrogen atoms.
  • R 11 and R 12 can also be branched or unbranched C 1 -C 10 -alkyl groups, for example methyl, ethyl, propyl, butyl, pentyl or a -CO-CH 2 -S-CH 2 -CH 2 R 13 or a -CO -NH-CH 2 -CH 2 -CH 2 -R 13 group.
  • R 11 and R 12 may also be a -CH 2 -CH 2 -SO 2 -OH group.
  • Preferred compounds are those in which one of the radicals R 11 or R 12 is a pentyl radical, and the second radical is -CO-CH 2 -S-CH 2 -CH 2 R 13 or -CO-NH-CH 2 - CH 2 -CH 2 -R 13 stands.
  • R 13 can be a methyl, a phenyl or a pyridinyl radical.
  • R 13 is a pyridinyl radical.
  • one of the radicals R 1 -R 10 is a group
  • the compounds of general formula I can be used for the treatment of CNS diseases, for example for the treatment of Alzheimer's, Parkinson's disease, dementia and multiple sclerosis.
  • the compounds of general formula I continue to be effective in the treatment of depression, glaucoma, tinnitus and neuropathies.
  • the compounds of general formula I are effective against schizophrenia, drug and nicotine abuse and pain.
  • autoimmune diseases such as lupus erythematosus.
  • the compounds also show efficacy in the treatment of bacterial diseases (eg malaria) and of viral diseases such as influenza, including various variants of avian influenza such as A-H5N1.
  • the compounds of general formula I are also effective in the treatment of diabetes, presumably because of the action of the compounds as dipeptidyl peptidase-4 (DPP-4) inhibitors.
  • DPP-4 dipeptidyl peptidase-4
  • the present invention teaches a pharmaceutical composition containing at least one compound of the invention.
  • one or more physiologically acceptable excipients and / or carriers may be mixed with the compound and the mixture galenically prepared for local or systemic administration, especially orally, parenterally, for infusion, for injection.
  • the choice of additives and / or adjuvants will depend on the chosen dosage form.
  • the galenic preparation of the pharmaceutical composition according to the invention is carried out in the usual way.
  • ionic compounds are, for example, Ca ++ , Na + , K + , Li + or cyclohexylammonium, or Cl " , Br " , acetate, propionate, lactate, oxalate, malonate, maleate, citrate, benzoate, salicylate or the like Question.
  • Suitable solid or liquid pharmaceutical preparation forms are, for example, granules, powders, dragees, tablets, microcapsules, suppositories, syrups, juices, suspensions, emulsions, drops or solutions for injection (iv, ip, im, sc) or nebulization (aerosols), forms of preparation for Dry powder inhalation, transdermal systems as well as preparations with sustained-release release, in the production of which conventional auxiliaries such as carriers, blasting agents, binders, coating substances, swelling or lubricants, flavorings, sweeteners and solubilizers are used.
  • auxiliaries such as carriers, blasting agents, binders, coating substances, swelling or lubricants, flavorings, sweeteners and solubilizers are used.
  • excipients include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycols and solvents such as sterile water and monohydric or polyhydric alcohols such as glycerine ,
  • a pharmaceutical composition according to the invention can be prepared by mixing at least one substance combination used according to the invention in defined doses with a pharmaceutically suitable and physiologically acceptable carrier and optionally further suitable active ingredients, additives or excipients with a defined dose and prepared to the desired administration form.
  • Suitable diluents are polyglycols, ethanol, water and buffer solutions.
  • Suitable buffer substances are, for example, N, N-dibenzylethylenediamine, diethanolamine, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, diethylamine, phosphate, sodium bicarbonate and sodium carbonate.
  • N, N-dibenzylethylenediamine, diethanolamine ethylenediamine, N-methylglucamine
  • N-benzylphenethylamine diethylamine
  • phosphate sodium bicarbonate and sodium carbonate.
  • the pharmaceutical composition is prepared and administered in dosage units, each unit containing as active ingredient a defined dose of the compound of formula I according to the invention.
  • this dose may be from 0.1 to 1000 mg, preferably from 1 to 300 mg, and in the case of injection solutions in the form of ampoules from 0.01 to 1000 mg, preferably from 1 to 100 mg.
  • daily doses for the treatment of an adult, patients weighing 50-100 kg, for example 70 kg, daily doses of 0.1-1,000 mg active substance, preferably 1-500 mg, are indicated. However, higher or lower daily doses may be appropriate.
  • the administration of the daily dose can be carried out by single administration in the form of a single unit dose or several smaller dosage units as well as by multiple subdivided doses at specific intervals. production method
  • tert-alkoxy-amines can be carried out according to the literature (Hasan Palandoken et al., Tetrahedron Letters 46 (2005) 6667-6669), which can be easily adapted by the skilled person to different requirements.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Obesity (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé de formule générale (I) et son utilisation pour traiter des maladies du SNC et le diabète. Dans ladite formule, l'un des radicaux R1-R10 est un groupe -ONR11R12 -CH2-ONR11R12, -(CH2)2-ONR11R12, -O(C=O)NR11R12, -CH2-O(C=O)NR11R12, -(CH2)2-O(C=O)NR11R12, -(C=O)-O-NR11R12, -CH2(C=O)-O-NR11R12, -(CH2)2(C=O)-O-NR11R12 ou l'un des groupes de formules de II à IX ou l'un des groupes définis en supplément dans la revendication 1.
PCT/DE2008/000835 2007-05-08 2008-05-08 Dérivés d'adamantyloxyamine et composés apparentés en tant que modulateurs de nmda et/ou dpp-4 pour traiter des maladies du snc et le diabète WO2008135041A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102007022007.5 2007-05-08
DE102007022007A DE102007022007A1 (de) 2007-05-08 2007-05-08 Neuartike Pharmazeutika, Verfahren zu ihrer Herstellung und ihre Verwendung in der Prophylaxe und Therapie von ZNS-Erkrankungen und Diabetes

