EP1047685A1 - Substituted beta,gamma-anellated lactones - Google Patents

Substituted beta,gamma-anellated lactones

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Publication number
EP1047685A1
EP1047685A1 EP99903604A EP99903604A EP1047685A1 EP 1047685 A1 EP1047685 A1 EP 1047685A1 EP 99903604 A EP99903604 A EP 99903604A EP 99903604 A EP99903604 A EP 99903604A EP 1047685 A1 EP1047685 A1 EP 1047685A1
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EP
European Patent Office
Prior art keywords
compounds
document
general formula
date
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP99903604A
Other languages
German (de)
French (fr)
Inventor
Andreas Stolle
Horst-Peter Antonicek
Stephan Lensky
Arnd Voerste
Thomas Müller
Jörg Baumgarten
Karsten Von Dem Bruch
Gerhard Müller
Udo Stropp
Ervin Horvath
Jean-Marie-Viktor De Vry
Rudy Schreiber
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Bayer AG
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Bayer AG
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Publication of EP1047685A1 publication Critical patent/EP1047685A1/en
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
    • C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • R 3 represents hydrogen, (C, -C 6 ) alkyl or (C 2 -C 6 ) alkenyl
  • R 4 represents a radical of the formula -CH -R 5 ,
  • R 5 is aryl having 6 to 10 carbon atoms or benzothiophene bonded via the heterocycle, the ring systems optionally being substituted one to more times, identically or differently, by halogen or (C, -C 6 ) -alkyl,
  • R 3 represents (C 2 -C 6 ) alkenyl
  • R 4 represents hydrogen
  • the compounds according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers).
  • the invention relates to both the enantiomers or diastereomers or their respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.
  • Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids.
  • Propionic acid lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
  • Salts which can be mentioned are salts with customary bases, such as, for example, alkali metal salts (e.g. sodium or potassium salts), alkaline earth metal salts (e.g. calcium or
  • Amines such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine,
  • Aryl generally represents an aromatic radical having 6 to 10 carbon atoms.
  • Preferred aryl radicals are phenyl and naphthyl.
  • (CC f i) -alkyl in the context of the invention represents a straight-chain or branched alkyl radical having 1 to 6 carbon atoms.
  • a straight-chain or branched alkyl radical having 1 to 4 carbon atoms is preferred. Examples include: methyl, ethyl, propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.
  • (C 2 -C 6 ) alkenyl represents a straight-chain or branched alkenyl radical having 2 to 6 carbon atoms.
  • a straight-chain or branched alkenyl radical having 3 to 5 carbon atoms is preferred. Examples include: vinyl, allyl, isopropenyl, but-3-en-1-yl, n-pent-3-en-1-yl and n-hex-3-en-1-yi.
  • R 3 represents hydrogen or (C 2 -C 5 ) alkenyl
  • R 4 represents a radical of the formula -CH 2 -R 5 ,
  • R 5 denotes phenyl, naphthyl or benzothiophene bonded via the heterocycle, the ring systems optionally being substituted one to more times, identically or differently, by fluorine, chlorine, bromine or (C 1 -C 4 ) -alkyl,
  • R 3 represents (C 2 -C 5 ) alkenyl
  • R 4 represents hydrogen
  • R 3 represents hydrogen or (C 3 -C 5 ) alkenyl
  • R 4 represents a radical of the formula -CH 2 -R 5 ,
  • R 5 is phenyl, naphthyl or benzothiophene bonded via the heterocycle, the ring systems optionally being one to two times, identical or different, by fluorine, chlorine, bromine or (C, -
  • R 3 represents (C 3 -C 5 ) alkenyl
  • R 4 represents hydrogen -
  • the compounds of the general formula (I) according to the invention can be prepared by:
  • R 4 has the meaning given above
  • A represents halogen, preferably bromine
  • R, R and R have the meaning given above, - -
  • R 3 has the meaning of R 3 given above, but does not represent hydrogen
  • D represents halogen, preferably bromine
  • Suitable solvents are all inert solvents that do not change under the reaction conditions. These preferably include ethers such as diethyl ether,
  • Tetrahydrofuran is particularly preferred.
  • bases are suitable as bases. These preferably include alkali metal hydroxides such as sodium or potassium hydroxide, or alkali metal carbonates such as sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethanolate or potassium tert-butoxide, or amides such as sodium amide, lithium bis (trimethylsilyl) amide, lithium diisopropylamide , or organometallic compounds such as butyllithium or phenyllithium. Lithium diisopropylamide and lithium bis (trimethylsilyl) amide are preferred.
  • the base is used in an amount of 1 to 5, preferably 1 to 2, mol, based on 1 mol of the compounds of the general formulas (III) and (IV).
  • the reaction generally takes place in a temperature range from -78 ° C to
  • Reflux temperature preferably from -78 ° C to + 20 ° C.
  • the reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.
  • the compounds of the general formula (I) according to the invention are suitable for use as medicaments in the treatment of humans and animals.
  • the compounds of the general formula (I) according to the invention are suitable for modulating metabotropic glutamate receptors and therefore influence the glutamatergic neurotransmitter system.
  • a modulator of the metabotropic glutamate receptor in the sense of the invention is an agonist or antagonist of this receptor.
  • the compounds according to the invention are particularly suitable as modulators of the metabotropic glutamate receptor of subtype 1, very particularly as antagonists of this receptor subtype.
  • the compounds of the invention can be based on their pharmacological
  • the compounds according to the invention are also suitable for the therapy of primary and / or secondary pathological conditions in the brain, for example during or after cerebral vasospasm, hypoxia and / or anoxia of a genesis not mentioned above, perinatal asphyxia, autoimmune diseases, metabolic and organ diseases associated with Damage to the brain can go hand in hand as well as damage to the brain due to primary brain diseases, for example
  • Seizures and atherosclerotic and / or atherosclerotic changes For the treatment of chronic or psychiatric conditions such as depression, neurodegenerative diseases such as Alzheimer's, Parkinson's or Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, neurodegeneration due to acute and / or chronic viral or bacterial infections and multi-infarct dementia.
  • chronic or psychiatric conditions such as depression
  • neurodegenerative diseases such as Alzheimer's, Parkinson's or Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, neurodegeneration due to acute and / or chronic viral or bacterial infections and multi-infarct dementia.
  • the compounds can be used as medicines for the prevention and / or treatment of dementias of different origins, brain disorders in old age, memory disorders, spinal cord injuries, painful conditions, anxiety states of different origins, drug-related Parkinson's syndrome, psychoses (such as schizophrenia), cerebral edema, neuronal damage after hypoglycemia, vomiting, nausea, obesity, addiction and withdrawal symptoms, CNS-mediated cramps, sedation and movement disorders.
  • the compounds can also be used to promote neuronal regeneration in the post-acute phase of cerebral injuries or chronic diseases of the nervous system.
  • They are preferably used as medicinal products for the prevention and / or treatment of cerebral ischaemia, skull / brain trauma, pain or CNS-mediated cramps (such as epilepsy).
  • the modulation of substances on the metabotropic glutamate receptor can be checked on primary cerebellar cell cultures from the cerebellum. Electrophysiological measurements on these cell cultures in the "cell attached" mode show that L-type Ca 2+ channels in this preparation are activated by mGluRl glutamate receptors (J. Neurosci. 1995, 15, 135), whereas they by group II receptors can be blocked (J. Neurosci. 1994, 14, 7067).
  • the experimental arrangement can be used to control the modulatory effect of pharmacological test substances on glutamate receptors Subtype DNA take place (WO 92/10583).
  • test models can be used to demonstrate the anti-ischemic activity of the compounds in vivo.
  • the cerebral artery is unilaterally dissected using electrocoagulation and this and its secondary branches are irreversibly closed.
  • a cerebral infarction develops.
  • the animal's body temperature is kept at 37 ° C.
  • the anesthetic has subsided, the animals are released back into their cages.
  • the substance- Application takes place according to different time schedules and via different application routes (ivip) after the occlusion.
  • the infarct size is determined after 7 days. For this purpose, the brain is removed, histologically processed and the infarct volume determined using a computer-aided evaluation system.
  • the animals are injected with subdural autologous blood under anesthesia.
  • An infarction forms under the hematoma.
  • the substance is administered according to different time schedules and via different application routes (i.v. i.p.).
  • the infarct size is determined as described in the model of permanent focal ischemia in the rat (MCA-O).
  • the anti-epileptic effect can be tested according to the method described in NeuroReport 1996, 7, 1469-1474.
  • the suitability of the compounds according to the invention for the treatment of schizophrenia can be determined according to the methods described in Science 1998, 281, 1349-1352 and Eur. J. Pharmacol. 1996, 316, 129-136 methods can be determined.
  • the present invention also includes pharmaceutical preparations which, in addition to inert, non-toxic, pharmaceutically suitable auxiliaries and excipients, contain one or more compounds of the general formulas (I), (Ia) and (Ib), or which consist of one or more active ingredients of the Formulas (I), (Ia) and (Ib) exist, and processes for the preparation of these preparations.
  • the active compounds of the formulas (I), (Ia) and (Ib) should be present in these preparations in a concentration of 0.1 to 99.5% by weight, preferably 0.5 to 95% by weight, of the total mixture . - -
  • the pharmaceutical preparations can also contain other active pharmaceutical ingredients.
  • the pharmaceutical preparations listed above can be prepared in a customary manner by known methods, for example using the excipient or excipients.
  • the active compound or formulas (I), (Ia) and (Ib) in total amounts from about 0.01 to about 100 mg / kg, preferably in total amounts from about 1 mg / kg to 50 mg / kg body weight per 24
  • Example 2 fraction 1, diastereomer A
  • example 3 fraction 2, diasteromer B
  • Example 4 In analogy to the procedure of Example 4, the title compound is made from 0.55 g (3.3 mmol) of the compound from Example 3, 4 ml of 1 molar lithium bis (trimethylsilyl) amide solution in THF and 0.73 g (3.3 mmol) of 2- ( Bromomethyl) -naphthalene prepared in 15 ml THF. Yield: 823 mg (81.2%) of a colorless oil. - -
  • Example 9 (Fraction 2)
  • Example 10 (Fraction 3)
  • Example 11 (Fraction 4)
  • the compounds listed in Table 1 below were prepared in analogy to the instructions of Examples 1-7.
  • Example 3 In analogy to the procedure of Example 3, the title compound was obtained from 0.79 g (3 mmol) of the compound from Example 7, 3 ml of 1 molar lithium bis (trimethylsilyl) amide solution in THF and 0.36 g (3 mmol) Allyl bromide made in 10 ml THF.
  • the chromatographic purification was carried out with a mixture of dichloromethane and petroleum ether (40-60) in a ratio of 100: 4. Yield: 684 mg (74.8%) of a pale yellow oil; Diastereomeric purity:> 99% de (HPLC).
  • HPLC Examples 22, 23, 24 and 25.
  • Example 4 In analogy to the procedure of Example 4, the title compound was made from 0.23 g (1.38 mmol) of the compound from Example 16, 1.4 ml of 1 molar lithium bis (trimethylsilyl) amide solution in THF and 0.3 g (1.38 mmol) 2 -Bromomethylnaphthalene made in 5 ml THF.
