WO2004012649A2 - Nouveaux composes pour stimuler la croissance nerveuse, inhiber la formation de tissus cicatriciels et/ou reduire une lesion secondaire - Google Patents

Nouveaux composes pour stimuler la croissance nerveuse, inhiber la formation de tissus cicatriciels et/ou reduire une lesion secondaire 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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WO
WIPO (PCT)
Prior art keywords
compounds according
treatment
scar tissue
vivo
neutralization
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PCT/EP2003/008444
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German (de)
English (en)
Inventor
Alexander Dömling
Barbara Beck
Bernhard Mueller
Bernd Stahl
Christian Leppert
Original Assignee
Morphochem Aktiengesellschaft für kombinatorische Chemie
Migragen Ag
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Application filed by Morphochem Aktiengesellschaft für kombinatorische Chemie, Migragen Ag filed Critical Morphochem Aktiengesellschaft für kombinatorische Chemie
Priority to AU2003255331A priority Critical patent/AU2003255331A1/en
Publication of WO2004012649A2 publication Critical patent/WO2004012649A2/fr

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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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux macrocycles de formule (I), des procédés pour leur préparation, ainsi que leur utilisation pour stimuler in vivo la croissance nerveuse, pour inhiber in vivo la formation de tissus cicatriciels et/ou pour réduire in vivo une lésion secondaire. Dans la formule (I), M représente le squelette d'un composé obtenu au moyen d'une réaction de plusieurs composants, et X et Y représentent, indépendamment l'un de l'autre, des groupes alkylène, alcénylène, alcynylène, hétéroalkylène, arylène, hétéroarylène, cycloalkylène, alkylcycloalkylène, hétéroalkylcycloalkylène, hétérocycloalkylène, aralkylène ou hétéroaralkylène.
PCT/EP2003/008444 2002-07-30 2003-07-30 Nouveaux composes pour stimuler la croissance nerveuse, inhiber la formation de tissus cicatriciels et/ou reduire une lesion secondaire WO2004012649A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003255331A AU2003255331A1 (en) 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

Applications Claiming Priority (2)

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DE10234697.6 2002-07-30
DE2002134697 DE10234697A1 (de) 2002-07-30 2002-07-30 Neue Verbindungen zur Stimulation des Nervenwachstums, zur Inhibition der Narbengewebsbildung und/oder Reduktion eines Sekundärschadens

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WO2004012649A2 true WO2004012649A2 (fr) 2004-02-12

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996030534A1 (fr) 1995-03-24 1996-10-03 Genzyme Corporation Vecteurs d'adenovirus pour therapie genique
EP1923467A2 (fr) 1995-03-24 2008-05-21 Genzyme Corporation Vecteurs d'adénovirus pour thérapie génétique
EP2000134A1 (fr) * 2007-06-06 2008-12-10 Neuraxo Biopharmaceuticals GmbH Utilisation d'une substance pour l'amélioration des lésions pns

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996030534A1 (fr) 1995-03-24 1996-10-03 Genzyme Corporation Vecteurs d'adenovirus pour therapie genique
EP1923467A2 (fr) 1995-03-24 2008-05-21 Genzyme Corporation Vecteurs d'adénovirus pour thérapie génétique
EP2000134A1 (fr) * 2007-06-06 2008-12-10 Neuraxo Biopharmaceuticals GmbH Utilisation d'une substance pour l'amélioration des lésions pns

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Publication number Publication date
AU2003255331A8 (en) 2004-02-23
DE10234697A1 (de) 2004-02-19
AU2003255331A1 (en) 2004-02-23

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