WO2008135041A1 - Adamantyloxyamine derivatives and related compounds for use as nmda and/or dpp-4 modulators for the therapy of cns diseases and diabetes - Google Patents

Adamantyloxyamine derivatives and related compounds for use as nmda and/or dpp-4 modulators for the therapy of cns diseases and diabetes Download PDF

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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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compound
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Hans Scheefers
Ursula Scheefers-Borchel
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Schebo Biotech Ag
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    • 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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  • Diabetes (AREA)
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  • Obesity (AREA)
  • Hospice & Palliative Care (AREA)
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Abstract

The invention relates to the compound of formula (I), wherein one of the groups R1-R10 represents a group -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 or one of the following groups (formulae II - IX) or one of the other groups defined in claim 1, and to the use thereof in the prophylaxis and therapy of CNS diseases and diabetes.

Description

ADAMANTYLOXYAMIN-DERIVATE UND VERWANDTE VERBINDUNGEN ALS NMDA UND/ODER DPP-4 MODULATOREN ZUR BEHANDLUNG VON ZNS-ERKRANKUNGEN UND ADAMANTYLOXYAMINE DERIVATIVES AND RELATED COMPOUNDS AS NMDA AND / OR DPP-4 MODULATORS FOR THE TREATMENT OF CNS DISEASES AND
DIABETESDIABETES
Die vorliegende Patentanmeldung betrifft neuartige Pharmazeutika der allgemeinen 5 Formel I1 Verfahren zu Ihrer Herstellung und ihre Verwendung in der Therapie von ZNS-Erkrankungen und Diabetes. Die Anmeldung nimmt die Priorität der Deutschen Patentanmeldung DE 10 2007022 007 vom 8.5.2007 in Anspruch.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.
Hintergrund und Stand der TechnikBackground and state of the art
Adamantan-Derivate, insbesondere 1-Amino-3,5-dimethyl-adamantan (auch bekannt 10 als Memantine) sind bekannt als Alzheimer-Therapeutika. Ihre Wirksamkeit ist begrenzt, es gibt eine Reihe bekannter Nebenwirkungen. Weitere Entwicklungen, wie z.B. Donepezil, haben sich als unwirksam in der Therapie von Alzheimer erwiesen. Es gibt daher Bedarf an weiteren Alzheimer- und anderen ZNS-Therapeutika.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.
Beschreibung der ErfindungDescription of the invention
15 Es wurde nun gefunden, dass Verbindungen der allgemeinen Formel IIt has now been found that compounds of general formula I
Figure imgf000003_0001
Figure imgf000003_0001
in der einer der Reste R1-R10 für 20 eine Gruppe -ONR11R12 -CH2-ONR11R12 , -(CHz)2-ONR11R12,in which one of the radicals R 1 -R 10 represents a group -ONR 11 R 12 -CH 2 -ONR 11 R 12 , - (CHz) 2 -ONR 11 R 12 ,
-0(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 -O (C = O) NR 11 R 12 , -CH 2 -O (C = O) NR 11 R 12 , - (CH 2 ) 2 -O (C = O) NR 11 R 12 , - (C = O ) -O-NR 11 R 12 , -CH 2 (C = O) -O-NR 11 R 12 , - (CH 2 ) 2 (C = O) -O-NR 11 R 12
oder eine der folgenden Gruppen
Figure imgf000004_0001
or one of the following groups
Figure imgf000004_0001
Figure imgf000004_0002
Figure imgf000004_0003
steht, worin R11 und R12 unabhängig voneinander für ein Wasserstoffatom, eine verzweigte oder unverzweigte Ci-Cio-Alkyigruppe
Figure imgf000004_0002
Figure imgf000004_0003
in which R 11 and R 12 independently of one another represent a hydrogen atom, a branched or unbranched C 1 -C 10 -alkyl group
eine Gruppe -(CH2)n-(CO)m-(CH2)o-(S)p-(CH2)q-R13 eine Gruppe -(CH2)n-(NH)m-(CH2)0-(S)p-(CH2VR13 eine Gruppe -(CO)n-(NH)m-(CH2)o-(S)p-(CH2)q-R13 eine Gruppe -(CH2)n-(NH)m-(CH2)o-(SO2)p-(CH2)q-R13 stehen, worin n für 0, 1 oder 2 steht m für 0 oder 1 steht o für 0 oder 1 steht p für 0 oder 1 steht q für 0, 1 oder 2 steht R13 für -CH3, -OH oder einen Aryl- oder Heteroarylrest stehta 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
und worin die anderen Reste R1-R10 unabhängig voneinander für ein Wasserstoffatom, eine Hydroxygruppe, eine Methoxygruppe, eine Methyl- oder eine Ethylgruppe stehen sowie deren optische Isomeren und deren Salze mit physiologische verträglichen Gegenionen, überraschenderweise hervorragende Eignung als ZNS-Therapeutika aufweisen. Sie sind darüber hinaus wirksam in der Therapie von Diabetes.and wherein the other 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.