  • R 3 represents hydrogen, (C, -C 6 ) alkyl or (C 2 -C 6 ) alkenyl
  • R 4 represents a radical of the formula -CH 2 -R 5 ,
  • R 5 denotes aryl having 6 to 10 carbon atoms or benzothiophene bonded via the heterocycle, the ring systems optionally being substituted one to more times, identically or differently, by halogen or (C, -C 6 ) alkyl,

Abstract

The invention relates to novel substituted β,η-anellated lactones, to methods for producing said β,η-anellated lactones, and to their use for preventing and/or treating diseases caused by the hyper- or hypofunction of the glutamatergic system, especially cerebral ischaemia, cranial/cerebral trauma, pain or CNS-mediated cramps.

Description

- - - -
R3 für Wasserstoff, (C,-C6)-Alkyl oder für (C2-C6)-Alkenyl stehtR 3 represents hydrogen, (C, -C 6 ) alkyl or (C 2 -C 6 ) alkenyl
undand
R4 für einen Rest der Formel -CH -R5 steht,R 4 represents a radical of the formula -CH -R 5 ,
worinwherein
R5 Aryl mit 6 bis 10 Kohlenstoffatomen oder über den Hetero- cyclus gebundenes Benzothiophen bedeutet, wobei die Ringsysteme gegebenenfalls ein- bis mehrfach, gleich oder verschieden durch Halogen oder (C,-C6)-Alkyl substituiert sind,R 5 is aryl having 6 to 10 carbon atoms or benzothiophene bonded via the heterocycle, the ring systems optionally being substituted one to more times, identically or differently, by halogen or (C, -C 6 ) -alkyl,
oderor
R3 für (C2-C6)-Alkenyl stehtR 3 represents (C 2 -C 6 ) alkenyl
undand
R4 für Wasserstoff stehtR 4 represents hydrogen
und deren pharmazeutisch verträgliche Salze.and their pharmaceutically acceptable salts.
Die erfindungsgemäßen Verbindungen können in stereoisomeren Formen, die sich entweder wie Bild und Spiegelbild (Enantiomere), oder die sich nicht wie Bild und Spiegelbild (Diastereomere) verhalten, existieren. Die Erfindung betrifft sowohl die Enantiomeren oder Diastereomeren oder deren jeweilige Mischungen. Die Racem- formen lassen sich ebenso wie die Diastereomeren in bekannter Weise in die Stereo isomer einheitlichen Bestandteile trennen. Physiologisch unbedenkliche Salze der erfindungsgemäßen Verbindungen können Salze der erfindungsgemäßen Stoffe mit Mineralsäuren, Carbonsäuren oder Sulfon- säuren sein. Besonders bevorzugt sind z.B. Salze mit Chlorwasserstoffsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure, Methansulfonsäure, Ethansulfon- säure, Toluolsulfonsäure, Benzolsulfonsäure, Naphthalindisulfonsäure, Essigsäure,The compounds according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers). The invention relates to both the enantiomers or diastereomers or their respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner. Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids. Particularly preferred are, for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid,
Propionsäure, Milchsäure, Weinsäure, Zitronensäure, Fumarsäure, Maleinsäure oder Benzoesäure.Propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
Als Salze können Salze mit üblichen Basen genannt werden, wie beispielsweise Alkali- metallsalze (z.B. Natrium- oder Kaliumsalze), Erdalkalisalze (z.B. Calcium- oderSalts which can be mentioned are salts with customary bases, such as, for example, alkali metal salts (e.g. sodium or potassium salts), alkaline earth metal salts (e.g. calcium or
Magnesiumsalze) oder Ammoniumsalze, abgeleitet von Ammoniak oder organischenMagnesium salts) or ammonium salts derived from ammonia or organic
Aminen wie beispielsweise Diethylamin, Triethylamin, Ethyldiisopropylamin, Prokain,Amines such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine,
Dibenzylamin, N-Methylmorpholin, Dihydroabietylamin, 1-Ephenamin oder Methyl- piperidin.Dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine or methylpiperidine.
Aryl steht im allgemeinen für einen aromatischen Rest mit 6 bis 10 Kohlenstoffatomen.Aryl generally represents an aromatic radical having 6 to 10 carbon atoms.
Bevorzugte Arylreste sind Phenyl und Naphthyl.Preferred aryl radicals are phenyl and naphthyl.
(C Cfi)-Alkyl steht im Rahmen der Erfindung für einen geradkettigen oder verzweigten Alkylrest mit 1 bis 6 Kohlenstoffatomen. Bevorzugt ist ein geradkettiger oder verzweigter Alkylrest mit 1 bis 4 Kohlenstoffatomen. Beispielsweise seien genannt: Methyl, Ethyl, Propyl, Isopropyl, tert.-Butyl, n-Pentyl und n-Hexyl.(CC f i) -alkyl in the context of the invention represents a straight-chain or branched alkyl radical having 1 to 6 carbon atoms. A straight-chain or branched alkyl radical having 1 to 4 carbon atoms is preferred. Examples include: methyl, ethyl, propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.
(C2-C6)-Alkenyl steht im Rahmen der Erfindung für einen geradkettigen oder ver- zweigten Alkenylrest mit 2 bis 6 Kohlenstoffatomen. Bevorzugt ist ein geradkettiger oder verzweigter Alkenylrest mit 3 bis 5 Kohlenstoffatomen. Beispielsweise seien genannt: Vinyl, Allyl, Isopropenyl, But-3-en-l-yl, n-Pent-3-en-l-yl und n-Hex-3-en-l- yi.In the context of the invention, (C 2 -C 6 ) alkenyl represents a straight-chain or branched alkenyl radical having 2 to 6 carbon atoms. A straight-chain or branched alkenyl radical having 3 to 5 carbon atoms is preferred. Examples include: vinyl, allyl, isopropenyl, but-3-en-1-yl, n-pent-3-en-1-yl and n-hex-3-en-1-yi.
Bevorzugt sind erfϊndungsgemäße Verbindungen der allgemeinen Formel (I), - -Compounds of the general formula (I) according to the invention are preferred, - -
in welcherin which
R1 und R2 gemeinsam für Reste der FormelnR 1 and R 2 together for residues of the formulas
die gegebenenfalls bis zu 3 -fach durch Hydroxy substituiert sind, which are optionally substituted up to 3 times by hydroxy,
R3 für Wasserstoff oder für (C2-C5)-Alkenyl stehtR 3 represents hydrogen or (C 2 -C 5 ) alkenyl
undand
R4 für einen Rest der Formel -CH2-R5 steht,R 4 represents a radical of the formula -CH 2 -R 5 ,
worinwherein
R5 Phenyl, Naphthyl oder über den Heterocyclus gebundenes Benzothiophen bedeutet, wobei die Ringsysteme gegebenenfalls ein- bis mehrfach, gleich oder verschieden durch Fluor, Chlor, Brom oder (C,-C4)-Alkyl substituiert sind,R 5 denotes phenyl, naphthyl or benzothiophene bonded via the heterocycle, the ring systems optionally being substituted one to more times, identically or differently, by fluorine, chlorine, bromine or (C 1 -C 4 ) -alkyl,
oderor
R3 für (C2-C5)-Alkenyl stehtR 3 represents (C 2 -C 5 ) alkenyl
undand
R4 für Wasserstoff stehtR 4 represents hydrogen
und deren pharmazeutisch verträgliche Salze. Besonders bevorzugt sind erfindungsgemäße Verbindungen der allgemeinen Formel (I),and their pharmaceutically acceptable salts. Compounds of the general formula (I) according to the invention are particularly preferred
in welcherin which
R1 und R2 gemeinsam für Reste der FormelnR 1 and R 2 together for residues of the formulas
(7 / / oder stehen, die gegebenenfalls bis zu 2-fach durch Hydroxy substituiert sind,(7 / / or stand, which are optionally substituted up to 2 times by hydroxy,
R3 für Wasserstoff oder für (C3-C5)-Alkenyl stehtR 3 represents hydrogen or (C 3 -C 5 ) alkenyl
undand
R4 für einen Rest der Formel -CH2-R5 steht,R 4 represents a radical of the formula -CH 2 -R 5 ,
worinwherein
R5 Phenyl, Naphthyl oder über den Heterocyclus gebundenes Benzothiophen bedeutet, wobei die Ringsysteme gegebenenfalls ein- bis zweifach, gleich oder verschieden durch Fluor, Chlor, Brom oder (C,-R 5 is phenyl, naphthyl or benzothiophene bonded via the heterocycle, the ring systems optionally being one to two times, identical or different, by fluorine, chlorine, bromine or (C, -
C3)-Alkyl substituiert sind,C 3 ) alkyl are substituted,
oderor
R3 für (C3-C5)-Alkenyl stehtR 3 represents (C 3 -C 5 ) alkenyl
undand
R4 für Wasserstoff steht -R 4 represents hydrogen -
und deren Salze.and their salts.
Ganz besonders bevorzugt sind erfindungsgemäße Verbindungen mit folgender Struktur:Compounds according to the invention having the following structure are very particularly preferred:
Struktur:Structure:
Die erfindungsgemäßen Verbindungen der allgemeinen Formel (I) können hergestellt werden, indem manThe compounds of the general formula (I) according to the invention can be prepared by:
[A] Verbindungen der allgemeinen Formel (II), -[A] compounds of the general formula (II), -
in welcher in which
R und R die oben angegebene Bedeutung haben,R and R have the meaning given above,
mit Verbindungen der allgemeinen Formel (III)with compounds of the general formula (III)
R4-A (III)R 4 -A (III)
in welcherin which
R4 die oben angegebene Bedeutung hatR 4 has the meaning given above
undand
A für Halogen, vorzugsweise Brom steht,A represents halogen, preferably bromine,
in inerten Lösemitteln und in Anwesenheit einer Base zu den Verbindungen der allgemeinen Formel (Ia)in inert solvents and in the presence of a base to give the compounds of the general formula (Ia)
in welcher in which
R , R und R die oben angegebene Bedeutung haben, - -R, R and R have the meaning given above, - -
umsetzt,implements
und im Fall, daß R3 nicht Wasserstoff bedeutet, die Verbindungen der allgemeinen Formel (Ia) mit Verbindungen der allgemeinen Formel (IV)and in the event that R 3 is not hydrogen, the compounds of the general formula (Ia) with compounds of the general formula (IV)
R3 -D (IV)R 3 -D (IV)
in welcherin which
R3 die oben angegebene Bedeutung von R3 hat, aber nicht für Wasserstoff steht,R 3 has the meaning of R 3 given above, but does not represent hydrogen,
D für Halogen, vorzugsweise Brom steht,D represents halogen, preferably bromine,
in inerten Lösemitteln und in Anwesenheit einer Base umsetzt,reacted in inert solvents and in the presence of a base,
oderor
[B] zunächst Verbindungen der allgemeinen Formel (II) mit Verbindungen der allgemeinen Formel (IV) wie unter [A] beschrieben zu den Verbindungen der allgemeinen Formel (Ib)[B] firstly compounds of the general formula (II) with compounds of the general formula (IV) as described under [A] to give the compounds of the general formula (Ib)
in welcher in which
R , R und R die oben angegebene Bedeutung haben,R, R and R have the meaning given above,
und in einem zweiten Schritt mit Verbindungen der allgemeinen Formel (III) umsetzt. - -and reacted in a second step with compounds of the general formula (III). - -
Die erfindungsgemäßen Verfahren können durch folgendes Formelschema beispielhaft erläutert werden:The methods according to the invention can be illustrated by the following formula scheme:
[B][B]
Als Lösemittel eignen sich alle inerten Lösemittel, die sich unter den Reaktionsbe- dingungen nicht verändern. Hierzu gehören bevorzugt Ether wie Diethylether,Suitable solvents are all inert solvents that do not change under the reaction conditions. These preferably include ethers such as diethyl ether,
Dioxan, Tetrahydrofuran, Glykoldimethylether oder Diethylenglykoldimethylether. Besonders bevorzugt ist Tetrahydrofuran.Dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether. Tetrahydrofuran is particularly preferred.
