WO2004012649A2 - Novel compounds for stimulation of nerve growth, for the inhibition of scar tissue formation and/or reduction of secondary damage - Google Patents

Novel compounds for stimulation of nerve growth, for the inhibition of scar tissue formation and/or reduction of secondary damage Download PDF

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Publication number
WO2004012649A2
WO2004012649A2 PCT/EP2003/008444 EP0308444W WO2004012649A2 WO 2004012649 A2 WO2004012649 A2 WO 2004012649A2 EP 0308444 W EP0308444 W EP 0308444W WO 2004012649 A2 WO2004012649 A2 WO 2004012649A2
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compounds according
treatment
scar tissue
vivo
neutralization
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PCT/EP2003/008444
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German (de)
French (fr)
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Alexander Dömling
Barbara Beck
Bernhard Mueller
Bernd Stahl
Christian Leppert
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Morphochem Aktiengesellschaft für kombinatorische Chemie
Migragen Ag
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Priority to AU2003255331A priority Critical patent/AU2003255331A1/en
Publication of WO2004012649A2 publication Critical patent/WO2004012649A2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to new macrocycles, processes for their preparation and their use for Z ⁇ -vivo stimulation of nerve growth, in-vivo inhibition of scar tissue formation and / or in-vivo reduction of secondary damage.
  • the spinal cord and brain form the central nervous system (CNS) in vertebrates.
  • the spinal cord runs in the longitudinal direction of the body and is surrounded by the spinal canal. In humans, it can be divided into eight neck, twelve breast, five lumbar, five sacrum and one or two coccyx segments.
  • the central gray matter with its lateral bulges (front and rear horn) is formed by the cell bodies of the nerve cells, and the peripheral white matter is formed by the bundles of nerve fibers containing the pulp. In the white
  • Substances run afferent (ascending, sensitive) and efferent (descending, effectoric) conduction pathways.
  • the descending tracts of the spinal cord are divided into the pyramidal tracts (voluntary movements) and extrapyramidal tracts (involuntary movements; distribution of muscle tone).
  • the majority of the pyramidal fibers run crossed in the pyramid branch line of the opposite side and to a smaller extent un cross in the pyramid front line to Vorderhorn- und
  • Paralysis as a result of an accident is based on a permanent interruption of the management function of the affected nerve fibers.
  • Paralysis resulting from complete failure of at least one segment is called paraplegia.
  • the result is the loss of sensitive (e.g. temperature, pain and pressure sensations), motor (voluntary and involuntary movement) and vegetative functions (e.g. bladder and bowel function) for all areas below the affected segment. Due to the poor regenerative capabilities of the nerve fibers, the paralysis of the voluntary motor system and complete loss of sensitivity persists.
  • Alzheimer's disease Parkinson's disease, multiple sclerosis and similar diseases that are associated with nerve fiber loss and demarking, as well as amyotrophic lateral sclerosis and other motor neuron diseases, ischemia, stroke, epilepsy, Huntington's disease, AIDS dementia complex and prion diseases.
  • the aim of the research is therefore to regenerate the nerve axons across the injury in spinal cord lesions and to stimulate nerve growth in other diseases of the peripheral and central nervous system.
  • the formation of scars in the central nervous system of mammals represents an enormous inhibition of regeneration for growing nerve fibers.
  • Components of this scar tissue are Proteins with a high sugar or carbohydrate content, so-called proteoglycans. For this reason, slowing down or preventing scarring and stimulating nerve fiber growth are essential therapeutic goals in neurodegenerative treatment concepts.
  • the present invention relates to new cyclic compounds (macrocycles) of the general formula (I):
  • M is the basic structure of a compound produced by a multicomponent reaction
  • X and Y independently of one another optionally substituted alkylene, alkenylene, alkynylene, heteroalkylene, arylene, heteroarylene, cycloalkylene, alkylcycloalkylene, heteroalkylcycloalkylene,
  • alkyl refers to a saturated, straight-chain or branched hydrocarbon group which has 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, particularly preferably 1 to 6 carbon atoms, for example the methyl, ethyl, propyl, isopropyl, isobutyl , tert-butyl, n-hexyl, 2, 2-dimethylbutyl or n-octyl group.
  • alkenyl and alkynyl refer to at least partially unsaturated, straight-chain or branched hydrocarbon groups which have 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, particularly preferably 2 to 6 carbon atoms, e.g. B. the ethenyl, allyl, acetylenyl, propargyl, isoprenyl or hex-2-enyl group.
  • heteroalkyl refers to an alkyl, an alkenyl or an alkynyl group in which one or more (preferably 1, 2 or 3) carbon atoms have been replaced by an oxygen, nitrogen, phosphorus or sulfur atom (preferably oxygen or nitrogen), e.g. an alkyloxy group such as e.g. Methoxy or ethoxy, or a methoxymethyl, nitrile, methylcarboxyalkyl ester, carboxyalkyl ester or 2,3-dioxyethyl group.
  • heteroalkyl also refers to a carboxylic acid or a group derived from a carboxylic acid, such as. B. acyl, acyloxy, carboxyalkyl, carboxyalkyl esters e.g. Methyl carboxyalkyl ester, carboxyalkylamide, alkoxycarbonyl or alkoxycarbonyloxy.
  • cycloalkyl or cyclo refers to a saturated or partially unsaturated cyclic Group which has one or more rings which form a skeleton which contains 3 to 14 carbon atoms, preferably 3 to 10 carbon atoms, for example the cyclopropyl, cyclohexyl, tetralin or cyclohex-2-enyl group.
  • heterocycloalkyl or heterocyclo refers to a cycloalkyl group as defined above in which one or more (preferably 1, 2 or 3) carbon atoms are replaced by an oxygen, nitrogen, phosphorus or sulfur atom and can be used, for example, for the piperidine -, Morpholine, N-methylpiperazine or N-phenylpiperazine group.
  • alkylcycloalkyl or heteroalkylcycloalkyl refer to groups which, in accordance with the above definitions, contain both cycloalkyl or heterocycloalkyl and also alkyl, alkenyl, alkynyl and / or heteroalkyl groups.
  • aryl or Ar refers to an aromatic group which has one or more rings and is formed by a skeleton which contains 5 to 14 carbon atoms, preferably 5 or 6 to 10 carbon atoms, e.g. a phenyl, naphthyl, 2-, 3- or 4-methoxyphenyl, 2-, 3- or 4-ethoxyphenyl, 4-carboxyphenylalkyl or 4-hydroxyphenyl group.
  • heteroaryl refers to an aryl group in which one or more (preferably 1, 2 or 3) carbon atoms are replaced by an oxygen, nitrogen, phosphorus or sulfur atom, for example that 4-pyridyl, 2-imidazolyl, 3-pyrazolyl and isoquinolinyl group.
  • aralkyl or heteroaralkyl refer to groups which, according to the above definitions, contain both aryl or heteroaryl and also alkyl, alkenyl, alkynyl and / or heteroalkyl and / or cycloalkyl and / or heterocycloalkyl groups, e.g. the tetrahydroisoquinolinyl, benzyl, 2- or 3-ethylindolyl or methylpyridino group.
  • alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl and the term “optionally substituted” also refer to groups in which one or more hydrogen atoms of such groups are fluorine, chlorine or bromine - Or iodine atoms or OH, SH, NH 2 or N0 groups are replaced. These terms also refer to groups substituted with unsubstituted alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl groups.
  • Compounds of formula (I) can contain one or more centers of chirality due to their substitution.
  • the present invention therefore encompasses all pure enantiomers and all pure diastereomers, as well as their mixtures in any mixing ratio.
  • M has the following structure:
  • radicals R independently of one another are hydrogen atoms, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radicals, one of the radicals R is a direct bond to X and another of the radicals R is a direct bond to Y, and
  • radicals R 'independently of one another are hydrogen atoms, alkyl, alkenyl, alkynyl,
  • Heteroalkyl, aryl, heteroaryl, cycloalkyl, alkyl are cycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radicals.
  • M preferably has the following structure:
  • A is an oxygen atom or a group of the formula NR 1 , wherein R 1 is a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl -, Aralkyl- or a heteroaralkyl radical and Het is a nitrogen-containing heteroaryl group.
  • Het is particularly preferably an optionally substituted pyridine ring.