Detaillierte Beschreibung der Erfindung und bevorzugte AusführungsformenDetailed description of the invention and preferred embodiments
Bei den Verbindungen der allgemeinen Formel I handelt es sich um Adamantan- Derivate. In den Verbindungen der allgemeinen Formel I steht einer der Reste R1-R10 für eine Gruppe -ONR11R12 oder -CH2-ONR11R12 oder -(CH2)2-ONR11R12 und die anderen Reste unabhängig voneinander für ein Wasserstoffatom, eine Hydroxygruppe, eine Methoxygruppe, eine Methyl- oder eine Ethylgruppe. Bevorzugt sind solche Verbindungen, bei denen mehr als fünf der Reste R1-R10 für Wasserstoffatome stehen. Besonders bevorzugt stehen die Gruppen R5 und R8 für Methylgruppen. Innerhalb der Gruppen -ONR11R12 oder -CH2-ONR11R12 oder -(CH2)2-ONR11R12 können R11 und R12 für Wasserstoffatome stehen. R11 und R12 können auch für verzweigte oder unverzweigte CrC-io-Alkylgruppen, zum Beispiel Methyl, Ethyl, Propyl, Butyl, Pentyl oder für eine -CO-CH2-S-CH2-CH2R13 oder eine -CO-NH-CH2-CH2-CH2-R13 Gruppe stehen. R11 und R12 können ferner auch für eine -CH2-CH2-SO2-OH Gruppe stehen.The compounds of general formula I are adamantane derivatives. In the compounds of the general formula I, 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. Preference is given to those compounds in which more than five of the radicals R 1 -R 10 are hydrogen atoms. Particularly preferably, the groups R 5 and R 8 are methyl groups. Within the groups -ONR 11 R 12 or -CH 2 -ONR 11 R 12 or - (CH 2 ) 2 -ONR 11 R 12 , 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.
Bevorzugte Verbindungen sind solche, bei denen einer der Reste R11 oder R12 für einen Pentylrest stehen, und der zweite Rest für -CO-CH2-S-CH2-CH2R13 oder für -CO-NH-CH2-CH2-CH2-R13 steht. R13 kann dabei ein Methyl, ein Phenyl oder ein Pyridinylrest sein. Bevorzugt steht R13 für einen Pyridinylrest.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. Preferably, R 13 is a pyridinyl radical.
In einer besonders bevorzugten Ausführungsform der Erfindung steht einer der Reste R1-R10 für eine GruppeIn a particularly preferred embodiment of the invention, one of the radicals R 1 -R 10 is a group
Figure imgf000006_0001
oder eine Gruppe
Figure imgf000006_0001
or a group
Figure imgf000006_0002
Figure imgf000006_0002
Weitere besonders bevorzugte Verbindungen der allgemeinen Formel I sind Gegenstand der Unteransprüche, insbesondere des Anspruchs 7.Further particularly preferred compounds of the general formula I are the subject matter of the subclaims, in particular of claim 7.
