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WO1999036419A1 - Lactones substituees utilisees comme modulateurs de recepteurs metabotropes de glutamate - Google Patents

Lactones substituees utilisees comme modulateurs de recepteurs metabotropes de glutamate Download PDF

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Publication number
WO1999036419A1
WO1999036419A1 PCT/EP1999/000023 EP9900023W WO9936419A1 WO 1999036419 A1 WO1999036419 A1 WO 1999036419A1 EP 9900023 W EP9900023 W EP 9900023W WO 9936419 A1 WO9936419 A1 WO 9936419A1
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WO
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Prior art keywords
substituted
compounds
alkyl
general formula
alkenyl
Prior art date
Application number
PCT/EP1999/000023
Other languages
German (de)
English (en)
Inventor
Andreas Stolle
Horst-Peter Antonicek
Stephan Lensky
Arnd Voerste
Thomas Müller
Jörg Baumgarten
Karsten Von Dem Bruch
Gerhard Müller
Udo Stropp
Ervin Horváth
Jean-Marie-Viktor De Vry
Rudy Schreiber
Original Assignee
Bayer Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Aktiengesellschaft filed Critical Bayer Aktiengesellschaft
Priority to AU25156/99A priority Critical patent/AU2515699A/en
Publication of WO1999036419A1 publication Critical patent/WO1999036419A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/18—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member containing only hydrogen and carbon atoms in addition to the ring hetero atom
    • 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
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/28—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • the present invention relates to ⁇ -substituted lactones, their use as medicaments and processes for their preparation.
  • the amino acid L-glutamate is the most important excitatory neurotransmitter in the brain. Glutamate receptors can be divided into two broad classes: 1. ionotropic receptors that control ion channels directly and 2. metabotropic receptors (mGluRs).
  • Metabotropic glutamate receptors are a heterogeneous class of G protein-coupled receptors. They pre- or post-synaptically modulate the release of glutamate or the sensitivity of the cell to glutamate. The effects are caused by different second messenger cascades. This
  • the answer in turn affects the ionotropic glutamate receptors.
  • metabotropic glutamate receptors 8 different types are currently known, which differ in terms of second messenger cascade, pharmacology and localization in the brain (for an overview: Ann. Rev. Pharmacol. Toxicol. 1997, 37, 205).
  • 3-benzyl-3-methyltetrahydropyran-2-one, 3-benzyl-3-methyltetrahydrofuran-2-one, 3-3-dibenzyltetrahydrofuran-2-one are known from synthesis publications (cf. Bull. Soc. Chim. 1970, 3661, 3667; CR Acad.Sc. Paris, Ser. C, 267 1968, 983; J. Org. Chem. 1979, 44, 2165 and J. Am. Chem. Soc. 1955, 77,
  • R 1 represents hydrogen, (C, -C 6 ) acyl, (C 2 -C 6 ) alkenyl, cycloalkenyl having 3 to 7 carbon atoms, or represents (C, -C 6 ) alkyl, which is optionally replaced by (Cg -C j o) aryl or cyano is substituted,
  • R 2 represents (C, -C 6 ) alkyl or (C 2 -C 6 ) alkenyl, which are substituted by (C 6 -C 10 ) aryl, which in turn is substituted one or more times, identically or differently, by substituents can be substituted, selected from the group consisting of:
  • Halogen trifluoromethyl, cyano, (C, -C 6 ) alkoxy, (C, -C 6 ) alkoxycarbonyl,
  • a represents a number 1 or 2
  • 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, 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 (for example sodium or potassium salts), alkaline earth metal salts (for example calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine or methylpiperidine.
  • alkali metal salts for example sodium or potassium salts
  • alkaline earth metal salts for example calcium or magnesium salts
  • ammonium salts derived from ammonia or organic amines such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine or methylpipe
  • Cycloalkenyl generally represents a cyclic hydrocarbon radical having 3 to 7 carbon atoms and a double bond. Examples include cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl. Cyclopentenyl, cyclohexenyl and cycloheptenyl are preferred.
  • (-C ⁇ n ) aryl generally represents an aromatic radical having 6 to 10 carbon atoms.
  • Preferred aryl radicals are phenyl and naphthyl.
  • (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, prop-1-en-yl, isopropenyl, n-but-2-en-yl, n-pent-2-enyl and n-hex-2-enyl.
  • (C r C 6 ) -alkyl represents a straight-chain or branched alkyl radical having 1 to 6 carbon atoms.
  • a straight-chain or branched lower alkyl radical having 1 to 4 carbon atoms is preferred. Examples include: methyl, ethyl, propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.
  • (C, -C 6 ) -alkoxy stands for a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms.
  • a straight-chain or branched lower alkoxy radical having 1 to 4 carbon atoms is preferred. Examples include: methoxy, ethoxy, propoxy, isopropoxy, teitbutoxy, n-pentoxy and n-
  • Hexoxy. (C ⁇ -C 6 ) - Alkoxycarbonyl in the context of the invention is a straight-chain or branched alkoxycarbonyl radical having 1 to 6 carbon atoms.
  • a straight-chain or branched lower alkoxycarbonyl radical having 1 to 4 carbon atoms is preferred. Examples include: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tert.butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.
  • (C r C 6 ) -acyl represents a straight-chain or branched acyl radical having 1 to 6 carbon atoms.
  • a straight-chain or branched acyl radical having 1 to 4 carbon atoms is preferred.
  • Preferred acyl radicals are acetyl and propionyl.
  • R 1 represents hydrogen, (C, -C 4 ) acyl, (C 2 -C 5 ) alkenyl, cyclopentyl, cyclopentenyl or cyclohexenyl or represents (C, -C 4 ) alkyl, optionally substituted by phenyl, naphthyl or