  • the cyclic compound more preferably has 10 to 36, preferably 15 to 25, ring atoms. This means in particular that the smallest ring which comprises X, M, Y and the double bond shown in formula (I)
  • the macrocycle preferably has 10 to 36, preferably 15 to 25 ring atoms, where, if X itself comprises a cycle, only those atoms are counted which form the shortest link between M and the double bond represented in formula (I), and, if Y itself comprises a cycle, only those atoms are counted that have the shortest link form between M and the double bond shown in formula (I).
  • X is preferably a heteroalkyl, heteroalkyl-cycloalkyl, heterocycloalkyl or heteroaralkyl group.
  • Y is further preferably a heteroalkyl, heteroalkylcycloalkyl, heterocycloalkyl or heteroaralkyl group.
  • Examples of pharmacologically acceptable salts of the compounds of formula (I) are salts of physiologically acceptable mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid or salts of organic acids such as methanesulfonic acid, p-toluenesulfonic acid, lactic acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fu ar - acid, maleic acid and salicylic acid.
  • Compounds of formula (I) can be solvated, in particular hydrated. The hydration can e.g. occur during the manufacturing process or as a result of the hygroscopic nature of the initially anhydrous compounds of formula (I). If the compounds of the formula (I) contain asymmetric C atoms, they can be present either as mixtures of diastereomers, mixtures of enantiomers or as optically pure compounds.
  • compositions according to the present invention contain at least one compound of the formula (I) as active ingredient and optionally excipients and / or adjuvants.
  • the pro-drugs which are also the subject of the present invention, consist of a
  • Compound of formula (I) and at least one pharmacologically acceptable protecting group which is split off under physiological conditions e.g. an alkoxy, aralkyloxy, acyl or acyloxy group, e.g. an ethoxy, benzyloxy, acetyl or acetyloxy group.
  • the present invention also relates to the use of these active ingredients for the production of medicaments for the in vivo stimulation of nerve growth, the in vivo inhibition of scar tissue formation and / or Tn-vi o reduction of secondary damage, and for the treatment of tumor diseases (in particular cancer) Invention.
  • compounds of formula (I) are administered using the known and acceptable modes, either individually or in combination with any other therapeutic agent.
  • Such therapeutically useful agents can be administered in one of the following ways: orally, for example as dragées, coated tablets, pills, semi-solids, soft or hard capsules, solutions, emulsions or suspensions; parenterally, eg as an injectable solution; intratekal; rectally as suppositories; by inhalation, for example as a powder formulation or spray, transdermally or intranasally.
  • the therapeutically usable product can be mixed with pharmacologically inert, inorganic or organic medicament carrier substances, for example with lactose, sucrose, glucose, gelatin, malt, silica gel, starch or derivatives thereof, talc, stearic acid or their salts, dry skimmed milk and the like.
  • pharmacologically inert, inorganic or organic medicament carrier substances for example with lactose, sucrose, glucose, gelatin, malt, silica gel, starch or derivatives thereof, talc, stearic acid or their salts, dry skimmed milk and the like.
  • pharmaceutical carriers such as vegetable oils, petroleum, animal or synthetic oils, wax, fat, polyols can be used.
  • drug carriers such as water, alcohols, aqueous salt solution, aqueous dextrose, polyols, glycerin, vegetable oils, petroleum, animal or synthetic oils
  • hydrogels such as e.g. B. NeuroGel TM from Organogel
  • drug carriers such as vegetable oils, petroleum, animal or synthetic oils, wax, fat and polyols
  • Compressed gases suitable for this purpose such as oxygen, nitrogen and carbon dioxide, can be used for aerosol formulations.
  • the pharmaceutically usable agents can also contain additives for preservation, stabilization, emulsifiers, sweeteners, flavorings, salts for changing the osmotic pressure, buffers, coating additives and antioxidants.
  • Compounds of the formula (I) can be subjected to a multicomponent reaction (see, for example, BA Dömling, I. Ugi, Angew. Che. 2000, 112, 3300-3344) with subsequent ring closure by a Metathesis reaction with the Grubbs catalyst (AK Chatterjee et al. Org. Lett. 2002, 4, 1939-1942; JP Morgan et al. Org. Lett. 2002, 4, 67-70; S. Randl Synlett 2001, 430-432; S. Imhof Chem. Commun. 2001, 1692-1693).
  • a multicomponent reaction see, for example, BA Dömling, I. Ugi, Angew. Che. 2000, 112, 3300-3344) with subsequent ring closure by a Metathesis reaction with the Grubbs catalyst (AK Chatterjee et al. Org. Lett. 2002, 4, 1939-1942; JP Morgan et al. Org. Lett. 2002, 4, 67-70
  • CSPG chondroitin sulfate proteoglycans
  • UV-sterilized coverslips are precoated with Poly-L-Lysine (200 ⁇ g / ml Poly-L-Lysine [Sigma], in PBS, pH 7.4, 37 ° C, 2-3 h), washed in PBS and at 37 ° C for 2-3 h coated with a CSPG-laminin mixture (20 ⁇ g / ml chondroitin sulfate proteoglycan [Chemicon] and 20 ⁇ g / ml laminin [Becton Dickinson]).
  • the coated coverslips are placed in 24-well plates. 20-30 retina mini explants (300 x 300 ⁇ m, from embryonic chickens, E7) in 500 ⁇ l culture medium are pipetted onto each of these coverslips (Ham's F-12 without L-glutamine, 10% fetal calf serum, 2% chicken serum, 2 M L-glutamine, 100 units / ml penicillin, 100 ⁇ g / ml streptomycin [all components from PAA Laboratories]).
  • Example 1 Before adding the compound from Example 1, the retina mini-explants are incubated for 25-35 min at 37 ° C. and 4% CO 2 , so that the explants can attach to the coverslip.
  • Example 1 is dissolved in 500 ⁇ l of culture medium (37 ° C.), shaken briefly and added to the retina mini-explants. The retina cultures are then incubated for 24 h at 37 ° C and 4% CO 2 . The retina cultures are then fixed overnight at 2-8 ° C. with 1 ml of 4% paraformaldehyde (in PBS, pH 7.4) per well.
  • the fixed cultures are washed with PBS and incubated for 10 min with 0.1% Triton X-100 (in PBS [Roth]) and washed again.
  • the adult axons are then stained with 300 ⁇ l Alexa P alloidin (Alexa ' Fluor 488 phalloidin [Molecular Probes], 1:40 in' PBS containing 1% bovine serum albumin and 0.02% sodium azide, 30-40 min, room temperature).
  • the cultures are washed again with PBS and embedded with Mowiol [Hoechst].
  • the average length of the adult axons per explant is determined with the aid of a digital camera (Axioca [Zeiss]) mounted on a fluorescence microscope (Axioplan 2 [Zeiss]) and a measuring software (AxioVision 3.0 [Zeiss]). Explants without the addition of Example 1 are used as controls.
  • Example 1 The regeneration-promoting effect of Example 1 was determined in the concentrations 10 and 50 ⁇ M in the CSPG growth assay.
  • Example 1 In the CSPG growth assay, the compound from Example 1 neutralizes the growth and / or regeneration-inhibiting effect of the CSPG and promote the growth of the retinal axons.
  • Example 1 has the strongest regenerative effect in a concentration of 10 ⁇ M.
  • the axon growth increases by a factor of 2 to 3 compared to the control.
  • the axon growth is increased by a factor of 1.3.

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Abstract

The invention relates to novel macro cyclenes of formula (I), a method for the production thereof and the use thereof for in-vivo stimulation of nerve growth, the in-vivo inhibition of scar tissue formation and/or in-vivo reduction of secondary damage. M is the sketal structure of a compound produced by means of a multicomponent reaction and X and Y independently from each other represent alkylene, alkenylene, alkinylene, heteroalkylene, arylene, heteroarylene, cycloalkylene, alkylcycloalkylene, heteroalkylcycloalkylene, heterocycloalkylene, aralkylene or heteroaralkylene groups.

Description

Neue Verbindungen zur Stimulation des Nervenwachstums, zur Inhibition der Narbengewebsbildung und/oder New compounds for stimulating nerve growth, inhibiting scar tissue formation and / or
Reduktion eines SekundärSchadens.Reduction of secondary damage.