Verwendungenuses
Die Verbindungen der allgemeinen Formel I können für die Behandlung von ZNS- Erkrankungen verwendet werden, beispielsweise für die Behandlung von Alzheimer, Parkinsons Disease, Demenz und Multipler Sklerose. Als NMDA-Rezeptorantagonist wirken sie in allen Krankheiten, die über den NMDA-Rezeptor vermittelt werden. Die Verbindungen der allgemeinen Formel I wirken weiterhin bei der Behandlung von Depression, Glaukom, Tinnitus und Neuropathien. Ferner sind die Verbindungen der allgemeinen Formel I wirksam gegen Schizophrenie, Drogen- und Nikotinmissbrauch und Schmerzen. Bemerkenswert ist die weitere Eignung zur Behandlung von bestimmten Autoimmun- Erkrankungen, wie Lupus Erythematosus. Die Verbindungen zeigen darüber hinaus Wirksamkeit bei der Behandlung bakteriellen Erkrankungen (z.B. Malaria) und von von viralen Erkrankungen, wie z.B. Influenza, inklusive verschiedener Varianten der Vogelgrippe, wie z.B. A-H5N1.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. As an NMDA receptor antagonist they work in all diseases that are mediated via the NMDA receptor. The compounds of general formula I continue to be effective in the treatment of depression, glaucoma, tinnitus and neuropathies. Furthermore, the compounds of general formula I are effective against schizophrenia, drug and nicotine abuse and pain. Noteworthy is the further suitability for the treatment of certain 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.
Völlig überraschend sind die Verbindungen der allgemeinen Formel I auch bei der Behandlung von Diabetes wirksam, vermutlich wegen der Wirkung der Verbindungen als Dipeptidylpeptidase-4 (DPP-4) Inhibitoren.Quite surprisingly, 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.
Formulierungenformulations
Die vorliegende Erfindung lehrt eine pharmazeutische Zusammensetzung enthaltend mindestens eine erfindungsgemäße Verbindung. Optional können ein oder mehrere physiologisch verträgliche Hilfsstoffe und/oder Trägersstoffe mit der Verbindung gemischt und die Mischung galenisch zur lokalen oder systemischen Gabe, insbesondere oral, parenteral, zur Infusion, zur Injektion hergerichtet sein. Die Auswahl der Zusatz- und/oder Hilfsstoffe wird von der gewählten Darreichungsform abhängen. Die galenische Herrichtung der erfindungsgemäßen pharmazeutischen Zusammensetzung erfolgt in fachüblicher Weise. Als Gegenion für ionische Verbindungen kommen beispielsweise Ca++, Na+, K+, Li+ oder Cyclohexylammonium, bzw. Cl", Br", Azetat, Propionat, Laktat, Oxalat, Malonat, Maleinat, Citrat, Benzoat, Salizylat oder ähnliches in Frage. Geeignete feste oder flüssige galenische Zubereitungsformen sind beispielsweise Granulate, Pulver, Dragees, Tabletten, Mikrokapseln, Suppositorien, Sirupe, Säfte, Suspensionen, Emulsionen, Tropfen oder Lösungen zur Injektion (i.v., i.p., i.m., s.c.) oder Vernebelung (Aerosole), Zubereitungsformen zur Trockenpulverinhalation, transdermale Systeme sowie Präparate mit retardierter Wirkstofffreigabe, bei deren Herstellung übliche Hilfsmittel wie Trägerstoffe, Spreng-, Binde-, Überzugs-, Quellungs-, Gleit- oder Schmiermittel, Geschmacksstoffe, Süßungsmittel und Lösungsvermittler Verwendung finden. Als Hilfsstoffe seien beispielsweise Magnesiumkarbonat, Titandioxyd, Laktose, Mannit und andere Zucker, Talkum, Milcheiweiß, Gelatine, Stärke, Zellulose und ihre Derivate, tierische und pflanzliche Öle wie Lebertran, Sonnenblumen-, Erdnuss- oder Sesamöl, Polyethylenglykole und Lösungsmittel wie etwa steriles Wasser und ein- oder mehrwertige Alkohole, beispielsweise Glyzerin, genannt.The present invention teaches a pharmaceutical composition containing at least one compound of the invention. Optionally, 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. As a counter ion for 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. Examples of 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 ,
Eine erfindungsgemäße pharmazeutische Zusammensetzung ist dadurch herstellbar, dass mindestens eine erfindungsgemäß verwendete Substanzkombination in definierter Dosis mit einem pharmazeutisch geeigneten und physiologisch verträglichen Träger und ggf. weiteren geeigneten Wirk-, Zusatz- oder Hilfsstoffen mit definierter Dosis gemischt und zu der gewünschten Darreichungsform hergerichtet ist.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.