Als Basen eignen sich die üblichen anorganischen oder organischen Basen. Hierzu gehören bevorzugt Alkalihydroxide wie beispielsweise Natrium- oder Kaliumhydroxid, oder Alkalicarbonate wie Natrium- oder Kaliumcarbonat, oder Natriumoder Kaliummethanolat, oder Natrium- oder Kaliumethanolat oder Kalium- tert.butylat, oder Amide wie Natriumamid, Lithium-bis-(trimethylsilyl)amid, Lithiumdiisopropylamid, oder metallorganische Verbindungen wie Butyllithium oder Phenyllithium. Bevorzugt sind Lithiumdiisopropylamid und Lithium-bis-(trimethyl- silyl)amid. Die Base wird in hierbei in einer Menge von 1 bis 5, bevorzugt von 1 bis 2 Mol, bezogen auf 1 Mol der Verbindungen der allgemeinen Formeln (III) und (IV) eingesetzt.The usual inorganic or organic bases are suitable as bases. These preferably include alkali metal hydroxides such as sodium or potassium hydroxide, or alkali metal carbonates such as sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethanolate or potassium tert-butoxide, or amides such as sodium amide, lithium bis (trimethylsilyl) amide, lithium diisopropylamide , or organometallic compounds such as butyllithium or phenyllithium. Lithium diisopropylamide and lithium bis (trimethylsilyl) amide are preferred. The base is used in an amount of 1 to 5, preferably 1 to 2, mol, based on 1 mol of the compounds of the general formulas (III) and (IV).
Die Reaktion erfolgt im allgemeinen in einem Temperaturbereich von -78°C bis zuThe reaction generally takes place in a temperature range from -78 ° C to
Rückflußtemperatur, bevorzugt von -78°C bis +20°C.Reflux temperature, preferably from -78 ° C to + 20 ° C.
Die Umsetzung kann bei normalem, erhöhtem oder bei erniedrigtem Druck durchgeführt werden (z.B. von 0,5 bis 5 bar). Im allgemeinen arbeitet man bei Normaldruck.The reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.
Die erfindungsgemäßen Verbindungen der allgemeinen Formel (I) eignen sich zur Verwendung als Medikamente in der Behandlung von Menschen und Tieren.The compounds of the general formula (I) according to the invention are suitable for use as medicaments in the treatment of humans and animals.
Die erfindungsgemäßen Verbindungen der allgemeinen Formel (I) eignen sich zur Modulation von metabotropen Glutamatrezeptoren und beeinflussen daher das glutamaterge Neurotransmittersystem.The compounds of the general formula (I) according to the invention are suitable for modulating metabotropic glutamate receptors and therefore influence the glutamatergic neurotransmitter system.
Ein Modulator des metabotropen Glutamatrezeptors im Sinne der Erfindung ist ein Agonist oder Antagonist dieses Rezeptors.A modulator of the metabotropic glutamate receptor in the sense of the invention is an agonist or antagonist of this receptor.
Die erfindungsgemäßen Verbindungen sind besonders als Modulatoren des metabotropen Glutamatrezeptors vom Subtyp 1 geeignet, ganz besonders als Antagonisten dieses Rezeptorsubtyps.The compounds according to the invention are particularly suitable as modulators of the metabotropic glutamate receptor of subtype 1, very particularly as antagonists of this receptor subtype.
Die erfindungsgemäßen Verbindungen können aufgrund ihrer pharmakologischenThe compounds of the invention can be based on their pharmacological
Eigenschaften allein oder in Kombination mit anderen Arzneimitteln zur Behandlung und/oder Prävention von neuronalen Schädigungen oder Erkrankungen, die mit einer Entgleisung der physiologischen oder bei pathophysiologischen Zustände des glutamatergen Systems im zentralen und peripheren Nervensystem in Verbindung gebracht werden, eingesetzt werden. Zur Behandlung und/oder Prävention von neuronalen Schädigungen beispielsweise verursacht durch ischämischen, thromb- und/oder thrombemolischen, und hämorrha- gischen Schlaganfall, Zuständen nach direkten und indirekten Verletzungen im Bereich des Gehirnes und des Schädels. Ferner zur Behandlung und/oder Prävention von cere- bralen Ischämien nach sämtlichen operativen Eingriffen am Gehirn oder peripherenProperties alone or in combination with other drugs for the treatment and / or prevention of neuronal damage or diseases that are associated with derailment of the physiological or pathophysiological conditions of the glutamatergic system in the central and peripheral nervous system. For the treatment and / or prevention of neuronal damage caused, for example, by ischemic, thrombic and / or thrombemolic and hemorrhagic stroke, conditions after direct and indirect injuries in the area of the brain and skull. Also for the treatment and / or prevention of cerebral ischemia after all surgical interventions on the brain or peripheral
Organen bzw. Körperteilen und damit einhergehenden oder vorausgehenden Zuständen krankhafter bzw. allergischer Natur, die primär und/oder sekundär zu einer neuronalen Schädigung fuhren können.Organs or parts of the body and associated or previous conditions of a pathological or allergic nature, which can primarily and / or secondarily lead to neuronal damage.
Gleichfalls eignen sich die erfindungsgemäßen Verbindungen auch zur Therapie von primären und/oder sekundären krankhaften Zuständen des Gehirnes, beispielsweise während oder nach cerebralen Vasospasmen, Hypoxie und/oder Anoxie nicht vorher genannter Genese, perinataler Asphyxie, Autoimmunerkrankungen, Stoffwechsel- und Organerkrankungen, die mit einer Schädigung des Gehirnes einhergehen können sowie Schädigungen des Gehirnes infolge primärer Gehirnerkrankungen beispielsweiseLikewise, the compounds according to the invention are also suitable for the therapy of primary and / or secondary pathological conditions in the brain, for example during or after cerebral vasospasm, hypoxia and / or anoxia of a genesis not mentioned above, perinatal asphyxia, autoimmune diseases, metabolic and organ diseases associated with Damage to the brain can go hand in hand as well as damage to the brain due to primary brain diseases, for example
Krampfleiden und artero- und/oder arteriosklerotischer Veränderungen. Zur Behandlung chronischer oder psychiatrischer Leiden wie beispielsweise Depression, neuro- degenerativer Erkrankungen wie beispielsweise Alzheimersche, Parkinsonsche oder Huntingtonsche Erkrankung, Multiple Sklerose, amyotrophische laterale Sklerose, Neurodegeneration durch akute und/oder chronische virale oder bakterielle Infektionen und Multiinfarktdemenz.Seizures and atherosclerotic and / or atherosclerotic changes. For the treatment of chronic or psychiatric conditions such as depression, neurodegenerative diseases such as Alzheimer's, Parkinson's or Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, neurodegeneration due to acute and / or chronic viral or bacterial infections and multi-infarct dementia.
Darüberhinaus können sie als Arzneimittel eingesetzt werden zur Prävention und/oder Behandlung von Demenzen unterschiedlichen Ursprungs, Hirnleistungs- Störungen im Alter, Gedächtnisstörungen, Rückenmarksverletzungen, Schmerzzuständen, Angstzuständen unterschiedlichen Ursprungs, medikamentös bedingtem Parkinson-Syndrom, Psychosen (wie zum Beispiel Schizophrenie), Hirnödem, neuronalen Schädigungen nach Hypoglykämie, Emesis, Übelkeit, Fettsucht, Suchterkrankungen und Entzugserscheiningen, ZNS-vermittelte Krämpfe, Sedation sowie Bewegungsstörungen. Außerdem können die Verbindungen verwendet werden zur Förderung der neuronalen Regeneration in der post-akuten Phase cerebraler Verletzungen oder chronischer Erkrankungen des Nervensystems.In addition, they can be used as medicines for the prevention and / or treatment of dementias of different origins, brain disorders in old age, memory disorders, spinal cord injuries, painful conditions, anxiety states of different origins, drug-related Parkinson's syndrome, psychoses (such as schizophrenia), cerebral edema, neuronal damage after hypoglycemia, vomiting, nausea, obesity, addiction and withdrawal symptoms, CNS-mediated cramps, sedation and movement disorders. The compounds can also be used to promote neuronal regeneration in the post-acute phase of cerebral injuries or chronic diseases of the nervous system.
Bevorzugt werden sie als Arzneimittel eingesetzt zur Prävention und/oder Behandlung von cerebralen Ischämien, Schädel-/Hirntrauma, Schmerzzuständen oder ZNS- vermittelten Krämpfen (wie z.B. Epilepsie).They are preferably used as medicinal products for the prevention and / or treatment of cerebral ischaemia, skull / brain trauma, pain or CNS-mediated cramps (such as epilepsy).
Die Modulation von Substanzen am metabotropen Glutamatrezeptor (direkte oder in- direkte Beeinflussung der Kopplungseffizienz des Glutamat-Rezeptors an G-Pro- teinen) kann an primären Körnerzellkulturen aus dem Kleinhirn überprüft werden. Elektrophysiologische Messungen an diesen Zellkulturen im „cell attached"-Modus zeigen, daß L-Typ-Ca2+-Kanäle in dieser Präparation durch mGluRl Glutamat- Rezeptoren aktiviert werden (J. Neurosci. 1995, 15, 135), wohingegen sie durch Gruppe II Rezeptoren blockiert werden (J. Neurosci. 1994, 14, 7067). Durch entsprechende experimentelle Anordnung kann die modulatorische Wirkung von pharmakologischen Prüfsubstanzen an Glutamatrezeptoren kontrolliert werden. Eine detaillierte Überprüfung der Subtypspezifität unter kontrollierten Bedingungen kann an Xenopus-Oocyten durch Injektion der entsprechenden mGluR-Subtyp-DNA erfolgen (WO 92/10583).The modulation of substances on the metabotropic glutamate receptor (direct or indirect influence on the coupling efficiency of the glutamate receptor on G proteins) can be checked on primary cerebellar cell cultures from the cerebellum. Electrophysiological measurements on these cell cultures in the "cell attached" mode show that L-type Ca 2+ channels in this preparation are activated by mGluRl glutamate receptors (J. Neurosci. 1995, 15, 135), whereas they by group II receptors can be blocked (J. Neurosci. 1994, 14, 7067). The experimental arrangement can be used to control the modulatory effect of pharmacological test substances on glutamate receptors Subtype DNA take place (WO 92/10583).
Mit den folgenden Testmodellen kann die antiischämische Wirksamkeit der Verbindungen in vivo belegt werden.The following test models can be used to demonstrate the anti-ischemic activity of the compounds in vivo.