Die vorliegende Erfindung betrifft neue Macrocyclen, Verfahren zu ihrer Herstellung sowie deren Verwendung zur Zπ-vivo-Stimulation des Nervenwachstums, der In- vivo-Inhibition der Narbengewebsbildung und/oder In- vivo-Reduktion eines SekundärSchadens .The present invention relates to new macrocycles, processes for their preparation and their use for Zπ-vivo stimulation of nerve growth, in-vivo inhibition of scar tissue formation and / or in-vivo reduction of secondary damage.
Rückenmark und Gehirn bilden bei den Wirbeltieren das zentrale Nervensystem (ZNS) . Das Rückmark verläuft in Körperlängsrichtung und wird von dem Wirbelkanal umgeben. Es lässt sich beim Menschen in acht Hals-, zwölf Brust-, fünf Lenden-, fünf Kreuzbein- und ein bis zwei Steißbeinsegmente gliedern. Die zentrale graue Substanz mit ihren seitlichen Ausbuchtungen (Vorder- und Hinterhorn) wird von den Zellkörpern der Nervenzellen und die periphere weiße Substanz durch die markhaltigen Nervenfaserbündel gebildet. In der weißenThe spinal cord and brain form the central nervous system (CNS) in vertebrates. The spinal cord runs in the longitudinal direction of the body and is surrounded by the spinal canal. In humans, it can be divided into eight neck, twelve breast, five lumbar, five sacrum and one or two coccyx segments. The central gray matter with its lateral bulges (front and rear horn) is formed by the cell bodies of the nerve cells, and the peripheral white matter is formed by the bundles of nerve fibers containing the pulp. In the white
Substanz verlaufen afferente (aufsteigende, sensible) und efferente (absteigende, effektorische) Leitungsbahnen. Die absteigenden Bahnen des Rückenmarks werden in die Pyramidenbahnen (willkürliche Bewegungen) und extrapyramidale Bahnen (unwillkürliche Bewegungen; Verteilung des Muskeltonus) unterschieden. Der größte Teil der pyramidalen Fasern verläuft gekreuzt in der Pyramidenseitenstrangbahn der Gegenseite und zum kleineren Teil ungekreuzt in der Pyramidenvorderstrangbahn zu Vorderhorn- undSubstances run afferent (ascending, sensitive) and efferent (descending, effectoric) conduction pathways. The descending tracts of the spinal cord are divided into the pyramidal tracts (voluntary movements) and extrapyramidal tracts (involuntary movements; distribution of muscle tone). The majority of the pyramidal fibers run crossed in the pyramid branch line of the opposite side and to a smaller extent un cross in the pyramid front line to Vorderhorn- und
Hinterhornzellen der verschiedenen Rückenmarksegmente.Dorsal horn cells of the different spinal cord segments.
Eine Verletzung des Rückenmarks z. B. infolge eines Unfalls führt zu einer dauerhaften Unterbrechung der Leitungsfunktion der betroffenen Nervenfasern. Eine Lähmung in Folge eines Unfalls beruht auf einer dauerhaften Unterbrechung der Leitungsfunktion der betroffenen Nervenfasern. Eine Lähmung in Folge eines völligen Ausfalls von mindestens einem Segment bezeichnet man als Querschnittslähmung. Die Folge ist der Verlust der sensiblen (z. B. Temperatur-, Schmerz- und Druckempfindungen) , motorischen (willkürliche und unwillkürliche Bewegung) und vegetativen Funktionen (z. B. Blasen- und Darmfunktion) für alle Gebiete unterhalb des betroffenen Segments. Aufgrund der schlechten regenerativen Fähigkeiten der Nervenfasern bleibt die Lähmung der Willkürmotorik und der vollständige Sensibilitätsverlust dauerhaft bestehen.An injury to the spinal cord e.g. B. due to an accident leads to a permanent interruption of the Management function of the affected nerve fibers. Paralysis as a result of an accident is based on a permanent interruption of the management function of the affected nerve fibers. Paralysis resulting from complete failure of at least one segment is called paraplegia. The result is the loss of sensitive (e.g. temperature, pain and pressure sensations), motor (voluntary and involuntary movement) and vegetative functions (e.g. bladder and bowel function) for all areas below the affected segment. Due to the poor regenerative capabilities of the nerve fibers, the paralysis of the voluntary motor system and complete loss of sensitivity persists.
Es sind aber auch neurologische und neurodegenerative Erkrankungen des peripheren und zentralen Nervensystems bekannt, bei denen Nervenzellen zugrunde gehen. Dies sind z. B. Morbus Alzheimer, Morbus Parkinson, Multiple Sklerose und ähnliche Erkrankungen, die mit einem Nervenfaserverlust und Entmarkung einhergehen, sowie Amyotrophe Lateral Sklerose und andere Motoneuonenerkrankungen, Ischämie, Schlaganfall, Epilepsie, Morbus Huntington, AIDS Demenz Komplex und Prionen-Erkrankungen.However, there are also known neurological and neurodegenerative diseases of the peripheral and central nervous system in which nerve cells perish. These are e.g. B. Alzheimer's disease, Parkinson's disease, multiple sclerosis and similar diseases that are associated with nerve fiber loss and demarking, as well as amyotrophic lateral sclerosis and other motor neuron diseases, ischemia, stroke, epilepsy, Huntington's disease, AIDS dementia complex and prion diseases.
Ziel der Forschung ist es daher, bei Läsionen des Rückenmarks eine Regeneration der Nervenaxone über die Verletzung hinweg zu bewerkstelligen und bei anderen Krankheiten des peripheren und zentralen Nervensystems, das Nervenwachstum zu stimulieren. Die Narbenbildung im zentralen Nervensystem der Säugetiere stellt eine enorme Regenerationshemmung für wachsende Nervenfasern dar. Bestandteile dieses Narbengewebes sind Eiweißstoffe mit hohem Zucker- oder Kohlenhydratanteil, sogenannte Proteoglykane . Aus diesem Grund sind die Verlangsamung oder Verhinderung der Narbenbildung sowie die Stimulation des Nervenfaserwachstums wesentliche therapeutische Ziele bei neurodegenerativen Behandlungskonzepten .The aim of the research is therefore to regenerate the nerve axons across the injury in spinal cord lesions and to stimulate nerve growth in other diseases of the peripheral and central nervous system. The formation of scars in the central nervous system of mammals represents an enormous inhibition of regeneration for growing nerve fibers. Components of this scar tissue are Proteins with a high sugar or carbohydrate content, so-called proteoglycans. For this reason, slowing down or preventing scarring and stimulating nerve fiber growth are essential therapeutic goals in neurodegenerative treatment concepts.
Es ist also die Aufgabe der vorliegenden Erfindung, das Nervenwachstum in vivo zu stimulieren und insbesondere die Narbengewebsbildung in vivo zu inhibieren.It is therefore the object of the present invention to stimulate nerve growth in vivo and in particular to inhibit scar tissue formation in vivo.
Die vorliegende Erfindung betrifft neue cyclische Verbindungen (Macrocyclen) der allgemeinen Formel (I) :The present invention relates to new cyclic compounds (macrocycles) of the general formula (I):
/=\/ = \
X M X1 0) X MX 1 0)
worinwherein
M das Grundgerüst einer durch eine Multikomponentenreaktion hergestellten Verbindung ist undM is the basic structure of a compound produced by a multicomponent reaction and
X und Y unabhängig voneinander gegebenenfalls substituierte Alkylen-, Alkenylen-, Alkinylen-, Heteroalkylen-, Arylen-, Heteroarylen- , Cycloalkylen-, Alkylcycloalkylen-, Heteroalkylcyclo-alkylen- ,X and Y independently of one another optionally substituted alkylene, alkenylene, alkynylene, heteroalkylene, arylene, heteroarylene, cycloalkylene, alkylcycloalkylene, heteroalkylcycloalkylene,
Heterocycloalkylen-, Aralkylen- oder Hetero- aralkylengruppen sind,Are heterocycloalkylene, aralkylene or heteroaralkylene groups,
oder ein pharmakologisch akzeptables Salz, Solvat, Hydrat oder eine pharmakologisch akzeptable Formulierung derselben. Der Ausdruck Alkyl bezieht sich auf eine gesättigte, geradkettige oder verzweigte Kohlenwasserstoffgruppe, die 1 bis 20 Kohlenstoffatome, vorzugsweise 1 bis 12 Kohlenstoffatome, besonders bevorzugt 1 bis 6 Kohlenstoffatome aufweist, z.B. die Methyl-, Ethyl-, Propyl-, Isopropyl-, Isobutyl-, tert-Butyl, n-Hexyl-, 2 , 2-Dimethylbutyl- oder n-Octyl-Gruppe.or a pharmacologically acceptable salt, solvate, hydrate or a pharmacologically acceptable formulation thereof. The term alkyl refers to a saturated, straight-chain or branched hydrocarbon group which has 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, particularly preferably 1 to 6 carbon atoms, for example the methyl, ethyl, propyl, isopropyl, isobutyl , tert-butyl, n-hexyl, 2, 2-dimethylbutyl or n-octyl group.