Als Verdünnungsmittel kommen Polyglykole, Ethanol, Wasser und Pufferlösungen in Frage. Geeignete Puffersubstanzen sind beispielsweise N,N-Dibenzylethylendiamin, Diethanolamin, Ethylendiamin, N-Methylglukamin, N-Benzylphenethylamin, Diethylamin, Phosphat, Natriumbikarbonat und Natriumkarbonat. Es kann aber auch ohne Verdünnungsmittel gearbeitet werden.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. However, it is also possible to work without a diluent.
Vorzugsweise wird die pharmazeutische Zusammensetzung in Dosierungseinheiten herstellt und verabreicht, wobei jede Einheit als aktiven Bestandteil eine definierte Dosis der erfindungsgemäßen Verbindung gemäß Formel I enthält. Bei festen Dosierungseinheiten wie Tabletten, Kapseln, Dragees oder Suppositorien kann diese Dosis 0,1 - 1.000 mg, bevorzugt 1 - 300 mg, und bei Injektionslösungen in Ampullenform 0,01 - 1.000 mg, vorzugsweise 1 - 100 mg, betragen.Preferably, 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. In the case of solid dosage units such as tablets, capsules, dragees or suppositories, 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.
Für die Behandlung eines Erwachsenen, 50 - 100 kg schweren, beispielsweise 70 kg schweren, Patienten sind beispielsweise Tagesdosen von 0,1 - 1.000 mg Wirkstoff, vorzugsweise 1 - 500 mg, indiziert. Unter Umständen können jedoch auch höhere oder niedrigere Tagesdosen angebracht sein. Die Verabreichung der Tagesdosis kann sowohl durch Einmalgabe in Form einer einzelnen Dosierungseinheit oder aber mehrerer kleinerer Dosierungseinheiten als auch durch Mehrfachgabe unterteilter Dosen in bestimmten Intervallen erfolgen. HerstellungsverfahrenFor example, 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
1) Synthese von 3,5-Dimethyladamantyloxyamin1) Synthesis of 3,5-dimethyladamantyloxyamine
1.1) Synthese von 3,5-Dimethyladamantyloxyphthalimid1.1) Synthesis of 3,5-dimethyladamantyloxyphthalimide
5,55 mmol 3,5-Dimethylhydroxyadamanol werden unter Argonatmosphäre in 20 ml CH2CI2 gelöst auf 00C gekühlt und 5,55 mmol BF3OEt2 zugegeben. Nach 30 min. Rühren bei 00C werden 5,55 mmol N-Hydroxyphthalimid zugegeben und die Mischung auf Raumtemperatur erwärmt. Nach weiteren 12h Rühren wird die Mischung auf 100 ml Eiswasser gegeben, 3 mal mit 100 ml CH2CI2 extrahiert, über Na2SO4 getrocknet, und das Lösungsmittel im Vakuum entfernt. 4,03 mmol 3,5-Dimethyladamantyloxyphthalimid werden als weißer Feststoff erhalten (73%).5.55 mmol 3,5-Dimethylhydroxyadamanol are dissolved under argon atmosphere in 20 ml CH 2 CI 2 cooled to 0 0 C and 5.55 mmol of BF 3 OEt 2 was added. After 30 min. Stirring at 0 ° C., 5.55 mmol N-hydroxyphthalimide are added and the mixture is warmed to room temperature. After stirring for a further 12 h, the mixture is added to 100 ml of ice-water, extracted 3 times with 100 ml of CH 2 Cl 2 , dried over Na 2 SO 4 and the solvent removed in vacuo. 4.03 mmol of 3,5-dimethyladamantyloxyphthalimide are obtained as a white solid (73%).