Permanente focale cerebrale Ischämie bei der Ratte (MCA-O)Permanent focal cerebral ischemia in the rat (MCA-O)
Unter Isofluran Anästhesie wird die Arteria cerebri media einseitig freipräpariert mittels Elektrokoagulation diese und deren Nebenäste irreversibel verschlosssen. Als Folge des Eingriffs entsteht ein cerebraler Infarkt. Während der Operation wird die Körpertemperatur des Tieres auf 37°C gehalten. Nach Wundverschluß und Abklingen der Narkose werden die Tiere wieder in ihren Käfig entlassen. Die Substanz- applikation erfolgt nach unterschiedlichen zeitlichen Schemata und über unterschiedliche Applikationswege (i.v. i.p.) nach der Okklusion. Die Infarktgröße wird nach 7 Tagen bestimmt. Dazu wird das Gehirn entnommen, histologisch aufgearbeitet und mit Hilfe eines computergestützten Auswertsystemes das Infarkt- volumen bestimmt.Under isoflurane anesthesia, the cerebral artery is unilaterally dissected using electrocoagulation and this and its secondary branches are irreversibly closed. As a result of the procedure, a cerebral infarction develops. During the operation, the animal's body temperature is kept at 37 ° C. After the wound has closed and the anesthetic has subsided, the animals are released back into their cages. The substance- Application takes place according to different time schedules and via different application routes (ivip) after the occlusion. The infarct size is determined after 7 days. For this purpose, the brain is removed, histologically processed and the infarct volume determined using a computer-aided evaluation system.
Subdurales Hämaton bei der Ratte (SDH)Subdural Hematoma in the Rat (SDH)
Unter Anästhesie wird den Tieren einseitig subdural Eigenblut injiziert. Unter dem Hämatom bildet sich ein Infarkt. Die Substanzapplikation erfolgt nach unterschiedlichen zeitlichen Schemata und über unterschiedliche Applikationswege (i.v. i.p.). Die Bestimmung der Infarktgröße erfolgt wie beim Modell der Permanenten focalen Ischämie bei der Ratte (MCA-O) beschrieben.The animals are injected with subdural autologous blood under anesthesia. An infarction forms under the hematoma. The substance is administered according to different time schedules and via different application routes (i.v. i.p.). The infarct size is determined as described in the model of permanent focal ischemia in the rat (MCA-O).
Auf antiepileptische Wirkung kann nach der in NeuroReport 1996, 7, 1469-1474 beschriebenen Methode getestet werden.The anti-epileptic effect can be tested according to the method described in NeuroReport 1996, 7, 1469-1474.
Die Eignung der erfindungsgemäßen Verbindungen zur Behandlung von Schizophrenie kann nach den in Science 1998, 281, 1349-1352 und Eur. J. Pharmacol. 1996, 316, 129-136 beschriebenen Methoden bestimmt werden.The suitability of the compounds according to the invention for the treatment of schizophrenia can be determined according to the methods described in Science 1998, 281, 1349-1352 and Eur. J. Pharmacol. 1996, 316, 129-136 methods can be determined.
Zur vorliegenden Erfindung gehören auch pharmazeutische Zubereitungen, die neben inerten, nicht-toxischen, pharmazeutisch geeigneten Hilfs- und Trägerstoffen eine oder mehrere Verbindungen der allgemeinen Formeln (I), (Ia) und (Ib) enthalten, oder die aus einem oder mehreren Wirkstoffen der Formeln (I), (Ia) und (Ib) bestehen, sowie Verfahren zur Herstellung dieser Zubereitungen.The present invention also includes pharmaceutical preparations which, in addition to inert, non-toxic, pharmaceutically suitable auxiliaries and excipients, contain one or more compounds of the general formulas (I), (Ia) and (Ib), or which consist of one or more active ingredients of the Formulas (I), (Ia) and (Ib) exist, and processes for the preparation of these preparations.
Die Wirkstoffe der Formeln (I), (Ia) und (Ib) sollen in diesen Zubereitungen in einer Konzentration von 0,1 bis 99,5 Gew.-%, bevorzugt von 0,5 bis 95 Gew.-% der Gesamtmischung vorhanden sein. - -The active compounds of the formulas (I), (Ia) and (Ib) should be present in these preparations in a concentration of 0.1 to 99.5% by weight, preferably 0.5 to 95% by weight, of the total mixture . - -
Neben den Wirkstoffen der Formeln (I), (Ia) und (Ib) können die pharmazeutischen Zubereitungen auch andere pharmazeutische Wirkstoffe enthalten.In addition to the active ingredients of the formulas (I), (Ia) and (Ib), the pharmaceutical preparations can also contain other active pharmaceutical ingredients.
Die oben aufgeführten pharmazeutischen Zubereitungen können in üblicher Weise nach bekannten Methoden hergestellt werden, beispielsweise mit dem oder den Hilfsoder Trägerstoffen.The pharmaceutical preparations listed above can be prepared in a customary manner by known methods, for example using the excipient or excipients.
Im allgemeinen hat es sich als vorteilhaft erwiesen, den oder die Wirkstoffe der Formeln (I), (Ia) und (Ib) in Gesamtmengen von etwa 0,01 bis etwa 100 mg/kg, bevorzugt in Gesamtmengen von etwa 1 mg/kg bis 50 mg/kg Körpergewicht je 24In general, it has proven to be advantageous to use the active compound or formulas (I), (Ia) and (Ib) in total amounts from about 0.01 to about 100 mg / kg, preferably in total amounts from about 1 mg / kg to 50 mg / kg body weight per 24
Stunden, gegebenenfalls in Form mehrerer Einzelgaben, zur Erzielung des gewünschten Ergebnisses zu verabreichen.Hours, if necessary in the form of several single doses, to achieve the desired result.
Es kann aber gegebenenfalls vorteilhaft sein, von den genannten Mengen abzu- weichen, und zwar in Abhängigkeit von der Art und vom Körpergewicht des behandelten Objekts, vom individuellen Verhalten gegenüber dem Medikament, der Art und Schwere der Erkrankung, der Art der Zubereitung und Applikation, sowie dem Zeitpunkt bzw. Intervall, zu welchem die Verabreichung erfolgt. However, it may be advantageous to deviate from the amounts mentioned, depending on the type and body weight of the object being treated, on the individual behavior towards the medication, the type and severity of the disease, the type of preparation and application, and the time or interval at which the administration takes place.
AllgemeinesGeneral
Laufmittel zur ChromatographieChromatography solvent
I Dichlormethan / MethanolI dichloromethane / methanol
II Dichlormethan / EthanolII dichloromethane / ethanol
III Cyclohexan / EthylacetatIII cyclohexane / ethyl acetate
IV Cyclohexan / DichlormethanIV cyclohexane / dichloromethane
V Butylacetat (200), Butanol (26), Essigsäure (100), Phosphat-Puffer pH = 6 (60)V butyl acetate (200), butanol (26), acetic acid (100), phosphate buffer pH = 6 (60)
Abkürzung ;enAbbreviation; en
DME 1 ,2-DimethoxyethanDME 1,2-dimethoxyethane
HMPA HexamethylphosphorsäuretriamidHMPA hexamethylphosphoric triamide
LiHMDS LithiumbistrimethylsilylamidLiHMDS lithium bistrimethylsilylamide
LDA LithiumdiisopropylamidLDA lithium diisopropylamide
MTBE Methy 1-tert. buty letherMTBE methy 1-tert. buty lether
THF Tetrahydrofuran THF tetrahydrofuran
- -- -
AusgangsverbindungenOutput connections
Beispiel IAExample IA
Hexahydro-benzofuran-2-onHexahydro-benzofuran-2-one
7X77X7
2-Oxocyclohexylessigsäure (31.2 g, 200 mmol) wird in 125 ml 0.2 N Natronlauge gelöst und bei Raumtemperatur tropfenweise zu einer Lösung aus Natriumborhydrid2-Oxocyclohexylacetic acid (31.2 g, 200 mmol) is dissolved in 125 ml of 0.2 N sodium hydroxide solution and added dropwise at room temperature to a solution of sodium borohydride
(18.9 g, 500 mmol) in 150 ml 0.2 N Natronlauge gegeben. Nach 20 h Rühren wird die Mischung auf 0 °C abgekühlt und vorsichtig mit 6 N HCl angesäuert. Die stark saure Lösung wird danach 30 min auf 100 °C erhitzt und dann über Nacht gerührt. Anschließend wird die erkaltete Mischung mit MTBE extrahiert und die vereinigten Etherphasen mit 5%iger Natriumcarbonatlösung und ges. NaCl-Lösung gewaschen, über Magnesiumsulfat getrocknet, filtriert und eingedampft. Die Reinigung erfolgt durch Destillation (Sdp.: 75 °C/0.01 mm). Ausbeute: 22.9 g (81.7 %). MS (CI): m/z = 141 [M + H+] (18.9 g, 500 mmol) in 150 ml of 0.2 N sodium hydroxide solution. After stirring for 20 h, the mixture is cooled to 0 ° C. and carefully acidified with 6 N HCl. The strongly acidic solution is then heated to 100 ° C. for 30 minutes and then stirred overnight. The cooled mixture is then extracted with MTBE and the combined ether phases with 5% sodium carbonate solution and sat. Washed NaCl solution, dried over magnesium sulfate, filtered and evaporated. The purification is carried out by distillation (bp .: 75 ° C / 0.01 mm). Yield: 22.9 g (81.7%). MS (CI): m / z = 141 [M + H +]
- -- -
HerstellungsbeispieleManufacturing examples
Beispiele 1, 2 und 3Examples 1, 2 and 3
3-(Naphth-2-ylmethyl)-hexahydro-cyclopenta[b]furan-2-on3- (Naphth-2-ylmethyl) hexahydro-cyclopenta [b] furan-2-one
Zu einer auf -78 °C gekühlten Lösung von 1 g (7.9 mmol) Hexahydro-cyclo- penta[b]furan-2-on in 20 ml THF tropft man unter Argon 8.7 ml einer 1 molaren Lösung von Lithium-bis-(trimethylsilyl)-amid in THF so zu, daß die Temp. des Gemisches -65°C nicht überschreitet. Nach beendeter Zugabe rührt man noch 10 min bei -78 °C und fügt dann auf einmal 1.93 g (8.7 mmol) Naphth-2-ylmethylbromid hinzu. Unmittelbar danach wird das Kühlbad entfernt und man läßt das Gemisch auf Raumtemp. erwärmen. Nach 16 h Rühren bei Raumtemp. nimmt man das Gemisch mit Wasser/Diethylether auf und extrahiert die wäßrige Phase noch zweimal mit Diethylether. Die vereinigten organischen Phasen werden über Natriumsulfat getrocknet und anschließend eingeengt. Der Rückstand wird über Kieselgel (Eluent: Dichlormethan) chromatographiert; Ausbeute: 1.2 g, farbloses Öl, Diastereomerengemisch: 87:13 (Beispiel 1)8.7 ml of a 1 molar solution of lithium bis- (trimethylsilyl) are added dropwise under argon to a solution of 1 g (7.9 mmol) of hexahydro-cyclopenta [b] furan-2-one cooled to -78 ° C. in 20 ml of THF ) -amide in THF so that the temperature of the mixture does not exceed -65 ° C. When the addition is complete, the mixture is stirred for a further 10 min at -78 ° C. and then 1.93 g (8.7 mmol) of naphth-2-ylmethylbromide are added all at once. Immediately afterwards the cooling bath is removed and the mixture is left to room temperature. heat. After 16 h stirring at room temp. the mixture is taken up in water / diethyl ether and the aqueous phase is extracted twice more with diethyl ether. The combined organic phases are dried over sodium sulfate and then concentrated. The residue is chromatographed on silica gel (eluent: dichloromethane); Yield: 1.2 g, colorless oil, mixture of diastereomers: 87:13 (Example 1)
'H-NMR (200 MHz; [d6]-DMSO): δ[ppm]= 1.2-1.9 (br m,7H), 2.6 (m,lH), 2.87 (dd,'H NMR (200 MHz; [d 6 ] -DMSO): δ [ppm] = 1.2-1.9 (br m, 7H), 2.6 (m, lH), 2.87 (dd,
1H); 2.93 (dd,lH), 4.72/4.75 (m;lH), 7.48-7.55 (m;3H), 7.76 (s;lH), 7.81-7.951H); 2.93 (dd, lH), 4.72 / 4.75 (m; lH), 7.48-7.55 (m; 3H), 7.76 (s; lH), 7.81-7.95
(m;3H).(m; 3H).