Die Ausdrücke Alkenyl und Alkinyl beziehen sich auf zumindest teilweise ungesättigte, geradkettige oder verzweigte Kohlenwasserstoffgruppen, die 2 bis 20 Kohlenstoffatome, vorzugsweise 2 bis 12 Kohlenstoffatome, besonders bevorzugt 2 bis 6 Kohlenstoffatome aufweisen, z. B. die Ethenyl-, Allyl-, Acetylenyl-, Propargyl-, Isoprenyl- oder Hex-2-enyl-Gruppe .The terms alkenyl and alkynyl refer to at least partially unsaturated, straight-chain or branched hydrocarbon groups which have 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, particularly preferably 2 to 6 carbon atoms, e.g. B. the ethenyl, allyl, acetylenyl, propargyl, isoprenyl or hex-2-enyl group.
Der Ausdruck Heteroalkyl bezieht sich auf eine Alkyl-, eine Alkenyl- oder eine Alkinyl-Gruppe, in der ein oder mehrere (bevorzugt 1, 2 oder 3) Kohlenstoffatome durch ein Sauerstoff-, Stickstoff-, Phosphor- oder Schwefelatom ersetzt sind (bevorzugt Sauerstoff oder Stickstoff), z.B. eine Alkyloxy-Gruppe wie z.B. Methoxy oder Ethoxy, oder eine Methoxymethyl-, Nitril-, Methylcarboxyalkylester-, Carboxyalkylester- oder 2,3- Dioxyethyl-Gruppe. Der Ausdruck Heteroalkyl bezieht sich des weiteren auf eine Carbonsäure oder eine von einer Carbonsäure abgeleitete Gruppe wie z. B. Acyl, Acyloxy, Carboxyalkyl, Carboxyalkylester z.B. Methyl- carboxyalkylester, Carboxyalkylamid, Alkoxycarbonyl oder Alkoxycarbonyloxy.The term heteroalkyl refers to an alkyl, an alkenyl or an alkynyl group in which one or more (preferably 1, 2 or 3) carbon atoms have been replaced by an oxygen, nitrogen, phosphorus or sulfur atom (preferably oxygen or nitrogen), e.g. an alkyloxy group such as e.g. Methoxy or ethoxy, or a methoxymethyl, nitrile, methylcarboxyalkyl ester, carboxyalkyl ester or 2,3-dioxyethyl group. The term heteroalkyl also refers to a carboxylic acid or a group derived from a carboxylic acid, such as. B. acyl, acyloxy, carboxyalkyl, carboxyalkyl esters e.g. Methyl carboxyalkyl ester, carboxyalkylamide, alkoxycarbonyl or alkoxycarbonyloxy.
Der Ausdruck Cycloalkyl bzw. Cyclo- bezieht sich auf eine gesättigte oder teilweise ungesättigte cyclische Gruppe, die einen oder mehrere Ringe aufweist, die ein Gerüst bilden, welches 3 bis 14 Kohlenstoffatome, vorzugsweise 3 bis 10 Kohlenstoffatome enthält, z.B. die Cyclopropyl-, Cyclohexyl-, Tetralin- oder Cyclohex- 2-enyl-Gruppe.The term cycloalkyl or cyclo refers to a saturated or partially unsaturated cyclic Group which has one or more rings which form a skeleton which contains 3 to 14 carbon atoms, preferably 3 to 10 carbon atoms, for example the cyclopropyl, cyclohexyl, tetralin or cyclohex-2-enyl group.
Der Ausdruck Heterocycloalkyl bzw. Heterocyclo- bezieht sich auf eine Cycloalkylgruppe wie oben definiert, in der ein oder mehrere (bevorzugt 1, 2 oder 3) Kohlenstoffatome durch ein Sauerstoff-, Stickstoff-, Phosphor- oder Schwefelatom ersetzt sind und kann beispielsweise für die Piperidin-, Morpholin-, N-Methylpiperazin- oder N-Phenylpiperazin-Gruppe stehen.The term heterocycloalkyl or heterocyclo refers to a cycloalkyl group as defined above in which one or more (preferably 1, 2 or 3) carbon atoms are replaced by an oxygen, nitrogen, phosphorus or sulfur atom and can be used, for example, for the piperidine -, Morpholine, N-methylpiperazine or N-phenylpiperazine group.
Die Ausdrücke Alkylcycloalkyl bzw. Heteroalkyl- cycloalkyl beziehen sich auf Gruppen, die entsprechend den obigen Definitionen sowohl Cycloalkyl- bzw. Heterocycloalkyl- wie auch Alkyl-, Alkenyl-, Alkinyl- und/oder Heteroalkylgruppen enthalten.The terms alkylcycloalkyl or heteroalkylcycloalkyl refer to groups which, in accordance with the above definitions, contain both cycloalkyl or heterocycloalkyl and also alkyl, alkenyl, alkynyl and / or heteroalkyl groups.
Der Ausdruck Aryl bzw. Ar bezieht sich auf eine aromatische Gruppe, die einen oder mehrere Ringe hat, und durch ein Gerüst gebildet wird, das 5 bis 14 Kohlenstoffatome, vorzugsweise 5 oder 6 bis 10 Kohlenstoffatome enthält z.B. eine Phenyl-, Naphthyl-, 2-, 3- oder 4-Methoxyphenyl- , 2-, 3- oder 4-Ethoxyphenyl- , 4-Carboxyphenylalkyl- oder 4-Hydroxyphenyl-Gruppe .The term aryl or Ar refers to an aromatic group which has one or more rings and is formed by a skeleton which contains 5 to 14 carbon atoms, preferably 5 or 6 to 10 carbon atoms, e.g. a phenyl, naphthyl, 2-, 3- or 4-methoxyphenyl, 2-, 3- or 4-ethoxyphenyl, 4-carboxyphenylalkyl or 4-hydroxyphenyl group.
Der Ausdruck Heteroaryl bezieht sich auf eine Aryl- Gruppe, in der ein oder mehrere (bevorzugt 1, 2 oder 3) Kohlenstoff tome durch ein Sauerstoff-, Stickstoff-, Phosphor- oder Schwefelatom ersetzt sind, z.B. die 4-Pyridyl-, 2-Imidazolyl-, 3-Pyrazolyl- und Iso- chinolinyl-Gruppe .The term heteroaryl refers to an aryl group in which one or more (preferably 1, 2 or 3) carbon atoms are replaced by an oxygen, nitrogen, phosphorus or sulfur atom, for example that 4-pyridyl, 2-imidazolyl, 3-pyrazolyl and isoquinolinyl group.
Die Ausdrücke Aralkyl bzw. Heteroaralkyl beziehen sich auf Gruppen, die entsprechend den obigen Definitionen sowohl Aryl- bzw. Heteroaryl- wie auch Alkyl-, Alkenyl- , Alkinyl- und/oder Heteroalkyl- und/oder Cycloalkyl- und/oder Heterocycloalkylgruppen enthalten, z.B. die Tetrahydroisochinolinyl- , Benzyl-, 2- oder 3-Ethyl- indolyl- oder -Methylpyridino-Gruppe .The terms aralkyl or heteroaralkyl refer to groups which, according to the above definitions, contain both aryl or heteroaryl and also alkyl, alkenyl, alkynyl and / or heteroalkyl and / or cycloalkyl and / or heterocycloalkyl groups, e.g. the tetrahydroisoquinolinyl, benzyl, 2- or 3-ethylindolyl or methylpyridino group.