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WO2008135041A1 true WO2008135041A1 (fr) 2008-11-13

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PCT/DE2008/000835 WO2008135041A1 (fr) 2007-05-08 2008-05-08 Dérivés d'adamantyloxyamine et composés apparentés en tant que modulateurs de nmda et/ou dpp-4 pour traiter des maladies du snc et le diabète

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DE (1) DE102007022007A1 (fr)
WO (1) WO2008135041A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102009019852A1 (de) 2009-05-06 2010-11-11 Schebo Biotech Ag Polymere mit neuen Strukturelementen, Verfahren zu ihrer Herstellung und ihre Verwendung

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3369041A (en) * 1965-01-21 1968-02-13 Lilly Co Eli Adamantyl carbazates
WO2000034241A1 (fr) * 1998-12-10 2000-06-15 Novartis Ag 2-cyanopyrrolidines n-substitues
WO2002078615A2 (fr) * 2001-04-02 2002-10-10 Panorama Research, Inc. Nitroxydes et nitrones antioxydants comme agents therapeutiques
WO2004033422A2 (fr) * 2002-10-07 2004-04-22 The Regents Of The University Of California Modulation de l'anxiete par blocage de l'hydrolyse de l'anandamide
WO2005012249A2 (fr) * 2003-08-01 2005-02-10 Bristol-Myers Squibb Company Inhibiteurs a base d'adamantyglycine de la dipeptidyl peptidase iv et procedes associes
EP1512679A1 (fr) * 2003-09-02 2005-03-09 Rotta Research Laboratorium S.P.A. Nouveaux dérivés d'adamantane à activités neuroprotectrices, antidépressives et antiischémiques, et leur procédé de préparation
WO2005054179A2 (fr) * 2003-12-03 2005-06-16 Leo Pharma A/S Nouveaux esters d'acide hydroxamique et leurs utilisations pharmaceutiques
WO2006090244A1 (fr) * 2005-02-22 2006-08-31 Glenmark Pharmaceuticals S.A. Nouveaux derives d'adamantine utilises en tant qu'inhibiteurs de dipeptidyl peptidase iv, procedes de preparation associes, et compositions pharmaceutiques les contenant