Die Trennung der Diastereomeren und Enantiomeren erfolgt mit präparativer HPLC (Rainin Cl 8, Acetonitril/H2O 55:45).The diastereomers and enantiomers are separated using preparative HPLC (Rainin Cl 8, acetonitrile / H 2 O 55:45).
Beispiel 2 (Fraktion 1, Diastereomer A) und Beispiel 3 (Fraktion 2, Diasteromer B). - -Example 2 (fraction 1, diastereomer A) and example 3 (fraction 2, diasteromer B). - -
Beispiel 4Example 4
(3R*,3aR*,6aS*)-3-Allyl-3-(naphth-2-ylmethyl)-hexahydrocyclopenta[b]furan-2-on(3R *, 3aR *, 6aS *) - 3-allyl-3- (naphth-2-ylmethyl) hexahydrocyclopenta [b] furan-2-one
Zu einer auf -78 °C gekühlten Lösung von 0.5 g (1.88 mmol) der Verbindung aus Beispiel 1 in 20 ml THF tropft man unter Argon 1.9 ml einer 1 molaren Lösung von Lithium-bis-(trimethylsilyl)-amid in THF so zu, daß die Temp. des Gemisches -65°C nicht überschreitet. Nach beendeter Zugabe rührt man noch 10 min bei -78 °C und fügt dann auf einmal 0.26 g (2.25 mmol) Allylbromid hinzu. Unmittelbar danach wird das Kühlbad entfernt und man läßt das Gemisch auf Raumtemp. erwärmen. Nach 16 h Rühren bei Raumtemp. nimmt man das Gemisch mit Ammoniumchloridlösung und Essigester auf und extrahiert die wäßrige Phase noch zweimal mit Essigester. Die vereinigten organischen Phasen werden über Natriumsulfat getrocknet und anschließend eingeengt. Der Rückstand wurde über Kieselgel (Eluent: Dichlormethan) chromatographiert. Ausbeute: 255 mg (44%) eines farblosen Öls. 'H-NMR (200 MHz; CDC13) δ[ppm]= 1.55-2.2 (br m,6H), 2.3 (m, 2H), 2.61 (m,lH), 3.12 (d,lH), 3.3 (d,lH), 4.91 (m,lH), 5.05 (dd,lH), 5.11 (dd, 1H), 5.8 (ddt,lH), 7.35-1.9 ml of a 1 molar solution of lithium bis (trimethylsilyl) amide in THF are added dropwise to a solution of 0.5 g (1.88 mmol) of the compound from Example 1 in 20 ml of THF which is cooled to -78 ° C. that the temperature of the mixture does not exceed -65 ° C. When the addition is complete, the mixture is stirred at -78 ° C. for a further 10 min and then 0.26 g (2.25 mmol) of allyl bromide is added all at once. Immediately afterwards the cooling bath is removed and the mixture is left to room temperature. heat. After 16 h stirring at room temp. the mixture is taken up with ammonium chloride solution and ethyl acetate and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and then concentrated. The residue was chromatographed on silica gel (eluent: dichloromethane). Yield: 255 mg (44%) of a colorless oil. 'H NMR (200 MHz; CDC1 3 ) δ [ppm] = 1.55-2.2 (br m, 6H), 2.3 (m, 2H), 2.61 (m, lH), 3.12 (d, lH), 3.3 (d , lH), 4.91 (m, lH), 5.05 (dd, lH), 5.11 (dd, 1H), 5.8 (ddt, lH), 7.35-
7.5 (br m,3H), 7.72 (s,lH), 7.80 (m,3H). Diastereomerenreinheit: >99% de (HPLC). Beispiel 57.5 (br m, 3H), 7.72 (s, lH), 7.80 (m, 3H). Diastereomeric purity:> 99% de (HPLC). Example 5
3-Allyl-hexahydro-cycloρenta[b]furan-2-on3-allyl-hexahydro-cycloρenta [b] furan-2-one
In Analogie zur Vorschrift des Beispiels 1 wurde aus 1.2 g (9.5 mmol) Hexahydro- cyclopenta[b]furan-2-on, 10 ml 1 molarer Lithium-bis-(trimethylsilyl)-amid-Lösung in THF und 1.29 g (9.5 mmol) Allylbromid in 20 ml THF wird die Titelverbindung hergestellt.In analogy to the procedure of Example 1, 1.2 g (9.5 mmol) of hexahydrocyclopenta [b] furan-2-one, 10 ml of 1 molar lithium bis (trimethylsilyl) amide solution in THF and 1.29 g (9.5 mmol ) Allyl bromide in 20 ml THF, the title compound is prepared.
Ausbeute: 1.25 g (79%) eines farblosen Öls.Yield: 1.25 g (79%) of a colorless oil.
'H-NMR(200 MHZ; [d6]-DMSO): δ[ppm]: 1.47-1.89 (br m,6H), 2.15-2.55'H NMR (200 MHz; [d 6 ] -DMSO): δ [ppm]: 1.47-1.89 (br m, 6H), 2.15-2.55
(br m,4H), 4.41 (m,lH), 5.12 (dd,lH), 5.18 (dd,lH), 5.76 (ddt,lH)(br m, 4H), 4.41 (m, lH), 5.12 (dd, lH), 5.18 (dd, lH), 5.76 (ddt, lH)
Beispiel 6Example 6
(3S*,3aR*,6aS*)-3-Allyl-3-(naphth-2-ylmethyl)hexahydro-cyclopenta[b]furan-2-on(3S *, 3aR *, 6aS *) - 3-allyl-3- (naphth-2-ylmethyl) hexahydro-cyclopenta [b] furan-2-one
In Analogie zur Vorschrift des Beispiels 4 wird die Titelverbindung aus 0.55 g (3.3 mmol) der Verbindung aus Beispiel 3, 4 ml 1 molarer Lithium-bis-(trimethylsilyl)- amid-Lösung in THF und 0.73 g (3.3 mmol) 2-(Brommethyl)-naphthalin in 15 ml THF hergestellt. Ausbeute: 823 mg (81.2%) eines farblosen Öls. - - In analogy to the procedure of Example 4, the title compound is made from 0.55 g (3.3 mmol) of the compound from Example 3, 4 ml of 1 molar lithium bis (trimethylsilyl) amide solution in THF and 0.73 g (3.3 mmol) of 2- ( Bromomethyl) -naphthalene prepared in 15 ml THF. Yield: 823 mg (81.2%) of a colorless oil. - -
'H-NMR (200 MHz; CDC13): δ[ppm]: 1.4-1.85 (br m,6H), 2.47 (ddt,lH), 2.61 (br m,2H), 3.01 (d,lH), 3.11 (d,lH), 3.62 (m,lH), 5.25 (dd,lH), 5.29 (dd,lH), 5.96 (ddt,lH), 7.33 (dd,lH), 7.48 (m,2H), 7.67 (s,lH), 7.73-7.86 (br m,3H) Diastereomerenreinheit: >99% de (HPLC)'H NMR (200 MHz; CDC1 3 ): δ [ppm]: 1.4-1.85 (br m, 6H), 2.47 (ddt, lH), 2.61 (br m, 2H), 3.01 (d, lH), 3.11 (d, lH), 3.62 (m, lH), 5.25 (dd, lH), 5.29 (dd, lH), 5.96 (ddt, lH), 7.33 (dd, lH), 7.48 (m, 2H), 7.67 ( s, lH), 7.73-7.86 (br m, 3H) Diastereomeric purity:> 99% de (HPLC)
Beispiele 7, 8, 9, 10 und 11:Examples 7, 8, 9, 10 and 11:
3-(Naphth-2-ylmethyl)- 3,3a,6,6a-tetrahydro-cyclopenta[b]furan-2-on3- (Naphth-2-ylmethyl) - 3,3a, 6,6a-tetrahydro-cyclopenta [b] furan-2-one
In Analogie zur Vorschrift des Beispiels 1 wurde die Titelverbindung aus 7.4 g (59.6 mmol) 3,3a,6,6a-Tetrahydro-cyclopenta[b]füran-2-on, 60 ml einer 1 molarenIn analogy to the procedure of Example 1, the title compound was made from 7.4 g (59.6 mmol) of 3,3a, 6,6a-tetrahydro-cyclopenta [b] füran-2-one, 60 ml of a 1 molar
Lithium-bis-(trimethylsilyl)-amid-Lösung in THF und 13.2 g (59.7 mmol) 2-Lithium bis (trimethylsilyl) amide solution in THF and 13.2 g (59.7 mmol) 2-
(Brommethyl)-naphfhalin in 180 ml THF hergestellt. Die chromatographischer Reinigung erfolgt mit einem Gemisch aus Dichlormethan und Petrolether (40-60) im(Bromomethyl) -naphfhalin made in 180 ml THF. The chromatographic purification is carried out with a mixture of dichloromethane and petroleum ether (40-60) in
Verhältnis 100:4.Ratio 100: 4.
Ausbeute: 10.6 g (67.3%), blaßgelbes Öl, Diastereomerengemisch: 2.5:1 (BeispielYield: 10.6 g (67.3%), pale yellow oil, mixture of diastereomers: 2.5: 1 (example
7).7).
MS (ESI)[m/z]: 287 [M+Na+]MS (ESI) [m / z]: 287 [M + Na + ]
Die Trennung in die Diastereomeren und Enantiomeren erfolgt mit präparativer HPLC (Daicel Chiralpak AD, Heptan/Ethanol 9:1): Man erhält die Beispiele 8, 9, 10 und 11.The separation into the diastereomers and enantiomers is carried out using preparative HPLC (Daicel Chiralpak AD, heptane / ethanol 9: 1): Examples 8, 9, 10 and 11 are obtained.
Beispiel 8 (Fraktion 1)Example 8 (Fraction 1)
Beispiel 9 (Fraktion 2) Beispiel 10 (Fraktion 3) Beispiel 11 (Fraktion 4) Die in der folgenden Tabelle 1 aufgeführten Verbindungen wurden in Analogie zu den Vorschriften der Beispiele 1 - 7 hergestellt.Example 9 (Fraction 2) Example 10 (Fraction 3) Example 11 (Fraction 4) The compounds listed in Table 1 below were prepared in analogy to the instructions of Examples 1-7.