Die Ausdrücke Alkyl, Alkenyl, Alkinyl, Heteroalkyl, Cycloalkyl, Heterocycloalkyl, Aryl, Heteroaryl, Aralkyl und Heteroaralkyl sowie der Ausdruck "gegebenenfalls substituiert" beziehen sich auch auf Gruppen, in denen ein oder mehrere Wasserstoffatome solcher Gruppen durch Fluor-, Chlor-, Brom- oder Jodatome oder OH, SH, NH2 oder N0-Gruppen ersetzt sind. Diese Ausdrücke beziehen sich weiterhin auf Gruppen, die mit unsubstituierten Alkyl-, Alkenyl-, Alkinyl-, Heteroalkyl-, Cycloalkyl-, Heterocycloalkyl-, Aryl-, Heteroaryl-, Aralkyl- oder Heteroaralkyl-Gruppen substituiert sind.The terms alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl and the term “optionally substituted” also refer to groups in which one or more hydrogen atoms of such groups are fluorine, chlorine or bromine - Or iodine atoms or OH, SH, NH 2 or N0 groups are replaced. These terms also refer to groups substituted with unsubstituted alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl groups.
Verbindungen der Formel (I) können aufgrund ihrer Substitution ein oder mehrere Chiralitätszentren enthalten. Die vorliegende Erfindung umfasst daher sowohl alle reinen Enantiomere und alle reinen Diastereomere, als auch deren Gemische in jedem Mischungsverhältnis .Compounds of formula (I) can contain one or more centers of chirality due to their substitution. The present invention therefore encompasses all pure enantiomers and all pure diastereomers, as well as their mixtures in any mixing ratio.
Beispiele für Grundgerüste von Verbindungen (M) , die durch Multiko ponentenreaktionen hergestellt werden können, sind in A. Dömling, I. Ugi, Angew. Chem. 2000, 112, 3300-3344 beschrieben. Beispielsweise weist M die folgende Struktur auf :Examples of basic skeletons of compounds (M) that can be prepared by multi-component reactions are in A. Dömling, I. Ugi, Angew. Chem. 2000, 112, 3300-3344. For example, M has the following structure:
Figure imgf000008_0001
Figure imgf000008_0001
wobei die Reste R unabhängig voneinander Wasserstoffatome, Alkyl-, Alkenyl-, Alkinyl-, Heteroalkyl-, Aryl-, Heteroaryl-, Cycloalkyl-, Alkyl- cycloalkyl-, Heteroalkylcycloalkyl-, Heterocycloalkyl-, Aralkyl- oder Heteroaralkylreste sind, wobei einer der Reste R eine direkte Bindung zu X und ein anderer der Reste R eine direkte Bindung zu Y ist, undwherein the radicals R independently of one another are hydrogen atoms, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radicals, one of the radicals R is a direct bond to X and another of the radicals R is a direct bond to Y, and
wobei die Reste R' unabhängig voneinander Wasserstoffatome, Alkyl-, Alkenyl-, Alkinyl-,where the radicals R 'independently of one another are hydrogen atoms, alkyl, alkenyl, alkynyl,
Heteroalkyl-, Aryl-, Heteroaryl-, Cycloalkyl-, Alkyl- cycloalkyl-, Heteroalkylcycloalkyl- , Heterocycloalkyl-, Aralkyl- oder Heteroaralkylreste sind.Heteroalkyl, aryl, heteroaryl, cycloalkyl, alkyl are cycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radicals.
Bevorzugt weist M die folgende Struktur auf:M preferably has the following structure:
Figure imgf000009_0001
worin A ein Sauerstoffatom oder eine Gruppe der Formel NR1 ist, wobei R1 ein Wasserstoffatom, ein Alkyl-, Alkenyl-, Alkinyl-, Heteroalkyl-, Aryl-, Heteroaryl-, Cycloalkyl-, Alkylcycloalkyl- , Heteroalkylcycloalkyl-, Heterocyclo-alkyl-, Aralkyl- oder ein Heteroaralkylrest ist und Het eine stickstoffhaltige Heteroarylgruppe ist.
Figure imgf000009_0001
wherein A is an oxygen atom or a group of the formula NR 1 , wherein R 1 is a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl -, Aralkyl- or a heteroaralkyl radical and Het is a nitrogen-containing heteroaryl group.
Besonders bevorzugt ist Het ein gegebenenfalls substituierter Pyridinring.Het is particularly preferably an optionally substituted pyridine ring.
Weiter bevorzugt weist die cyclische Verbindung 10 bis 36, bevorzugt 15 bis 25 Ringatome auf. Das bedeutet insbesondere, daß der kleinste Ring, der X, M, Y und die in Formel (I) dargestellte Doppelbindung umfaßt,The cyclic compound more preferably has 10 to 36, preferably 15 to 25, ring atoms. This means in particular that the smallest ring which comprises X, M, Y and the double bond shown in formula (I)
10-36, bevorzugt 15-25 Ringatome umfaßt.10-36, preferably 15-25 ring atoms.
Mit anderen Worten weist der Makrocyclus vorzugsweise 10 bis 36, bevorzugt 15 bis 25 Ringatome auf, wobei, wenn X selbst einen Cyclus umfaßt, nur die Atome mitgezählt werden, die die kürzeste Verknüpfung zwischen M und der in Formel (I) dargestellten Doppelbindung bilden, und, wenn Y selbst einen Cyclus umfaßt, nur die Atome mitgezählt werden, die die kürzeste Verknüpfung zwischen M und der in Formel (I) dargestellten Doppelbindung bilden.In other words, the macrocycle preferably has 10 to 36, preferably 15 to 25 ring atoms, where, if X itself comprises a cycle, only those atoms are counted which form the shortest link between M and the double bond represented in formula (I), and, if Y itself comprises a cycle, only those atoms are counted that have the shortest link form between M and the double bond shown in formula (I).
Wiederum bevorzugt ist X eine Heteroalkyl-, Heteroalkyl-cycloalkyl-, Heterocycloalkyl- oder Heteroaralkylgruppe.Again, X is preferably a heteroalkyl, heteroalkyl-cycloalkyl, heterocycloalkyl or heteroaralkyl group.
Weiter bevorzugt ist Y eine Heteroalkyl-, Heteroalkylcycloalkyl-, Heterocycloalkyl- oder Heteroaralkylgruppe.Y is further preferably a heteroalkyl, heteroalkylcycloalkyl, heterocycloalkyl or heteroaralkyl group.
Beispiele für pharmakologisch akzeptable Salze der Verbindungen der Formel (I) sind Salze von physiologisch akzeptablen Mineralsäuren wie Salzsäure, Schwefelsäure und Phosphorsäure oder Salze von organischen Säuren wie Methansulfonsäure, p-Toluolsulfonsäure, Milchsäure, Essigsäure, Tri- fluoressigsäure, Zitronensäure, Bernsteinsäure, Fu ar- säure, Maleinsäure und Salicylsäure . Verbindungen der Formel (I) können solvatisiert, insbesondere hydratisiert sein. Die Hydratisierung kann z.B. während des Herstellungsverfahrens oder als Folge der hygroskopischen Natur der anfänglich wasserfreien Verbindungen der Formel (I) auftreten. Wenn die Verbin- düngen der Formel (I) asymmetrische C-Atome enthalten, können sie entweder als Diastereomeren-Gemische, Gemische von Enantiomeren oder als optisch reine Verbindungen vorliegen.Examples of pharmacologically acceptable salts of the compounds of formula (I) are salts of physiologically acceptable mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid or salts of organic acids such as methanesulfonic acid, p-toluenesulfonic acid, lactic acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fu ar - acid, maleic acid and salicylic acid. Compounds of formula (I) can be solvated, in particular hydrated. The hydration can e.g. occur during the manufacturing process or as a result of the hygroscopic nature of the initially anhydrous compounds of formula (I). If the compounds of the formula (I) contain asymmetric C atoms, they can be present either as mixtures of diastereomers, mixtures of enantiomers or as optically pure compounds.
Die pharmazeutischen Zusammensetzungen gemäß der vorliegenden Erfindung enthalten mindestens eine Verbindung der Formel (I) als Wirkstoff und fakultativ Trägerstoffe und/oder Adjuvantien. Die Pro-Drugs, die ebenfalls Gegenstand der vorliegenden Erfindung sind, bestehen aus einerThe pharmaceutical compositions according to the present invention contain at least one compound of the formula (I) as active ingredient and optionally excipients and / or adjuvants. The pro-drugs, which are also the subject of the present invention, consist of a
Verbindung der Formel (I) und mindestens einer pharmakologisch akzeptablen Schutzgruppe, die unter physiologischen Bedingungen abgespalten wird, z.B. einer Alkoxy-, Aralkyloxy-, Acyl- oder Acyloxy-Gruppe, wie z.B. einer Ethoxy- , Benzyloxy-, Acetyl- oder Acetyloxy-Gruppe .Compound of formula (I) and at least one pharmacologically acceptable protecting group which is split off under physiological conditions, e.g. an alkoxy, aralkyloxy, acyl or acyloxy group, e.g. an ethoxy, benzyloxy, acetyl or acetyloxy group.