1.2) Synthese von 3,5-Dimethyladamantyloxyamin1.2) Synthesis of 3,5-dimethyladamantyloxyamine
5,38 mmol 3,5-Dimethyladamantyloxyphthalimid werden in 25 ml /EtOH (1 :1) gelöst und bei Raumtemperatur 8,07 mmmol Hydrazinmonohydrat zugegeben. Die Reaktionsmischung wird 12 h bei Raumtemperatur gerührt und anschließend mit 100 ml. ges. Natriumhydrogencarbonatlösung und 100 ml. ges. NaCI-Lösung gewaschen, über Na2SO4 getrocknet, das Lösungsmittel im Vakuum entfernt und das Rohprodukt mittels Flash-Chromatographie an Kieselgel (PE: EE = 1 :1) aufgereinigt. 5,12 mmol 3,5-Dimethyladamantyloxyamin werden als gelbes Öl erhalten (95%). (1H-NMR Spektrum: siehe Figur 1 , IR-Spektrum: siehe Figur 5, Analysenübersicht: siehe Figur 6).5.38 mmol of 3,5-dimethyladamantyloxyphthalimide are dissolved in 25 ml / EtOH (1: 1) and 8.07 mmol of hydrazine monohydrate are added at room temperature. The reaction mixture is stirred for 12 h at room temperature and then with 100 ml. Ges. Sodium bicarbonate solution and 100 ml. Sat. NaCl solution, dried over Na 2 SO 4 , the solvent removed in vacuo and the crude product purified by flash chromatography on silica gel (PE: EE = 1: 1). 5.12 mmol of 3,5-dimethyladamantyloxyamine are obtained as a yellow oil (95%). ( 1 H-NMR spectrum: see Figure 1, IR spectrum: see Figure 5, analysis overview: see Figure 6).
Die Herstellung der weiteren erfindungsgemäßen Verbindungen der allgemeinen Formel I erfolgt über die dem Fachmann bekannten Verfahren der organischen Chemie, wobei die Einführung der C-O-N-C bevorzugt, aber nicht ausschließlich) über die oben beschriebene Phthalimid-Zwischenstufe (oder deren Analoga) verläuft.The other compounds of the general formula I according to the invention are prepared by the methods of organic chemistry known to those skilled in the art, the introduction of the C-O-N-C preferably, but not exclusively, via the phthalimide intermediate described above (or its analogs).
Mögliche Reaktionswege hierzu werden in den Figuren 2 - 4 offenbart.Possible reaction paths for this purpose are disclosed in FIGS. 2-4.
Die Herstellung von tert.-Alkoxy-Aminen kann gemäß der Literaturvorschrift (Hasan Palandoken et al., Tetrahedron Letters 46 (2005) 6667-6669) erfolgen, die vom Fachmann leicht an unterschiedliche Anforderungen angepasst werden kann. The preparation of 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.

Claims

Ansprüche: Claims:
1. Verbindung der allgemeinen Formel 1 gemäß Anspruch 11. A compound of general formula 1 according to claim 1
Figure imgf000010_0001
Figure imgf000010_0001
in der einer der Reste R1-R10 für eine Gruppe -ONR11R12 -CH2-ONR11R12 , -(CH2)2-ONR11R12,in which one of the radicals R 1 -R 10 is a group -ONR 11 R 12 -CH 2 -ONR 11 R 12 , - (CH 2 ) 2 -ONR 11 R 12 ,
-0(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 -O (C = O) NR 11 R 12 , -CH 2 -O (C = O) NR 11 R 12 , - (CH 2 ) 2 -O (C = O) NR 11 R 12 , - (C = O ) -O-NR 11 R 12 , -CH 2 (C = O) -O-NR 11 R 12 , - (CH 2 ) 2 (C = O) -O-NR 11 R 12
oder eine der folgenden Gruppenor one of the following groups
Figure imgf000010_0002
Figure imgf000010_0002
Figure imgf000010_0003
Figure imgf000011_0001
Figure imgf000010_0003
Figure imgf000011_0001
steht, worin R11 und R12 unabhängig voneinander für ein Wasserstoffatom, eine verzweigte oder unverzweigte Ci-Cio-Alkylgruppe eine Gruppe -(CH2)n-(CO)m-(CH2)o-(S)p-(CH2)q-R13 eine Gruppe -(CH2)n-(NH)m-(CH2)o-(S)p-(CH2)q-R13 eine Gruppe -(CO)n-(NH)m-(CH2)o-(S)p-(CH2)q-R13 eine Gruppe -(CH2)n-(NH)m-(CH2)o-(SO2)p-(CH2)q-R13 stehen, worin n für 0, 1 oder 2 steht m für 0 oder 1 steht o für 0 oder 1 steht p für 0 oder 1 steht q für 0, 1 oder 2 stehtwherein R 11 and R 12 independently of one another for a hydrogen atom, a branched or unbranched C 1 -C 10 -alkyl group, 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 ) o - (S) p - (CH 2 ) q - R 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 are where n is 0, 1 or 2 m is 0 or 1 is o is 0 or 1 is p is 0 or 1 is q is 0, 1 or 2
R13 für -CH3, -OH oder einen Aryl- oder Heteroarylrest stehtR 13 is -CH 3 , -OH or an aryl or heteroaryl radical
und worin die anderen Reste R1-R10 unabhängig voneinander für ein Wasserstoffatom, eine Hydroxygruppe, eine Methoxygruppe, eine Methyloder eine Ethylgruppe stehen sowie deren optische Isomeren und deren Salze mit physiologisch verträglichen Gegenionen.and wherein the other R 1 -R 10 are independently hydrogen, hydroxy, methoxy, methyl or ethyl as well as their optical isomers and their salts with physiologically acceptable counterions.