Tabelle 1:Table 1:
Beispiel 19:Example 19:
(3R*,3aR*,6aS*)-3-Allyl-3-(naphth-2-ylmethyl)-3,3a,6,6a-tetrahydrocyclo- penta[b]furan-2-on(3R *, 3aR *, 6aS *) - 3-allyl-3- (naphth-2-ylmethyl) -3,3a, 6,6a-tetrahydrocyclopenta [b] furan-2-one
In Analogie zur Vorschrift des Beispiels 3 wurde die Titel Verbindung aus 0.79 g (3 mmol) der Verbindung aus Beispiel 7, 3 ml 1 molarer Lithium-bis-(trimethyl- silyl)-amid-Lösung in THF und 0.36 g (3 mmol) Allylbromid in 10 ml THF hergestellt. Die chromatographische Reinigung erfolgte mit einem Gemisch aus Dichlormethan und Petrolether (40-60) im Verhältnis 100:4. Ausbeute: 684 mg (74.8%) eines blaßgelben Öls; Diastereomerenreinheit: >99% de (HPLC).In analogy to the procedure of Example 3, the title compound was obtained from 0.79 g (3 mmol) of the compound from Example 7, 3 ml of 1 molar lithium bis (trimethylsilyl) amide solution in THF and 0.36 g (3 mmol) Allyl bromide made in 10 ml THF. The chromatographic purification was carried out with a mixture of dichloromethane and petroleum ether (40-60) in a ratio of 100: 4. Yield: 684 mg (74.8%) of a pale yellow oil; Diastereomeric purity:> 99% de (HPLC).
MS (DCI/NH3) [m/z]: 322 (100, M+NH4 +) - -MS (DCI / NH 3 ) [m / z]: 322 (100, M + NH 4 + ) - -
'H-NMR (200 MHz; CDC13): δ[ppm]= 2.24 (dd,lH); 2.37 (dd,lH), 2.72 (m,2H), 3.16 (d,lH), 3.28 (d,lH), 3.48(m,lH), 5.03 (dd,lH), 5.05 (m,lH), 5.12 (dd,lH), 5.78 (ddt,lH), 5.89 (m,lH), 6.04 (m,lH), 7.4-7.5 (br m,3H), 7.75 (s,lH), 7.8 (m,3H)'H NMR (200 MHz; CDC1 3 ): δ [ppm] = 2.24 (dd, 1H); 2.37 (dd, lH), 2.72 (m, 2H), 3.16 (d, lH), 3.28 (d, lH), 3.48 (m, lH), 5.03 (dd, lH), 5.05 (m, lH), 5.12 (dd, lH), 5.78 (ddt, lH), 5.89 (m, lH), 6.04 (m, lH), 7.4-7.5 (br m, 3H), 7.75 (s, lH), 7.8 (m, 3H)
Beispiel 20Example 20
(3R*,3aR*,6aS*)-3-Allyl-3-(naphth-2-ylmethyl)-3,3a,6,6a-tetrahydrocyclo- penta[b]furan-2-on(3R *, 3aR *, 6aS *) - 3-allyl-3- (naphth-2-ylmethyl) -3,3a, 6,6a-tetrahydrocyclopenta [b] furan-2-one
In Analogie zu der Vorschrift des Beispiels 3 wurde die Titelverbindung aus 0.42 g (2.56 mmol) der Verbindung aus Beispiel 12, 2.6 ml 1 molarer Lithium-bis-(tri- methylsilyl)-amid-Lösung in THF und 0.57 g (2.56 mmol) 2-Brommethylnaphthalin in 5 ml THF hergestellt. Die chromatographische Reinigung erfolgte mit einem Gemisch aus Dichlormethan und Petrolether (40-60) im Verhältnis 100:4. Ausbeute: 487 mg (62.6%) eines blaßgelben Öls. Diastereomerenreinheit: >99% de (HPLC). MS (DCI/NH3)[m/zJ: 322 (100, M+NH4 +)In analogy to the procedure of Example 3, the title compound was made from 0.42 g (2.56 mmol) of the compound from Example 12, 2.6 ml of 1 molar lithium bis (trimethylsilyl) amide solution in THF and 0.57 g (2.56 mmol) 2-Bromomethylnaphthalene made in 5 ml THF. The chromatographic purification was carried out with a mixture of dichloromethane and petroleum ether (40-60) in a ratio of 100: 4. Yield: 487 mg (62.6%) of a pale yellow oil. Diastereomeric purity:> 99% de (HPLC). MS (DCI / NH 3 ) [m / zJ: 322 (100, M + NH 4 + )
'H-NMR (200 MHz; CDC13): δ[ppm]= 2.42 (m,2H), 2.45 (dd,lH), 2.67 (dd,lH), 3.03 (d,lH), 3.15 (d,lH), 3.51(m,lH), 3.53 (m,H), 5.31 (dd, IH), 5.33 (dd,lH), 5.72 (m,H), 6.03 (ddt,H), 7.36 (dd,l), 7.48 (m,2H), 7.69 (s,lH), 7.75-7.88 (br m,3H)'H NMR (200 MHz; CDC1 3 ): δ [ppm] = 2.42 (m, 2H), 2.45 (dd, lH), 2.67 (dd, lH), 3.03 (d, lH), 3.15 (d, lH) ), 3.51 (m, lH), 3.53 (m, H), 5.31 (dd, IH), 5.33 (dd, lH), 5.72 (m, H), 6.03 (ddt, H), 7.36 (dd, l) , 7.48 (m, 2H), 7.69 (s, lH), 7.75-7.88 (br m, 3H)
Beispiele 21, 22, 23, 24 und 25Examples 21, 22, 23, 24 and 25
3-(Naphth-2-ylmethyl)-3,3a,4,6a-tetrahydro-cyclopenta[b]füran-2-on - -3- (Naphth-2-ylmethyl) -3,3a, 4,6a-tetrahydro-cyclopenta [b] for an-2-one - -
In Analogie zur Vorschrift des Beispiels 1 wurde die Titelverbindung aus 0.31 g (2.5 mmol) 3,3a,4,6a-Tetrahydro-cyclopenta[b]ftιran-2-on, 2.5 ml einer 1 molaren Lithium-bis-(trimethylsilyl)-amid-Lösung in THF und 0.55 g (2.5 mmol) 2-(Brom~ methyl)-naphthalin in 10 ml THF hergestellt. Ausbeute: 498 mg (75.4%) eines blaßgelben Öls (Beispiel 21). Diastereomerengemisch: 94:6 (HPLC) MS (EI): m/z = 264 [M+] Die Trennung in die Diastereomeren und Enantiomeren erfolgt mit präparativerIn analogy to the procedure of Example 1, the title compound was obtained from 0.31 g (2.5 mmol) of 3,3a, 4,6a-tetrahydro-cyclopenta [b] ftιran-2-one, 2.5 ml of a 1 molar lithium bis (trimethylsilyl) - amide solution in THF and 0.55 g (2.5 mmol) of 2- (bromomethyl) naphthalene in 10 ml of THF. Yield: 498 mg (75.4%) of a pale yellow oil (Example 21). Diastereomer mixture: 94: 6 (HPLC) MS (EI): m / z = 264 [M + ] The separation into the diastereomers and enantiomers takes place with preparative
HPLC: Beispiel 22, 23, 24 und 25.HPLC: Examples 22, 23, 24 and 25.
Beispiel 26Example 26
3-Allyl-3,3a,4,6a-tetrahydro-cyclopenta[b]furan-2-on3-allyl-3,3a, 4,6a-tetrahydro-cyclopenta [b] furan-2-one
In Analogie zu den Vorschriften des Beispiels 1 wurde die Titelverbindung aus 0.31 g (2.5 mmol) 3,3a,4,6a-Tetrahydro-cyclopenta[b]furan-2-on, 2.5 ml einer 1 molarenIn analogy to the instructions of Example 1, the title compound was made from 0.31 g (2.5 mmol) of 3,3a, 4,6a-tetrahydro-cyclopenta [b] furan-2-one, 2.5 ml of a 1 molar
Lithium-bis-(trimethylsilyl)-amid-Lösung in THF und 0.36 g (2.5 mmol) Allylbromid in 7 ml THF hergestellt. Ausbeute: 278 mg (67.8%) eines farblosen Öls. MS (DCI/NH3): m/z = 182 [M+NH4 +] - -Lithium bis (trimethylsilyl) amide solution in THF and 0.36 g (2.5 mmol) allyl bromide in 7 ml THF. Yield: 278 mg (67.8%) of a colorless oil. MS (DCI / NH 3 ): m / z = 182 [M + NH 4 + ] - -
Beispiel 27Example 27
(3R*,3aR*,6aS*)-3-Allyl-3-(naphth-2-ylmethyl)-3,3a,4,6a-tetrahydrocyclo- penta[b] furan-2-on(3R *, 3aR *, 6aS *) - 3-allyl-3- (naphth-2-ylmethyl) -3,3a, 4,6a-tetrahydrocyclopenta [b] furan-2-one
In Analogie zur Vorschrift des Beispiels 4 wurde die Titelverbindung aus 0.4 g (1.5 mmol) der Verbindung aus Beispiel 15, 1.5 ml 1 molarer Lithium-bis- (trimethylsilyl)-amid-Lösung in THF und 0.22 g (1.8 mmol) Allylbromid in 10 mlIn analogy to the procedure of Example 4, the title compound was made from 0.4 g (1.5 mmol) of the compound from Example 15, 1.5 ml of 1 molar lithium bis (trimethylsilyl) amide solution in THF and 0.22 g (1.8 mmol) of allyl bromide in 10 ml
THF hergestellt.THF manufactured.
Ausbeute: 198 mg (43.2%) eines blaßgelben Öls.Yield: 198 mg (43.2%) of a pale yellow oil.
Diastereomerenreinheit: 72 %de (HPLC).Diastereomeric purity: 72% de (HPLC).
MS (DCI/NH3): m/z = 322 [M+NH4 +] Η-NMR(200 MHZ; CDC13): δ[ppm]: 2.29 (dd;lH), 2.41 (dd;lH), 2.79 (m;2H), 2.85MS (DCI / NH 3 ): m / z = 322 [M + NH 4 + ] Η NMR (200 MHz; CDC1 3 ): δ [ppm]: 2.29 (dd; lH), 2.41 (dd; lH), 2.79 (m; 2H), 2.85
(m;lH), 3.14 (d;lH), 3.34(d;lH), 5.09 (dd; IH), 5.16 (dd;lH), 5.31 (m;lH), 5.82(m; lH), 3.14 (d; lH), 3.34 (d; lH), 5.09 (dd; IH), 5.16 (dd; lH), 5.31 (m; lH), 5.82
(ddt;lH), 5.92 (m;lH), 6.22 (m;lH), 7.48 (dd;lH), 7.49 (m;2H), 7.7 (s;lH), 7.8(ddt; lH), 5.92 (m; lH), 6.22 (m; lH), 7.48 (dd; lH), 7.49 (m; 2H), 7.7 (s; lH), 7.8
(m;3H)(m; 3H)
Beispiel 28Example 28
(3R*,3aR*,6aS*)-3-Allyl-3-(naphth-2-ylmethyl)-3,3a,4,6a-tetrahydrocyclo- penta[b] furan-2-on - -(3R *, 3aR *, 6aS *) - 3-allyl-3- (naphth-2-ylmethyl) -3,3a, 4,6a-tetrahydrocyclopenta [b] furan-2-one - -
In Analogie zur Vorschrift des Beispiels 4 wurde die Titelverbindung aus 0.23 g (1.38 mmol) der Verbindung aus Beispiel 16, 1.4 ml 1 molarer Lithium-bis-(tri- methylsilyl)-amid-Lösung in THF und 0.3 g (1.38 mmol) 2-Brommethylnaphthalin in 5 ml THF hergestellt.In analogy to the procedure of Example 4, the title compound was made from 0.23 g (1.38 mmol) of the compound from Example 16, 1.4 ml of 1 molar lithium bis (trimethylsilyl) amide solution in THF and 0.3 g (1.38 mmol) 2 -Bromomethylnaphthalene made in 5 ml THF.