Die therapeutische Verwendung der Verbindungen der Formel (I) , ihrer pharmakologisch akzeptablen Salze bzw. Solvate und Hydrate sowie Formulierungen und pharmazeutischen Zusammensetzungen liegt ebenfalls im Rahmen der vorliegenden Erfindung.The therapeutic use of the compounds of formula (I), their pharmacologically acceptable salts or solvates and hydrates as well as formulations and pharmaceutical compositions is also within the scope of the present invention.
Auch die Verwendung dieser Wirkstoffe zur Herstellung von Arzneimitteln zur In-vivo-Stimulation des Nervenwachstums, der In-vivo-Inhibition der Narbengewebsbildung und/oder Tn-vi o-Reduktion eines Sekundärschadens sowie zur Behandlung von Tumorerkrankungen (insbesondere Krebs) ist Gegenstand der vorliegenden Erfindung. Im allgemeinen werden Verbindungen der Formel (I) unter Anwendung der bekannten und akzeptablen Modi, entweder einzeln oder in Kombina- tion mit einem beliebigen anderen therapeutischen Mittel verabreicht. Solche therapeutisch nützlichen Mittel können auf einem der folgenden Wege verabreicht werden: oral, z.B. als Dragees, überzogene Tabletten, Pillen, Halbfeststoffe, weiche oder harte Kapseln, Lösungen, Emulsionen oder Suspensionen; parenteral, z.B. als injizierbare Lösung; intratekal; rektal als Suppositorien; durch Inhalation, z.B. als Pulverformulierung oder Spray, transdermal oder intranasal. Zur Herstellung solcher Tabletten, Pillen, Halbfeststoffe, überzogenen Tabletten, Dragees und harten Gelatinekapseln kann das therapeutisch verwendbare Produkt mit pharmakologisch inerten, anorganischen oder organischen Arznei- mittelträgersubstanzen vermischt werden, z.B. mit Lactose, Sucrose, Glucose, Gelatine, Malz, Silicagel, Stärke oder Derivaten derselben, Talkum, Stearinsäure oder ihren Salzen, Trockenmagermilch und dgl . Zur Herstellung von weichen Kapseln kann man Arzneimittel- trägerstoffe wie z.B. pflanzliche Öle, Petroleum, tierische oder synthetische Öle, Wachs, Fett, Polyole einsetzen. Zur Herstellung von flüssigen Lösungen und Sirups kann man Arzneimittelträgerstoffe wie z.B. Wasser, Alkohole, wäßrige Salzlösung, wäßrige Dextrose, Polyole, Glycerin, pflanzliche Öle, Petroleum, tierische oder synthetische Öle verwenden. Für die intratekale Verabreichung können Hydrogele wie z. B. NeuroGel™ der Firma Organogel verwendet werden. Für Suppositorien kann man Arzneimittelträgerstoffe wie z.B. pflanzliche Öle, Petroleum, tierische oder synthetische Öle, Wachs, Fett und Polyole verwenden. Für Aerosol-Formulierungen kann man komprimierte Gase, die für diesen Zweck geeignet sind, wie z.B. Sauerstoff, Stickstoff und Kohlendioxid einsetzen. Die pharma- zeutisch verwendbaren Mittel können auch Zusatzstoffe zur Konservierung, Stabilisierung, Emulgatoren, Süßstoffe, Aromastoffe, Salze zur Veränderung des osmotischen Drucks, Puffer, Umhüllungszusatzstoffe und Antioxidantien enthalten.The present invention also relates to the use of these active ingredients for the production of medicaments for the in vivo stimulation of nerve growth, the in vivo inhibition of scar tissue formation and / or Tn-vi o reduction of secondary damage, and for the treatment of tumor diseases (in particular cancer) Invention. In general, compounds of formula (I) are administered using the known and acceptable modes, either individually or in combination with any other therapeutic agent. Such therapeutically useful agents can be administered in one of the following ways: orally, for example as dragées, coated tablets, pills, semi-solids, soft or hard capsules, solutions, emulsions or suspensions; parenterally, eg as an injectable solution; intratekal; rectally as suppositories; by inhalation, for example as a powder formulation or spray, transdermally or intranasally. To make such tablets, pills, Semi-solids, coated tablets, dragees and hard gelatin capsules, the therapeutically usable product can be mixed with pharmacologically inert, inorganic or organic medicament carrier substances, for example with lactose, sucrose, glucose, gelatin, malt, silica gel, starch or derivatives thereof, talc, stearic acid or their salts, dry skimmed milk and the like. For the production of soft capsules, pharmaceutical carriers such as vegetable oils, petroleum, animal or synthetic oils, wax, fat, polyols can be used. For the preparation of liquid solutions and syrups, drug carriers such as water, alcohols, aqueous salt solution, aqueous dextrose, polyols, glycerin, vegetable oils, petroleum, animal or synthetic oils can be used. For intratecal administration, hydrogels such as e.g. B. NeuroGel ™ from Organogel can be used. For suppositories, drug carriers such as vegetable oils, petroleum, animal or synthetic oils, wax, fat and polyols can be used. Compressed gases suitable for this purpose, such as oxygen, nitrogen and carbon dioxide, can be used for aerosol formulations. The pharmaceutically usable agents can also contain additives for preservation, stabilization, emulsifiers, sweeteners, flavorings, salts for changing the osmotic pressure, buffers, coating additives and antioxidants.
Verbindungen der Formel (I) können über eine Multikomponenmtenreaktion (siehe z. B. A. Dömling, I. Ugi, Angew. Che . 2000, 112, 3300-3344) mit anschliessendem Ringschluss durch eine Metathesereaktion mit dem Grubbs Katalysator (A. K. Chatterjee et al . Org. Lett. 2002, 4, 1939-1942; J. P. Morgan et al . Org. Lett. 2002, 4, 67-70; S. Randl Synlett 2001, 430-432; S. Imhof Chem. Commun. 2001, 1692-1693) hergestellt werden.Compounds of the formula (I) can be subjected to a multicomponent reaction (see, for example, BA Dömling, I. Ugi, Angew. Che. 2000, 112, 3300-3344) with subsequent ring closure by a Metathesis reaction with the Grubbs catalyst (AK Chatterjee et al. Org. Lett. 2002, 4, 1939-1942; JP Morgan et al. Org. Lett. 2002, 4, 67-70; S. Randl Synlett 2001, 430-432; S. Imhof Chem. Commun. 2001, 1692-1693).
BeispieleExamples
Beispiel 1 : Summen f ormel 2δH36N 0 Molgewicht : 512 , 61 g/mol Ausbeute : 36 %Example 1: Total formula 2δ H 36 N 0 Molecular weight: 512.61 g / mol Yield: 36%
Figure imgf000013_0001
Figure imgf000013_0001
MS (ESI-TOF) : m/z = 513 [M+H]' 535 [M+Na] + MS (ESI-TOF): m / z = 513 [M + H] ' 535 [M + Na] +
Auswachsassay auf inhibitorischen Chondroitinsulfat- proteoglykanen (CSPG)Growth assay on inhibitory chondroitin sulfate proteoglycans (CSPG)
Nach Verletzungen des zentralen Nervensystems bildet sich am Verletzungsort eine Narbe. Diese Narbe ist sowohl eine physikalische als auch eine chemische Barriere für regenerierende Nervenfasern. Ein wichtiger regenerationshemmender Bestandteil der Narbe sind Chondroitinsulfatproteoglykane (CSPG) (Fawcett and Asher, Brain Res Bull, 1999, 49(6): 377-391). Es wurde nun gefunden, dass CSPG das Aus-wachsen von Axonen aus retinalen Explantaten hemmen. Diese hemmende Wirkung der CSPG kann durch regenerationsfördernde Substanzen aufgehoben werden. CSPG-Auswachsassay:After injuries to the central nervous system, a scar forms at the site of the injury. This scar is both a physical and a chemical barrier for regenerating nerve fibers. An important regeneration-inhibiting component of the scar are chondroitin sulfate proteoglycans (CSPG) (Fawcett and Asher, Brain Res Bull, 1999, 49 (6): 377-391). It has now been found that CSPG inhibit axon outgrowth from retinal explants. This inhibitory effect of CSPG can be eliminated by substances that promote regeneration. CSPG Auswachsassay:
UV-sterilisierte Deckgläser werden mit Poly-L-Lysine (200 μg/ml Poly-L-Lysine [Sigma] , in PBS, pH 7,4, 37°C, 2-3 h) vorbeschichtet, in PBS gewaschen und bei 37°C für 2-3 h mit einer CSPG-Laminin-Mischung beschichtet (20 μg/ml Chondroitinsulfatproteoglykan [Chemicon] und 20 μg/ml Laminin [Becton Dickinson] ) .UV-sterilized coverslips are precoated with Poly-L-Lysine (200 μg / ml Poly-L-Lysine [Sigma], in PBS, pH 7.4, 37 ° C, 2-3 h), washed in PBS and at 37 ° C for 2-3 h coated with a CSPG-laminin mixture (20 μg / ml chondroitin sulfate proteoglycan [Chemicon] and 20 μg / ml laminin [Becton Dickinson]).