  • R 2 represents (C, -C 4 ) -alkyl or (C 2 -C 5 ) -alkenyl which are substituted by phenyl or naphthyl, which in turn are substituted one or more times, identically or differently, by substituents selected from the group, it consists of:
  • Phenyl, phenoxy and benzoyl can be substituted, the latter ring systems optionally being substituted by fluorine, chlorine or bromine, or (C, -C 4 ) alkyl which in turn can be substituted by carboxyl or (C, -C 4 ) alkoxycarbonyl,
  • a represents a number 1 or 2
  • R 1 is hydrogen, (C, -C 3 ) acyl, (C 3 -C 5 ) alkenyl, cyclopentyl or cyclohexenyl or represents (C, -C 3 ) -alkyl which is optionally substituted by phenyl, naphthyl or cyano,
  • R 2 represents (C, -C 3 ) alkyl or (C r C 4 ) alkenyl which are substituted by phenyl or naphthyl, which in turn are substituted one or more times, identically or differently, by substituents selected from the group consisting of consists:
  • Phenyl, phenoxy and benzoyl can be substituted, the latter
  • Ring systems are optionally substituted by fluorine, chlorine or bromine, or
  • a represents a number 1 or 2
  • the compounds of the general formula (I) according to the invention can be prepared by:
  • R 1 has the meaning of R 1 given above, but does not represent hydrogen
  • R 2 has the meaning given above, and
  • Halogen preferably represents bromine
  • R 1 and R 2 have the meaning given above,
  • Suitable solvents are all inert solvents that do not change under the reaction conditions. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl 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 invention also relates to compounds of the general formula (I)
  • R 1 represents hydrogen, or represents (C, -C 6 ) acyl, or represents (C 2 -C 6 ) alkenyl, or represents cycloalkenyl having 3 to 7 carbon atoms, or represents (C, -C 6 ) -alkyl which is optionally substituted by aryl or cyano,
  • R 2 represents (C, -C 6 ) alkyl or (C 2 -C 6 ) alkenyl which are substituted by aryl, which in turn can be substituted one or more times, identically or differently, by substituents selected from the group , which consists of:
  • Halogen trifluoromethyl, cyano, (C, -C 6 ) alkoxy, (C r C 6 ) alkoxycarbonyl,
  • a represents a number 1 or 2, and their pharmaceutically acceptable salts, for use as a medicament in the treatment of humans and animals.
  • the invention further relates to pharmaceutical compositions which comprise as active ingredient at least one compound of the general formula (I) and its pharmaceutically acceptable salts, in admixture with at least one pharmaceutically acceptable, essentially non-toxic carrier or excipient.
  • the compounds 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 according to the invention can be used alone or in combination with other medicaments for the treatment and / or prevention of neuronal damage or diseases which are associated with derailment of the physiological or in the case of pathophysiological conditions of the glutamatergic system in the central and peripheral nervous system. be used.
  • neuronal damage for example caused by ischemic, thrombic and / or thrombemolic, and hemorrhagic stroke, conditions after direct and indirect injuries in the area of the brain and skull.
  • cerebral ischemia after all surgical interventions on the brain or peripheral
  • 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 as a result of primary brain diseases, for example convulsions and arterosclerotic and / or arteriosclerotic changes. to
  • Treatment of chronic or psychiatric disorders 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.
  • they can be used as pharmaceuticals for the prevention and / or treatment of dementias of various origins, brain disorders in old age, memory disorders, spinal cord injuries, painful conditions, anxiety states of different origins, medication-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.
  • 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 are blocked (J. Neurosci. 1994, 14, 7067).
  • the modulatory effect of pharmacological test substances on glutamate receptors can be controlled by appropriate experimental arrangement. A detailed examination of the subtype specificity under controlled conditions can be carried out on Xenopus oocytes by injection of the corresponding mGluR Subtype DNA take place (WO 92/10583).
  • the animals are injected with subdural autologous blood under anesthesia.
  • An infarction forms under the hematoma.
  • the substance application takes place according to different time schedules and via different application routes
  • 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) and (Ia), or which consist of one or more active compounds of the formulas (I) and (la) exist, and processes for the preparation of these preparations.
  • the active compounds of the formulas (I) and (Ia) 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 pharmaceutical active ingredients.
  • the pharmaceutical preparations listed above can be prepared in a customary manner by known methods, for example using the excipient or excipients.
  • Example 1 2.3 g (47%);
  • Example 2 0.2 g ( ⁇ 5%)
  • Example 2 "H-NMR (200 MHz; [d 6 ] -DMSO): ⁇ [ppm]: 1.25 (q; 2H), 1.87 (t; 2H), 2.9 (d; 2H), 3.50 (d; 2H) , 3.72 (t; 2H), 7.37 (dd; 2H), 7.45-7.49 (br m; 4H), 7.72 (s; 2H), 7.88 (m; 6H)
  • Example 4 4.8 g (35.4%)
  • Example 5 1.2 g (2.7%).
  • Diisopropylamine (7.8 ml, 55 mmol) is placed in 50 ml THF at 0 ° C. under argon and butyllithium (20 ml, 55 mmol, 2.5 M in hexane) is added dropwise. The mixture is stirred for 15 min at 0 ° C., cooled to -78 ° C. and then a solution of 3-benzyl-dihydro-furan-2-one (8.8 g g, 50 mmol) in 20 ml THF is added dropwise.
  • Table 1 The compounds listed in Table 1 are prepared in analogy to the regulations listed above. Table 1:
  • Diisopropylamine (8.4 ml, 60 mmol) is placed in 60 ml THF at 0 ° C. under argon and butyllithium (24 ml, 60 mmol, 2.5 M in hexane) is added dropwise.
  • butyllithium 24 ml, 60 mmol, 2.5 M in hexane