Ausbeute: 259 mg (61.8%) eines blaßgelben Öls. Diastereomerenreinheit: >99% de (HPLC).Yield: 259 mg (61.8%) of a pale yellow oil. Diastereomeric purity:> 99% de (HPLC).
'H-NMR (200 MHz; CDC13): δ[ppm]: 2.62 (m;4H), 2.95 (dd;lH), 3.5 (d;lH), 3.17(d;lH), 4.11 (m;lH), 5.28 (m;2H), 5.53 (m;lH), 5.96 (ddt;2H), 6.07(m;lH), 7.36'H NMR (200 MHz; CDC1 3 ): δ [ppm]: 2.62 (m; 4H), 2.95 (dd; lH), 3.5 (d; lH), 3.17 (d; lH), 4.11 (m; lH ), 5.28 (m; 2H), 5.53 (m; lH), 5.96 (ddt; 2H), 6.07 (m; lH), 7.36
(dd;lH), 7.49 (m;2H), 7.60 (s;lH), 7.78-7.88 (br m;3H)(dd; lH), 7.49 (m; 2H), 7.60 (s; lH), 7.78-7.88 (br m; 3H)
Beispiel 29 und Beispiel 30Example 29 and Example 30
8-Naph-2-yl-methyl-2,3-epoxy-6-oxabicyclo[3.3.0]octan-7-on8-Naph-2-yl-methyl-2,3-epoxy-6-oxabicyclo [3.3.0] octan-7-one
1.3 g (4.92 mmol) der Verbindung aus Beispiel 7 und 2 g (10 mmol) m-Chlorper- benzoesäure wurden in 50 ml Chloroform 4 h unter Rückfluß gekocht. Nach dem1.3 g (4.92 mmol) of the compound from Example 7 and 2 g (10 mmol) of m-chloroperbenzoic acid were boiled under reflux in 50 ml of chloroform for 4 h. After this
Abkühlen auf Raumtemperatur wurde das Gemisch mit Natriumhydrogensulfitlösung und mit ges. Natriumcarbonatlösung gewaschen, die organische Phase über Natriumsulfat getrocknet und anschließend eingeengt. Der Rückstand wurde über Kieselgel (Eluent: Dichlormethan/Methanol (100:0.5) chromatographiert. - -The mixture was cooled to room temperature with sodium bisulfite solution and with sat. Washed sodium carbonate solution, the organic phase dried over sodium sulfate and then concentrated. The residue was chromatographed on silica gel (eluent: dichloromethane / methanol (100: 0.5). - -
Ausbeute: zwei Diastereomerengemische (Beispiel 29 (315 mg; 22.8%) und Beispiel 30 (409 mg; 29%), die die epimeren Epoxide in etwa 1 :1 enthalten. Beispiel 29 : MS (ESI): m/z = 281 [M+H] Beispiel 30: MS (ESI) m/z = 281 [M+H]Yield: two diastereomer mixtures (Example 29 (315 mg; 22.8%) and Example 30 (409 mg; 29%), which contain the epimeric epoxides in about 1: 1. Example 29: MS (ESI): m / z = 281 [ M + H] Example 30: MS (ESI) m / z = 281 [M + H]
Beispiel 31Example 31
4,5-Dihydroxy-3-(naphth-2-ylmethyl)-hexahydro-cyclopenta[b]furan-2-on4,5-dihydroxy-3- (naphth-2-ylmethyl) hexahydro-cyclopenta [b] furan-2-one
200 mg (0.75 mmol) der Verbindung aus Beispiel 7, 0.08 ml einer 2.5%igen Osmiumtetroxidlösung in tert. -Butanol und 180 mg N-Methylmorpholin-N-oxid wurden in 2.5 ml Aceton gelöst und 15 h bei RT gerührt. Das Gemisch wurde eingeengt, und der Rückstand über Kieselgel (Eluent: Dichlormethan/Methanol (100:4)) chromatographiert.200 mg (0.75 mmol) of the compound from Example 7, 0.08 ml of a 2.5% strength osmium tetroxide solution in tert. -Butanol and 180 mg of N-methylmorpholine-N-oxide were dissolved in 2.5 ml of acetone and stirred at RT for 15 h. The mixture was concentrated and the residue was chromatographed on silica gel (eluent: dichloromethane / methanol (100: 4)).
Ausbeute: 161 mg eines Diastereomerengemisches. Diastereomerenverhältnis : 1 : 5 : 5 : 1 (HPLC) . MS (DCI NH3): m/z = 316 (M+NH4)Yield: 161 mg of a mixture of diastereomers. Diastereomer ratio: 1: 5: 5: 1 (HPLC). MS (DCI NH 3 ): m / z = 316 (M + NH 4 )
Beispiel 32Example 32
3-(2-Naphthylmethyl)-hexahydro-benzofuran-2-on - -3- (2-naphthylmethyl) hexahydro-benzofuran-2-one - -
Unter Argon wurde eine Lösung von Dusopropylamin (3.36 ml, 24 mmol) in 20 ml trockenem THF auf 0 °C abgekühlt und mit Butyllithium (9.6 ml, 24 mmol, 2.5 M in Hexan) versetzt. Die Lösung wurde 15 min unter Eiskühlung gerührt, auf -78 °C abgekühlt und mit einer Lösung von Hexahydro-benzofuran-2-on (2.8 g, 20 mmol) in 10 ml THF versetzt. Diese Mischung wurde 1 h bei -78 °C gerührt und dann eine Lösung von 2-Brommethylnaphthalin (5.31 g, 24 mmol) in 20 ml THF zugegeben. Der Ansatz wurde noch 2 h bei -78 °C und dann über Nacht bei Raumtemperatur gerührt. Anschließend wurde Wasser zugesetzt, das organische Lösungsmittel imA solution of diisopropylamine (3.36 ml, 24 mmol) in 20 ml of dry THF was cooled to 0 ° C. under argon and butyllithium (9.6 ml, 24 mmol, 2.5 M in hexane) was added. The solution was stirred under ice-cooling for 15 min, cooled to -78 ° C. and a solution of hexahydro-benzofuran-2-one (2.8 g, 20 mmol) in 10 ml THF was added. This mixture was stirred at -78 ° C for 1 h and then a solution of 2-bromomethylnaphthalene (5.31 g, 24 mmol) in 20 ml THF was added. The mixture was stirred for a further 2 h at -78 ° C and then overnight at room temperature. Then water was added, the organic solvent in
Vakuum entfernt und die wässrige Phase mit MTBE extrahiert. Die vereinigten Etherphasen wurden über Magnesiumsulfat getrocknet, filtriert und eingedampft. Die Reinigung erfolgte säulenchromatographisch. Ausbeute: 2.5 g (44.6 %). Rf (Cyclohexan/Ethylacetat 3:1) = 0.69, Rf (Cyclohexan/Ethylacetat 1 : 1 ) = 0.83 MS (CI): m/z = 281 [M + H+] Vacuum removed and the aqueous phase extracted with MTBE. The combined ether phases were dried over magnesium sulfate, filtered and evaporated. The purification was carried out by column chromatography. Yield: 2.5 g (44.6%). R f (cyclohexane / ethyl acetate 3: 1) = 0.69, R f (cyclohexane / ethyl acetate 1: 1) = 0.83 MS (CI): m / z = 281 [M + H +]
- -- -
Patentansprücheclaims
1. Verbindungen der allgemeinen Formel (I)1. Compounds of the general formula (I)
in welcher in which
R1 und R2 gemeinsam für Reste der FormelnR 1 and R 2 together for residues of the formulas
stehen, stand,
die gegebenenfalls bis zu 3-fach durch Hydroxy substituiert sind,which are optionally substituted up to 3 times by hydroxy,
R3 für Wasserstoff, (C,-C6)-Alkyl oder für (C2-C6)-Alkenyl stehtR 3 represents hydrogen, (C, -C 6 ) alkyl or (C 2 -C 6 ) alkenyl
undand
R4 für einen Rest der Formel -CH2-R5 steht,R 4 represents a radical of the formula -CH 2 -R 5 ,
worinwherein
R5 Aryl mit 6 bis 10 Kohlenstoffatomen oder über den Heterocyclus gebundenes Benzothiophen bedeutet, wobei die Ringsysteme gegebenenfalls ein- bis mehrfach, gleich oder verschieden durch Halogen oder (C,-C6)- Alkyl substituiert sind,R 5 denotes aryl having 6 to 10 carbon atoms or benzothiophene bonded via the heterocycle, the ring systems optionally being substituted one to more times, identically or differently, by halogen or (C, -C 6 ) alkyl,
oder or

Claims

- -
R3 für (C2-C6)-Alkenyl stehtR 3 represents (C 2 -C 6 ) alkenyl
undand
R4 für Wasserstoff stehtR 4 represents hydrogen
und deren pharmazeutisch verträgliche Salze.and their pharmaceutically acceptable salts.
Verbindungen der Formel (I) nach Anspruch 1 , worinCompounds of formula (I) according to claim 1, wherein
R' und R2 gemeinsam für Reste der FormelnR 'and R 2 together for residues of the formulas
oder V stehen, or V stand,
die gegebenenfalls bis zu 3-fach durch Hydroxy substituiert sind,which are optionally substituted up to 3 times by hydroxy,
R3 für Wasserstoff oder für (C2-C5)-Alkenyl stehtR 3 represents hydrogen or (C 2 -C 5 ) alkenyl
undand
R4 für einen Rest der Formel -CH2-R5 steht,R 4 represents a radical of the formula -CH 2 -R 5 ,
worinwherein
R5 Phenyl, Naphthyl oder über den Heterocyclus gebundenes Benzothiophen bedeutet, wobei die Ringsysteme gegebenenfalls ein- bis mehrfach, gleich oder verschieden durch Fluor, Chlor, Brom oder (C,-C4)-Alkyl substituiert sind,R 5 denotes phenyl, naphthyl or benzothiophene bonded via the heterocycle, the ring systems optionally being substituted one to more times, identically or differently, by fluorine, chlorine, bromine or (C 1 -C 4 ) -alkyl,
oder - -or - -
R3 für (C2-C5)-Alkenyl stehtR 3 represents (C 2 -C 5 ) alkenyl
undand
R4 für Wasserstoff stehtR 4 represents hydrogen
und deren pharmazeutisch verträgliche Salze.and their pharmaceutically acceptable salts.
Verbindungen der Formel (I) nach Anspruch 1 oder 2, worinCompounds of formula (I) according to claim 1 or 2, wherein
R1 und R2 gemeinsam für Reste der FormelnR 1 and R 2 together for residues of the formulas
oder stehen, or stand,
die gegebenenfalls bis zu 2-fach durch Hydroxy substituiert sind,which are optionally substituted up to 2 times by hydroxy,
R3 für Wasserstoff oder für (C3-C5)-Alkenyl stehtR 3 represents hydrogen or (C 3 -C 5 ) alkenyl
undand
R4 für einen Rest der Formel -CH2-R5 steht,R 4 represents a radical of the formula -CH 2 -R 5 ,
worinwherein
R5 Phenyl, Naphthyl oder über den Heterocyclus gebundenesR 5 phenyl, naphthyl or bound via the heterocycle
Benzothiophen bedeutet, wobei die Ringsysteme gegebenenfalls ein- bis zweifach, gleich oder verschieden durch Fluor, Chlor, Brom oder (CrC3)-Alkyl substituiert sind,Means benzothiophene, where the ring systems are optionally substituted once or twice, identically or differently, by fluorine, chlorine, bromine or (C r C 3 ) -alkyl,
oder - -or - -
R3 für (C3-C5)-Alkenyl stehtR 3 represents (C 3 -C 5 ) alkenyl
undand
R4 für Wasserstoff stehtR 4 represents hydrogen
und deren Salze.and their salts.