Die beschichten Deckgläschen werden in 24-Well Platten eingelegt. Auf diese Deckgläschen werden jeweils 20-30 Retina-Mini-Explantate (300 x 300 μm, von embryonalen Hühnchen, E7) in 500 μl Kulturmedium pipettiert (Ham's F-12 ohne L-Glutamin, 10% fetales Kälberserum, 2% Hühnchenserum, 2 M L-Glutamin, 100 Einheiten/ml Penicillin, 100 μg/ml Streptomycin [alle Komponenten von PAA Laboratories] ) .The coated coverslips are placed in 24-well plates. 20-30 retina mini explants (300 x 300 μm, from embryonic chickens, E7) in 500 μl culture medium are pipetted onto each of these coverslips (Ham's F-12 without L-glutamine, 10% fetal calf serum, 2% chicken serum, 2 M L-glutamine, 100 units / ml penicillin, 100 μg / ml streptomycin [all components from PAA Laboratories]).
Vor der Zugabe der Verbindung aus Beispiel 1 werden die Retina-Mini-Explantate für 25-35 min bei 37°C und 4% C02 inkubiert, damit die Explantate auf den Deckgläschen anheften können. Beispiel 1 wird in 500 μl Kulturmedium gelöst (37°C) , kurz aufgeschüttelt und zu den Retina-Mini-Explantaten gegeben. Die Retinakulturen werden dann für 24h bei 37°C und 4% C02 inkubiert. Anschließend werden die Retinakulturen über Nacht bei 2-8°C mit 1ml 4% Paraformaldehyd (in PBS, pH 7,4) pro Well fixiert.Before adding the compound from Example 1, the retina mini-explants are incubated for 25-35 min at 37 ° C. and 4% CO 2 , so that the explants can attach to the coverslip. Example 1 is dissolved in 500 μl of culture medium (37 ° C.), shaken briefly and added to the retina mini-explants. The retina cultures are then incubated for 24 h at 37 ° C and 4% CO 2 . The retina cultures are then fixed overnight at 2-8 ° C. with 1 ml of 4% paraformaldehyde (in PBS, pH 7.4) per well.
Die fixierten Kulturen werden mit PBS gewaschen und für 10 min mit 0,1% Triton X-100 (in PBS [Roth]) inkubiert und nochmals gewaschen. Dann erfolgt die Färbung der ausgewachsenen Axone mit 300 μl Alexa P alloidin (Alexa' Fluor 488 phalloidin [Molecular Probes] , 1:40 in ' PBS enthaltend 1% Rinderserumalbumin und 0,02% Natriumazid, 30-40 min, Raumtemperatur) . Die Kulturen werden nochmals mit PBS gewaschen und mit Mowiol [Hoechst] eingebettet . Die durchschnittliche Länge der ausgewachsenen Axone pro Explantat wird mit Hilfe einer auf ein Fiuoreszenzmikroskop (Axioplan 2 [Zeiss] ) montierten digitalen Kamera (Axioca [Zeiss] ) und einer Mess- Software (AxioVision 3.0 [Zeiss]) bestimmt. Als Kontrolle werden Explantate ohne Zugabe von Beispiel 1 verwendet .The fixed cultures are washed with PBS and incubated for 10 min with 0.1% Triton X-100 (in PBS [Roth]) and washed again. The adult axons are then stained with 300 μl Alexa P alloidin (Alexa ' Fluor 488 phalloidin [Molecular Probes], 1:40 in' PBS containing 1% bovine serum albumin and 0.02% sodium azide, 30-40 min, room temperature). The cultures are washed again with PBS and embedded with Mowiol [Hoechst]. The average length of the adult axons per explant is determined with the aid of a digital camera (Axioca [Zeiss]) mounted on a fluorescence microscope (Axioplan 2 [Zeiss]) and a measuring software (AxioVision 3.0 [Zeiss]). Explants without the addition of Example 1 are used as controls.
Die regenerationsfördernde Wirkung von Beispiel 1 wurde in den Konzentrationen 10 und 50 μM im CSPG- Auswachsassay bestimmt.The regeneration-promoting effect of Example 1 was determined in the concentrations 10 and 50 μM in the CSPG growth assay.
Im CSPG-Auswachsassay neutralisiert die Verbindung aus Beispiel 1 den Wachstums- und/oder regenerationshemmenden Effekt der CSPG und fördern das Auswachsen der retinalen Axone. Den stärksten regenerationsfördernden Effekt hat Beispiel 1 in einer Konzentration von 10μM. Hier vergrößert sich das Axonwachstum um den Faktor 2 bis 3 im Vergleich zur Kontrolle. In einer Konzentration von 50 μM ist das Axonwachstum um den Faktor 1.3 erhöht .In the CSPG growth assay, the compound from Example 1 neutralizes the growth and / or regeneration-inhibiting effect of the CSPG and promote the growth of the retinal axons. Example 1 has the strongest regenerative effect in a concentration of 10μM. Here the axon growth increases by a factor of 2 to 3 compared to the control. At a concentration of 50 μM, the axon growth is increased by a factor of 1.3.
Figure imgf000015_0001
Beispiel 2 :
Figure imgf000015_0001
Example 2:
Summenformel : C33H33N306 Molecular formula: C 33 H 33 N 3 0 6
Molgewicht: 567,65 g/molMolecular weight: 567.65 g / mol
Ausbeute: 15 %Yield: 15%
Figure imgf000016_0001
Figure imgf000016_0001
MS (ESI-TOF): m/z = 568 [M+H]+ ; 590 [M+Na] + MS (ESI-TOF): m / z = 568 [M + H] + ; 590 [M + Na] +
Beispiel 3 : Summenformel C34H34N207 Molgewicht : 582,66 g/mol Ausbeute : 14 %Example 3: Molecular Formula C 34 H 34 N 2 0 7 Molecular Weight: 582.66 g / mol Yield: 14%
Figure imgf000016_0002
Figure imgf000016_0002
MS (ESI-TOF) : m/z = 583 [M+H]+ ; 605 [M+Na] + MS (ESI-TOF): m / z = 583 [M + H] + ; 605 [M + Na] +
Beispiel 4: Summen formel : C23H37N304 Molgewicht: 419,57 g/mol Ausbeute : 19 %Example 4: Sum formula: C 23 H 37 N 3 0 4 Molecular weight: 419.57 g / mol Yield: 19%
Figure imgf000016_0003
Figure imgf000016_0003
MS (ESI-TOF) : m/z = 420 [M+H]+ ; 442 [M+Na] + Beispiel 5: Summenforme1 : C32H37N05 Molgewicht : 515,65 g/mol Ausbeute: 6 %MS (ESI-TOF): m / z = 420 [M + H] + ; 442 [M + Na] + Example 5: Sum forms 1: C 32 H 37 N0 5 Molecular weight: 515.65 g / mol Yield: 6%
Figure imgf000017_0001
Figure imgf000017_0001
MS (ESI-TOF): m/z = 516 [M+H]+ ; 538 [M+Na] + MS (ESI-TOF): m / z = 516 [M + H] + ; 538 [M + Na] +

Claims

Patentansprüche claims
1. Cyclische Verbindung der allgemeinen Formel (I)1. Cyclic compound of the general formula (I)
Figure imgf000018_0001
worin
Figure imgf000018_0001
wherein
M das Grundgerüst einer durch eine Multikomponentenreaktion hergestellten Verbindung ist undM is the basic structure of a compound produced by a multicomponent reaction and
X und Y unabhängig voneinander gegebenenfalls substituierte Alkylen-, Alkenylen-, Alkinylen-, Heteroalkylen- , Arylen-, Heteroarylen-, Cycloalkylen-, Alkylcycloalkylen-,X and Y independently of one another optionally substituted alkylene, alkenylene, alkynylene, heteroalkylene, arylene, heteroarylene, cycloalkylene, alkylcycloalkylene,
Heteroalkylcyclo-alkylen- , Heterocycloalkylen- , Aralkylen- oder Hetero-aralkylengruppen sind,Are heteroalkylcycloalkylene, heterocycloalkylene, aralkylene or heteroaralkylene groups,
oder ein pharmakologisch akzeptables Salz, Solvat, Hydrat oder eine pharmakologisch akzeptable Formulierung derselben.or a pharmacologically acceptable salt, solvate, hydrate or a pharmacologically acceptable formulation thereof.