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3369041A (en) * 1965-01-21 1968-02-13 Lilly Co Eli Adamantyl carbazates
WO2000034241A1 (fr) * 1998-12-10 2000-06-15 Novartis Ag 2-cyanopyrrolidines n-substitues
WO2002078615A2 (fr) * 2001-04-02 2002-10-10 Panorama Research, Inc. Nitroxydes et nitrones antioxydants comme agents therapeutiques
WO2004033422A2 (fr) * 2002-10-07 2004-04-22 The Regents Of The University Of California Modulation de l'anxiete par blocage de l'hydrolyse de l'anandamide
WO2005012249A2 (fr) * 2003-08-01 2005-02-10 Bristol-Myers Squibb Company Inhibiteurs a base d'adamantyglycine de la dipeptidyl peptidase iv et procedes associes
EP1512679A1 (fr) * 2003-09-02 2005-03-09 Rotta Research Laboratorium S.P.A. Nouveaux dérivés d'adamantane à activités neuroprotectrices, antidépressives et antiischémiques, et leur procédé de préparation
WO2005054179A2 (fr) * 2003-12-03 2005-06-16 Leo Pharma A/S Nouveaux esters d'acide hydroxamique et leurs utilisations pharmaceutiques
WO2006090244A1 (fr) * 2005-02-22 2006-08-31 Glenmark Pharmaceuticals S.A. Nouveaux derives d'adamantine utilises en tant qu'inhibiteurs de dipeptidyl peptidase iv, procedes de preparation associes, et compositions pharmaceutiques les contenant

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Title
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ARGUEELLO ET AL: "Fluorescent Quenching of the 2-Naphthoxide Anion by Aliphatic and Aromatic Halides. Mechanism and Consequences of Electron Transfer Reactions", JOURNAL OF ORGANIC CHEMISTRY, vol. 68, no. 6, 2003, pages 2362 - 2368, XP002497956 *
BARTON ET AL, JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1: ORGANIC AND BIOORGANIC CHEMISTRY (1972-1999), 1974, pages 2344 - 2346 *
BENALIL ET AL: "A Convenient and General Synthesis of Alkylcarbamates from Tertiary Isocyanates and Alcohols", SYNTHESIS, vol. 2, 1989, pages 131 - 132, XP002497961 *
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; 1974, XP002497965, Database accession no. BRN: 2529921 *
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; 1974, XP002497966, Database accession no. BRN: 2450824 *
DUGGAN ET AL: "Copper(I) Chloride Catalyzed Addition of Alcohols to Alkyl lsocyanates. A Mild and Expedient Method for Alkyl Carbamate Formation", SYNTHESIS, vol. 2, 1989, pages 131 - 132, XP002497959 *
GERZON ET AL: "The Adamantyl Group in Medicinal Agents. IV. Sedative Action of 3,5,7-Trimethyladamantane-1-carboxamide1 and Related Agents", JOURNAL OF MEDICINAL CHEMISTRY, vol. 10, 1967, pages 603 - 606, XP002497958 *
GRIGAT ET AL: "Zur Kenntnis einiger Hydroxamsäuren mit (s-trans)-Anordnung (p 1037-1043)", ARCHIV DER PHARMAZIE, vol. 319, no. 11, 1986, pages 1037 - 1043, XP002497963 *
LIN ET AL: "Conformationally restricted carbamate inhibitors of horse serum butyrylcholinesterase", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 8, no. 19, 1998, pages 2747 - 2750, XP002497962 *
MAVUNKEL ET AL: "Synthesis and opioid activities of some naltrexone oxime ethers", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 29, no. 9, 1994, pages 659 - 666, XP002497955 *
PALANDOKEN ET AL: "A facile synthesis of (tert-alkoxy)amines", TETRAHEDRON LETTERS, vol. 46, no. 39, 2005, pages 6667 - 6669, XP002497954 *
ROHDE ET AL, JOURNAL OF MEDICIAL CHEMISTRY, vol. 50, no. 1, 13 December 2006 (2006-12-13) - 2007, pages 149 - 164, XP002497957 *
VIGNE ET AL: "Microbial transformations 18. Regiospecific para-hydroxylation of aromatic carbamates mediated by the fungus Beauveria sulfurescens", TETRAHEDRON, vol. 47, no. 8, 1991, pages 1447 - 1458, XP002497960 *
VILLHAUER ET AL: "1-[[(3-Hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine: A Potent, Selective, and Orally Bioavailable Dipeptidyl Peptidase IV Inhibitor with Antihyperglycemic Properties", JOURNAL OF MEDICINAL CHEMISTRY, vol. 46, no. 13, 2003, pages 2774 - 2789, XP002497964 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102009019852A1 (de) 2009-05-06 2010-11-11 Schebo Biotech Ag Polymere mit neuen Strukturelementen, Verfahren zu ihrer Herstellung und ihre Verwendung

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