2. Verbindung der allgemeinen Formel 1 gemäß Anspruch 12. A compound of general formula 1 according to claim 1
Figure imgf000012_0001
Figure imgf000012_0001
in der einer der Reste R1-R10 für eine Gruppe -ONR11R12 oder -CH2-ONR11R12 oder -(CH2)2-ONR11R12 in one of the radicals R 1 -R 10 for a group -ONR 11 R 12 or -CH 2 -ONR 11 R 12 or - (CH 2 ) 2 -ONR 11 R 12
eine Gruppe
Figure imgf000012_0002
a group
Figure imgf000012_0002
oder eine Gruppe
Figure imgf000012_0003
or a group
Figure imgf000012_0003
steht, worin R11 und R12 unabhängig voneinander für ein Wasserstoffatom, eine verzweigte oder unverzweigte C-i-Cio-Alkylgruppe eine Gruppe -(CH2)n-(CO)m-(CH2)o-(S)p-(CH2)q-R13 eine Gruppe -(CH2)n-(NH)m-(CH2)0-(S)p-(CH2)q-R13 eine Gruppe -(CO)n-(NH)m-(CH2)o-(S)p-(CH2)q-R13 eine Gruppe -(CH2)n-(NH)m-(CH2)o-(SO2)p-(CH2)q-R13 stehen, worin n für 0, 1 oder 2 steht m für 0 oder 1 steht o für 0 oder 1 steht p für 0 oder 1 steht q für 0, 1 oder 2 stehtwhere R 11 and R 12 independently represent a hydrogen atom, a branched or unbranched Ci-Cio-alkyl group, a group - (CH 2) n (CO) m - (CH 2) o- (S) p- (CH2 ) q -R 13 is a group - (CH 2 ) n - (NH) m - (CH 2 ) O - (S) p - (CH 2 ) q - R 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 are where n is 0, 1 or 2 m is 0 or 1 o is 0 or 1 p is 0 or 1 stands q stands for 0, 1 or 2
R13 für -CH3, -OH oder einen Aryl- oder Heteroarylrest stehtR 13 is -CH 3 , -OH or an aryl or heteroaryl radical
und worin die anderen Reste R1 -R10 unabhängig voneinander für ein Wasserstoffatom, eine Hydroxygruppe, eine Methoxygruppe, eine Methyl- oder eine Ethylgruppe stehen sowie deren optische Isomeren und deren Salze mit physiologisch verträglichen Gegenionen.and wherein the other 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 compatible counterions.
3. Verbindung der allgemeinen Formel 1 gemäß Anspruch 1 oder 2, in der einer der Reste R1-R10 für -O-NH2 steht.3. A compound of general formula 1 according to claim 1 or 2, in which one of the radicals R 1 -R 10 is -O-NH 2 .
4. Verbindung der allgemeinen Formel 1 gemäß Anspruch 1 oder 2, in der einer der Reste R1-R10 für -ONR11R12 oder -CH2-ONR11R12 oder -(CH2)2-ONR11R12 steht, in der einer der Reste R11 und R12 können auch für Propyl, Butyl, Pentyl und der andere für für eine -CO-CH2-S-CH2-CH2R13 oder eine -CO-NH-CH2- CH2-CH2-R13 Gruppe stehen.4. A compound of general formula 1 according to claim 1 or 2, in which one of the radicals R 1 -R 10 is -ONR 11 R 12 or -CH 2 -ONR 11 R 12 or - (CH 2 ) 2 -ONR 11 R 12 where one of R 11 and R 12 may also be propyl, butyl, pentyl and the other may be a -CO-CH 2 -S-CH 2 -CH 2 R 13 or a -CO-NH-CH 2 - CH 2 -CH 2 -R 13 group stand.