2. Verbindung nach Anspruch 1, wobei M die folgende Struktur aufweist:2. The compound of claim 1, wherein M has the following structure:
Figure imgf000018_0002
worin A ein Sauerstoffatom oder eine Gruppe der Formel NR1 ist, wobei R1 ein Wasserstoffatom, ein Alkyl-, Alkenyl-, Alkinyl-, Heteroalkyl-, Aryl-, Heteroaryl-, Cycloalkyl-, Alkylcycloalkyl-, Heteroalkylcycloalkyl- , Heterocyclo-alkyl-, Aralkyl- oder ein Heteroaralkylrest ist und Het eine stickstoffhaltige Heteroarylgruppe ist.
Figure imgf000018_0002
wherein A is an oxygen atom or a group of the formula NR 1 , where R 1 is a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, Heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or a heteroaralkyl radical and Het is a nitrogen-containing heteroaryl group.
3. Verbindungen nach Anspruch 1 oder 2, wobei die cyclische Verbindung 10 bis 36 Ringatome aufweist3. Compounds according to claim 1 or 2, wherein the cyclic compound has 10 to 36 ring atoms
4. Verbindungen nach Anspruch 1 oder 2 , wobei cyclische Verbindung 15 bis 25 Ringatome aufweist.4. Compounds according to claim 1 or 2, wherein cyclic compound has 15 to 25 ring atoms.
5. Verbindungen nach einem der Ansprüche 2 bis 4, wobei Het ein gegebenenf lls substituierter Pyridinring ist.5. Compounds according to any one of claims 2 to 4, wherein Het is a possibly substituted pyridine ring.
6. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 5 zur Zn-vivo-Stimulation des Nervenwachstums .6. Use of compounds according to one of claims 1 to 5 for Zn vivo stimulation of nerve growth.
7. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 5 zur Jn-vivo-Inhibition der Narbengewebsbildung.7. Use of compounds according to any one of claims 1 to 5 for in vivo inhibition of scar tissue formation.
8. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 5 zur Jn-vivo-Reduktion eines8. Use of compounds according to one of claims 1 to 5 for the in vivo reduction of a
Sekundärschaden.Secondary damage.
9. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 5 zur Neutralisation von Regenerationsinhibitoren des Narbengewebes.9. Use of compounds according to one of claims 1 to 5 for the neutralization of regeneration inhibitors of the scar tissue.
10. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 5 zur Neutralisation von Regenerationsinhibitoren der Myelinhülle sowie der Oligodendrozyten .10. Use of compounds according to one of claims 1 to 5 for the neutralization of Regeneration inhibitors of the myelin sheath and of the oligodendrocytes.
11. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 5 zur Neutralisation von11. Use of compounds according to one of claims 1 to 5 for the neutralization of
Regenerationsinhibitoren auf der Oberfläche von Astrozyten, Makrophagen, Mikrogliazellen.Regeneration inhibitors on the surface of astrocytes, macrophages, microglial cells.
12. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 5 zur Neutralisation von12. Use of compounds according to one of claims 1 to 5 for the neutralization of
Regenerationsinhibitoren auf der Oberfläche Läsions-assoziierter Zellen des Immunsystems.Regeneration inhibitors on the surface of lesion-associated cells of the immune system.
13. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 5 zur Behandlung von Neuronenschäden .13. Use of compounds according to one of claims 1 to 5 for the treatment of neuronal damage.
14. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 5 zur Behandlung von akuten Verletzungen des Gehirns und des Rückenmarks.14. Use of compounds according to one of claims 1 to 5 for the treatment of acute injuries to the brain and spinal cord.
15. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 5 zur Behandlung von chronischen Schädigungen des Gehirns und des Rückenmarks .15. Use of compounds according to any one of claims 1 to 5 for the treatment of chronic damage to the brain and spinal cord.
16. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 5 zur Behandlung von neurologischen und neurodegenerativen Erkrankungen des zentralen Nervensystems.16. Use of compounds according to one of claims 1 to 5 for the treatment of neurological and neurodegenerative diseases of the central nervous system.
17. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 5 zur regenerativen Behandlung des Morbus Alzheimer, Morbus Parkinson, der Multiplen Sklerose und ähnlicher Erkrankungen, die mit einem Nervenfaserverlust und Entmarkung einhergehen, sowie der Amyotrophen Lateral Sklerose und anderer Motoneuronenerkrankungen .17. Use of compounds according to any one of claims 1 to 5 for the regenerative treatment of Alzheimer's disease, Parkinson's disease, multiple sclerosis and similar diseases with a Nerve fiber loss and demarking are associated, as well as amyotrophic lateral sclerosis and other motor neuron diseases.
18. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 5 zur regenerativen Behandlung der Ischämie, des Schlaganfalls, der Epilepsie, des Morbus Huntington, des AIDS Demenz Komplex und von Prionen-Erkrankungen .18. Use of compounds according to any one of claims 1 to 5 for the regenerative treatment of ischemia, stroke, epilepsy, Huntington's disease, AIDS dementia complex and prion diseases.
19. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 5 zur Behandlung von neurologischen und neurodegenerativen Erkrankungen des peripheren Nervensystems.19. Use of compounds according to one of claims 1 to 5 for the treatment of neurological and neurodegenerative diseases of the peripheral nervous system.
20. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 5 zur Behandlung von Läsionen peripherer Nerven.20. Use of compounds according to one of claims 1 to 5 for the treatment of lesions of peripheral nerves.
21. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 5 zur Behandlung von Lähmungserscheinungen, die durch Verletzungen peripherer Nerven verursacht wurden.21. Use of compounds according to one of claims 1 to 5 for the treatment of paralysis symptoms which were caused by injuries to peripheral nerves.
22. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 5 zur Behandlung von Merk- und Gedächtnisdefiziten auf der Basis der durch diese Inhibitoren induzierten Steigerung der Gehirndurchblutung . 22. Use of compounds according to one of claims 1 to 5 for the treatment of memory and memory deficits on the basis of the increase in blood flow to the brain induced by these inhibitors.
PCT/EP2003/008444 2002-07-30 2003-07-30 Novel compounds for stimulation of nerve growth, for the inhibition of scar tissue formation and/or reduction of secondary damage WO2004012649A2 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996030534A1 (en) 1995-03-24 1996-10-03 Genzyme Corporation Adenovirus vectors for gene therapy
EP1923467A2 (en) 1995-03-24 2008-05-21 Genzyme Corporation Adenovirus vectors for gene therapy
EP2000134A1 (en) * 2007-06-06 2008-12-10 Neuraxo Biopharmaceuticals GmbH Use of a substance for the improvement of pns lesions

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996030534A1 (en) 1995-03-24 1996-10-03 Genzyme Corporation Adenovirus vectors for gene therapy
EP1923467A2 (en) 1995-03-24 2008-05-21 Genzyme Corporation Adenovirus vectors for gene therapy
EP2000134A1 (en) * 2007-06-06 2008-12-10 Neuraxo Biopharmaceuticals GmbH Use of a substance for the improvement of pns lesions

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