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

Abstract

L'invention concerne de nouvelles α-lactones substituées, leurs procédés de production et leur utilisation pour prévenir et/ou traiter des maladies provoquées par une hyperfonction ou une hypofonction du système glutamatergène, notamment les ischémies cérébrales, les traumatismes crâniens/cérébraux, les douleurs ou les crampes induites par le SNC.
PCT/EP1999/000023 1998-01-17 1999-01-05 Lactones substituees utilisees comme modulateurs de recepteurs metabotropes de glutamate WO1999036419A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU25156/99A AU2515699A (en) 1998-01-17 1999-01-05 Substituted lactones as modulators of metabotropic glutamate receptors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE1998101648 DE19801648A1 (de) 1998-01-17 1998-01-17 alpha-Substituierte Lactone
DE19801648.4 1998-01-17

Publications (1)

Publication Number Publication Date
WO1999036419A1 true WO1999036419A1 (fr) 1999-07-22

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DE (1) DE19801648A1 (fr)
WO (1) WO1999036419A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7365174B2 (en) 2003-08-22 2008-04-29 Meiji Seika Kaisha, Ltd. Azalide and azalactam derivatives and method for producing the same

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Publication number Priority date Publication date Assignee Title
EP0246581A2 (fr) * 1986-05-22 1987-11-25 BASF Aktiengesellschaft Procédé pour la préparation de gamma-butyrolactones alpha-substitués
WO1993001172A1 (fr) * 1991-07-12 1993-01-21 Iowa State University Research Foundation, Inc. Arylation/alkylation catalysees au palladium de dienes non conjugues
WO1996007405A1 (fr) * 1994-09-08 1996-03-14 Eli Lilly And Company Antagonistes des recepteurs d'acides amines excitateurs
WO1996015099A1 (fr) * 1994-11-09 1996-05-23 Novo Nordisk A/S Composes heterocycliques, preparation et utilisation de ces composes
WO1997003973A1 (fr) * 1995-07-21 1997-02-06 Fujisawa Pharmaceutical Co., Ltd. Derives oxazole de 4,5-diaryle
EP0774461A1 (fr) * 1995-11-16 1997-05-21 Eli Lilly And Company Dérivés des aminoacides excitateurs
WO1997025041A1 (fr) * 1996-01-09 1997-07-17 Eli Lilly And Company Antagonistes benzimidazolyles du recepteur du neuropeptide y

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EP0246581A2 (fr) * 1986-05-22 1987-11-25 BASF Aktiengesellschaft Procédé pour la préparation de gamma-butyrolactones alpha-substitués
WO1993001172A1 (fr) * 1991-07-12 1993-01-21 Iowa State University Research Foundation, Inc. Arylation/alkylation catalysees au palladium de dienes non conjugues
WO1996007405A1 (fr) * 1994-09-08 1996-03-14 Eli Lilly And Company Antagonistes des recepteurs d'acides amines excitateurs
WO1996015099A1 (fr) * 1994-11-09 1996-05-23 Novo Nordisk A/S Composes heterocycliques, preparation et utilisation de ces composes
WO1997003973A1 (fr) * 1995-07-21 1997-02-06 Fujisawa Pharmaceutical Co., Ltd. Derives oxazole de 4,5-diaryle
EP0774461A1 (fr) * 1995-11-16 1997-05-21 Eli Lilly And Company Dérivés des aminoacides excitateurs
WO1997025041A1 (fr) * 1996-01-09 1997-07-17 Eli Lilly And Company Antagonistes benzimidazolyles du recepteur du neuropeptide y

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7365174B2 (en) 2003-08-22 2008-04-29 Meiji Seika Kaisha, Ltd. Azalide and azalactam derivatives and method for producing the same

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DE19801648A1 (de) 1999-07-22

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