5. Verbindung gemäß Anspruch 4, in der R13 für Phenyl oder Pyridinyl steht.5. A compound according to claim 4, wherein R 13 is phenyl or pyridinyl.
6. Verbindung der allgemeinen Formel 1 gemäß Anspruch 1 oder 2, in der einer der Reste R1-R10 für eine Gruppe6. A compound of general formula 1 according to claim 1 or 2, in which one of the radicals R 1 -R 10 is a group
Figure imgf000013_0001
steht.
Figure imgf000013_0001
stands.
7. Verbindungen gemäß Anspruch 1 oder 2, nämlich
Figure imgf000014_0001
Figure imgf000014_0002
7. Compounds according to claim 1 or 2, namely
Figure imgf000014_0001
Figure imgf000014_0002
Figure imgf000014_0003
Figure imgf000014_0004
Figure imgf000014_0003
Figure imgf000014_0004
Figure imgf000015_0001
Figure imgf000015_0001
Figure imgf000015_0002
Figure imgf000015_0002
8. Verwendung mindestens einer Verbindung gemäß einem der Ansprüche 1 bis 7 zur Herstellung eines Arzneimittels.8. Use of at least one compound according to any one of claims 1 to 7 for the manufacture of a medicament.
9. Verwendung mindestens einer Verbindung gemäß einem der Ansprüche 1 bis 7 gemäß Anspruch 8 zur Herstellung eines Arzneimittels zur Behandlung von ZNS-Erkrankungen. 9. Use of at least one compound according to any one of claims 1 to 7 according to claim 8 for the manufacture of a medicament for the treatment of CNS diseases.
10. Verwendung mindestens einer Verbindung gemäß einem der Ansprüche 1 bis 7 gemäß Anspruch 8 zur Herstellung eines Arzneimittels zur Behandlung von Alzheimer, Parkinsons Disease, Demenz, Multipler Sklerose, Schizophrenie, Drogenmissbrauch, Nikotinmissbrauch oder Schmerzen.10. Use of at least one compound according to any one of claims 1 to 7 according to claim 8 for the manufacture of a medicament for the treatment of Alzheimer's, Parkinson's disease, dementia, multiple sclerosis, schizophrenia, drug abuse, nicotine abuse or pain.
11. Verwendung mindestens einer Verbindung gemäß einem der Ansprüche 1 bis 7 gemäß Anspruch 8 zur Herstellung eines Arzneimittels zur Behandlung von Krankheiten, die über den NMDA-Rezeptor vermittelt werden oder zur Herstellung eines Arzneimittels zur Inhibition von Dipeptidylpeptidase-4 (DPP-4).11. Use of at least one compound according to any one of claims 1 to 7 according to claim 8 for the manufacture of a medicament for the treatment of diseases which are mediated via the NMDA receptor or for the manufacture of a medicament for the inhibition of dipeptidyl peptidase-4 (DPP-4).
12. Verwendung mindestens einer Verbindung gemäß einem der Ansprüche 1 bis 7 gemäß Anspruch 8 zur Hersteilung eines Arzneimittels zur Behandlung von Depression, Glaukom, Tinitus, Neuropathien, Autoimmun-Erkrankungen, wie Lupus Erythematosus, Malaria, Influenza, Vogelgrippe oder Diabetes.12. Use of at least one compound according to any one of claims 1 to 7 according to claim 8 for the preparation of a medicament for the treatment of depression, glaucoma, tinitus, neuropathies, autoimmune diseases such as lupus erythematosus, malaria, influenza, bird flu or diabetes.
13. Pharmazeutische Zusammensetzung, enthaltend mindestens eine Verbindung gemäß einem der Ansprüche 1 bis 7 zusammen mit üblichen Hilfs- und / oder Trägerstoffen. 13. A pharmaceutical composition containing at least one compound according to any one of claims 1 to 7 together with conventional excipients and / or carriers.
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DE102009019852A1 (en) 2009-05-06 2010-11-11 Schebo Biotech Ag New polymer compound comprising amine structural elements, useful as synthetic resins, coatings, foams, liquid crystals, adhesives, paints, varnishes, composite materials, in cosmetics, and in polymer electronics

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