4. Verbindungen nach irgendeinem der Ansprüche 1 bis 3, ausgewählt aus der4. Compounds according to any one of claims 1 to 3 selected from the
Gruppe bestehend ausGroup consisting of
3-Allyl-3-(naphth-2-ylmethyl)hexahydro-cyclopenta[b]furan-2-on; 3-(Naphth-2-ylmethyl)-3,3a,6,6a-tetrahydro-cyclopenta[b]furan-2-on; 3-(Naphth-2-ylmethyl)-3,3a,4,6a-tetrahydro-cyclopenta[b]furan-2-on.3-allyl-3- (naphth-2-ylmethyl) hexahydro-cyclopenta [b] furan-2-one; 3- (naphth-2-ylmethyl) -3,3a, 6,6a-tetrahydro-cyclopenta [b] furan-2-one; 3- (Naphth-2-ylmethyl) -3,3a, 4,6a-tetrahydro-cyclopenta [b] furan-2-one.
5. Verfahren zur Herstellung der Verbindungen der Formel (I) nach irgendeinem der Ansprüche 1 bis 4, indem man5. A process for the preparation of the compounds of formula (I) according to any one of claims 1 to 4 by
[A] Verbindungen der allgemeinen Formel (II),[A] compounds of the general formula (II),
in welcher in which
R1 und R2 die oben angegebene Bedeutung haben,R 1 and R 2 have the meaning given above,
mit Verbindungen der allgemeinen Formel (III)with compounds of the general formula (III)
R4-A (III) - -R 4 -A (III) - -
in welcherin which
R4 die oben angegebene Bedeutung hatR 4 has the meaning given above
undand
A für Halogen, vorzugsweise Brom steht,A represents halogen, preferably bromine,
in inerten Lösemitteln und in Anwesenheit einer Base zu den Verbindungen der allgemeinen Formel (Ia)in inert solvents and in the presence of a base to give the compounds of the general formula (Ia)
in welcher in which
R , R und R die oben angegebene Bedeutung haben,R, R and R have the meaning given above,
umsetzt,implements
und im Fall, daß R3 nicht Wasserstoff bedeutet, die Verbindungen der allgemeinen Formel (Ia) mit Verbindungen der allgemeinen Formel (IV)and in the event that R 3 is not hydrogen, the compounds of the general formula (Ia) with compounds of the general formula (IV)
R3'-D (IV)R 3 ' -D (IV)
in welcherin which
R3 die oben angegebene Bedeutung von R3 hat, aber nicht für Wasserstoff steht, - -R 3 has the meaning of R 3 given above, but does not represent hydrogen, - -
D für Halogen, vorzugsweise Brom steht,D represents halogen, preferably bromine,
in inerten Lösemitteln und in Anwesenheit einer Base umsetzt,reacted in inert solvents and in the presence of a base,
oderor
[B] zunächst Verbindungen der allgemeinen Formel (II) mit Verbindungen der allgemeinen Formel (IV) wie unter [A] beschrieben zu den Verbindungen der allgemeinen Formel (Ib)[B] firstly compounds of the general formula (II) with compounds of the general formula (IV) as described under [A] to give the compounds of the general formula (Ib)
in welcher in which
R', R2 und R3 die oben angegebene Bedeutung haben,R ', R 2 and R 3 have the meaning given above,
und in einem zweiten Schritt mit Verbindungen der allgemeinen Formel (III) umsetzt.and reacted in a second step with compounds of the general formula (III).
6. Verbindungen nach Anspruch 1 zur Verwendung als Medikamente in der6. Compounds according to claim 1 for use as medicaments in the
Behandlung von Menschen und Tieren.Treatment of humans and animals.
7. Pharmazeutische Zusammensetzung, die als aktiven Bestandteil mindestens eine Verbindung gemäß Anspruch 6 in Zusammenmischung mit mindestens einem pharmazeutisch verträglichen, im wesentlichen nicht giftigen Träger oder Exzipienten umfaßt. 7. A pharmaceutical composition which comprises as active ingredient at least one compound according to claim 6 in admixture with at least one pharmaceutically acceptable, essentially non-toxic carrier or excipient.
8. Verwendung der Verbindungen gemäß Anspruch 6 für die Herstellung eines Medikaments zur Prävention und/oder Behandlung von Erkrankungen, die durch eine Über- oder Unterfunktion des glutamatergen Systems ausgelöst werden.8. Use of the compounds according to claim 6 for the manufacture of a medicament for the prevention and / or treatment of diseases which are triggered by an over or under function of the glutamatergic system.
9. Verwendung der Verbindungen gemäß Anspruch 6 für die Herstellung eines Medikaments zur Prävention und/oder Behandlung von cerebralen Ischämien, SchädeU/Hirntrauma, Schmerzzuständen oder ZNS-vermittelten Krämpfen. 9. Use of the compounds according to claim 6 for the manufacture of a medicament for the prevention and / or treatment of cerebral ischemia, damage U / brain trauma, pain conditions or CNS-mediated cramps.
PCT/EP 99/00022PCT / EP 99/00022
A. CLASSIFICATION OF SUBJECT MATTERA. CLASSIFICATION OF SUBJECT MATTER
IPC 6 C07D307/93 C07D409/06 A61 31/365 A61K31/38IPC 6 C07D307 / 93 C07D409 / 06 A61 31/365 A61K31 / 38
According to International Patent Classification (IPC) or to both national classification and IPCAccording to International Patent Classification (IPC) or to both national classification and IPC
B. FIELDS SEARCHEDB. FIELDS SEARCHED
Minimum documentation searched (classification System followed by classification Symbols)Minimum documentation searched (classification system followed by classification symbols)
IPC 6 C07D A61KIPC 6 C07D A61K
Documentation searched otherthaπ minimum documentation to the extent that such documeπts are included in the fields searchedDocumentation searched otherthaπ minimum documentation to the extent that such documeπts are included in the fields searched
Electronic data base consulted during the international search (name of data base and, where practical, search ternns used)Electronic data base consulted during the international search (name of data base and, where practical, search ternns used)
C DOCUMENTS CONSIDERED TO BE RELEVANTC DOCUMENTS CONSIDERED TO BE RELEVANT
Category " Citation of document, with indication, where appropπate, of the relevant passages Relevant to Claim NoCategory "Citation of document, with indication, where appropπate, of the relevant passages Relevant to Claim No
SMITH A B, III ET AL: "Total synthesis of 1-3 the pani cul i des "SMITH A B, III ET AL: "Total synthesis of 1-3 the pani cul i des"
J. AM. CHEM. SOC. (JACSAT, 00027863) ;1983; VOL.105 (3); PP.575-85, XP002105720 Uni v . Pennsyl vani a;Monel l Chem. Senses Cent.; Philadelphia; 19104; PA; USA (US) see page 578, col umn 1 ; exampl e 20J. AM. CHEM. SOC. (JACSAT, 00027863); 1983; VOL.105 (3); PP.575-85, XP002105720 Uni v. Pennsyl vani a; Monel l Chem. Senses Cent .; Philadelphia; 19104; PA; USA (US) see page 578, col umn 1; exampl e 20
Further documents are Iisted in the continuation of box C Patent family members are Iisted in annexFurther documents are Iisted in the continuation of box C Patent family members are Iisted in annex
° Special categoπes of cited documents° Special categories of cited documents
"T" later document published after the international filiπg date"T" later document published after the international filiπg date
"A" document defining the general State of the art which is not or pπoπty date and not in confhct with the application but considered to be of particular relevance cited to understand the pπnciple or theory underlymg the invention"A" document defining the general State of the art which is not or pπoπty date and not in confhct with the application but considered to be of particular relevance cited to understand the pπnciple or theory underlymg the invention
"E" earlier document but published on or afterthe international "X" document of particular relevance, the claimed invention filiπg date cannot be considered novel or cannot be considered to"E" earlier document but published on or after the international "X" document of particular relevance, the claimed invention filiπg date cannot be considered novel or cannot be considered to
" " document which may throw doubts on pnoπty claιm(s) or iπvolve an inventive Step when the document is ta en alone which is cited to establish the pub cation date of another citation or other Special reason (as specified) "Y" document of particular relevance, the claimed invention cannot be considered to involve an inventive step when the"" document which may throw doubts on pnoπty claιm (s) or iπvolve an inventive Step when the document is ta en alone which is cited to establish the pub cation date of another citation or other Special reason (as specified) "Y" document of particular relevance, the claimed invention cannot be considered to involve an inventive step when the
"0" document referπng to an oral disclosure, use, exhibition or document is combined with one or more other such docuother means ments, such combination being obvious to a person skilled "P" document published pπor to the international filmg date but in the art later than the pπoπty date claimed "&* document member of the same patent family"0" document referπng to an oral disclosure, use, exhibition or document is combined with one or more other such docuother meansments, such combination being obvious to a person skilled "P" document published pπor to the international filmg date but in the art later than the pπoπty date claimed "& * document member of the same patent family
Date of the actual completion of the international search Date of mailing of the international search reportDate of the actual completion of the international search Date of mailing of the international search report
11 June 1999 28/06/199911 June 1999 28/06/1999
Name and mailing address of the ISA Authoπzed officerName and mailing address of the ISA Authoπzed officer
European Patent Office, P B 5818 Patentlaan 2 NL - 2280 HV Rijswij Tel (+31-70) 340-20 0, Tx 31 651 epo nl, Fax (+31-70) 340-3016 Pai sdor , BEuropean Patent Office, PB 5818 Patentlaan 2 NL - 2280 HV Rijswij Tel (+ 31-70) 3 40-20 0, Tx 31 651 epo nl, Fax (+ 31-70) 340-3016 Pai sdor, B
Form PCT ISA/210 (second shββt) (July 1992) Form PCT ISA / 210 (second shββt) (July 1992)
EP99903604A 1998-01-17 1999-01-05 Substituted beta,gamma-anellated lactones Ceased EP1047685A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19801647 1998-01-17
DE19801647A DE19801647A1 (en) 1998-01-17 1998-01-17 New beta, gamma-fused lactone glutamate receptor modulators for treating cerebral ischemia, cranial or brain trauma, pain or CNS-mediated spasms
PCT/EP1999/000022 WO1999036417A1 (en) 1998-01-17 1999-01-05 SUBSTITUTED β,η-ANELLATED LACTONES

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JP2004501970A (en) 2000-07-03 2004-01-22 イーベーヴェーエフ　インスティチュート　フュア　ビオテヒノロジ　ウント　ヴィルクシュトフ−フォルシュング　エーファウ Use of Galliera Lactone
TWI375121B (en) * 2004-06-28 2012-10-21 Fujifilm Corp Photosensitive composition and method for forming pattern using the same
HU226863B1 (en) * 2005-12-09 2009-12-28 Chinoin Gyogyszer Es Vegyeszet Process for separation of optical isomers of "corey-lactone" by liquid chromatography

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