WO1999036419A1

WO1999036419A1 - Substituted lactones as modulators of metabotropic glutamate receptors

Info

Publication number: WO1999036419A1
Application number: PCT/EP1999/000023
Authority: WO
Inventors: 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: 1998-01-17
Filing date: 1999-01-05
Publication date: 1999-07-22
Also published as: AU2515699A; DE19801648A1

Abstract

The invention relates to novel substituted alpha -lactones, to methods for producing said alpha -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

SUBSTITUTED LACTONE AS MODULATORS FROM MET ABOTROPEN

GLUTAMATE RECEPTORS

The present invention relates to α-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.

8 different types of metabotropic glutamate receptors 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).

In addition, 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,

5601).

In J. Am. Chem. Soc. 1955, 77, 5601 3-benzyl-tetrahydro-pyran-2-one is mentioned as a substance, but not isolated or characterized. The present invention relates to compounds of the general formula (I)

in which

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,

Phenyl, phenoxy and benzoyl, the latter ring systems optionally being substituted by halogen, or

(C, -C ₆ ) alkyl, which in turn can be substituted by carboxyl or (C, -C ₆ ) alkoxycarbonyl,

or

for a rest of the formula stands,

and

a represents a number 1 or 2,

and their pharmaceutically acceptable salts,

with the exception of 3-benzyl-3-methyltetrahydropyran-2-one, 3-benzyl-3-methyl-dihydrofuran-2-one and 3-3-dibenzyldihydrofuran-2-one.

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.

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 _{ι n} ) aryl) generally represents an aromatic radical having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.

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, prop-1-en-yl, isopropenyl, n-but-2-en-yl, n-pent-2-enyl and n-hex-2-enyl.

In the context of the invention, (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.

In the context of the invention, (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 ι -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.

In the context of the invention, (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.

Preferred compounds of the general formula (I) according to the invention are

in which

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

Cyano is substituted,

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:

Fluorine, chlorine, bromine, trifluoromethyl, cyano, (C, -C ₄ ) alkoxy,

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,

or

for a rest of the formula

stands,

and

a represents a number 1 or 2,

and their pharmaceutically acceptable salts,

Compounds of the general invention are particularly preferred

Formula (I),

in which

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:

Fluorine, chlorine, bromine, trifluoromethyl, cyano, (C, -C ₃ ) alkoxy,

Phenyl, phenoxy and benzoyl can be substituted, the latter

Ring systems are optionally substituted by fluorine, chlorine or bromine, or

(C, -C ₃ ) alkyl, which in turn can be substituted by carboxyl or (C, -C ₃ ) alkoxycarbonyl,

or

for a rest of the formula

and

a represents a number 1 or 2,

and their pharmaceutically acceptable salts, with the exception of 3-benzyl-3-methyltetrahydropyran-2-one, 3-benzyl-3-methyl-dihydrofuran-2-one and 3-3-dibenzyldihydrofuran-2-one.

Compounds according to the invention having the following structure are very particularly preferred:

structure

The compounds of the general formula (I) according to the invention can be prepared by:

Compounds of the general formula (II)

in which

has the meaning given above,

either first by reaction with compounds of the general formula (III) or (IV)

R ¹ halogen (III) or R ² halogen (IV),

in which

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,

in inert solvents and in the presence of a base in the compounds of the general formula (V) or (la)

in which

a, R ¹ and R ^{2 have} the meaning given above,

transferred and finally in the case of the compounds of the general formula (V) with compounds of the general formula (IV) and in the case of the compounds of the general formula (Ia) with compounds of the general formula (III) in inert solvents and in the presence of a base.

The process according to the invention can be illustrated by the following formula scheme:

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.

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).

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.

Some of the compounds of the general formulas (II), (III) and (IV) are known or can be prepared by customary methods.

Some of the compounds of the general formula (V) according to the invention are known or can be prepared as described above.

The invention also relates to compounds of the general formula (I)

in which

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,

(C, -C ₆ ) alkyl, which in turn can be substituted by carboxyl or (C _r C ₆ ) alkoxycarbonyl,

or

for a rest of the formula

stands,

and

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.

On the basis of their pharmacological properties, 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.

For the treatment and / or prevention of 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. Also for the treatment and / or prevention of cerebral ischemia after all surgical interventions on the brain or peripheral

Organs or parts of the body and associated or preceding conditions pathological or allergic in nature, which can primarily and / or secondarily lead to neuronal damage.

Likewise, 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.

In addition, 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.

They are preferably used as medicinal products for the treatment of cerebral

Ischemia, head trauma, pain, convulsions or epilepsy. 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 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).

With the following test models the anti-ischemic effectiveness of the

Compounds are proven in vivo.

Permanent focal cerebral ischemia in the rat (MCA-O)

Under isoflurane anesthesia, the cerebral artery is dissected free on one side by means of 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 is applied according to different time schedules and via different application routes (IV, IP) 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-assisted evaluation system. Subdural Hematoma in the Rat (SDH)

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

(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) 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.

In addition to the active ingredients of the formulas (I) and (Ia), 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. In general, it has proven advantageous to use the active ingredient (s) and (Ia) in total amounts of from about 0.01 to about 100 mg / kg, preferably in total amounts of from about 1 mg / tcg to 50 mg / kg Köφerge weight each 24 hours, if necessary in the form of several individual doses, to achieve the desired result.

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.

General

Chromatography solvent

I dichloromethane / methanol

II dichloromethane / ethanol

III cyclohexane / ethyl acetate

IV cyclohexane / dichloromethane

V butyl acetate (200), butanol (26), acetic acid (100), phosphate buffer pH = 6 (60)

Abbreviations

DME 1,2-dimethoxyethane

HMPA hexamethylphosphoric triamide

LiHMDS lithium bistrimethylsilylamide

LDA lithium diisopropylamide

MTBE methyl tert-butyl ether

THF tetrahydrofuran

Output connections

Example 1A

3 - Ally l-dihydro-furan-2-one

A solution of butyrolactone (12.9 g, 150 mmol) in 150 ml of THF is slowly added dropwise to a solution of LDA (82.5 ml, 165 mmol, 2 M in THF) at -78 ° C. and under argon. After the addition, the mixture is stirred for a further 30 min and then a solution of AUyl bromide (15.6 ml, 180 mmol) in 30 ml HMPA is slowly added dropwise. The solution is then warmed to -30 ° C. and stirred for a further 3 h. The mixture is then mixed with saturated ammonium chloride solution in the cold, the organic solvent is evaporated in vacuo and the aqueous phase is extracted with MTBE. The organic phase is washed once more with water, dried over magnesium sulfate and evaporated. The purification is carried out by column chromatography. Yield: 6.3 g (33.3%). R _f (cyclohexane / ethyl acetate = 3: 1) = 0.36 MS (CI): m / z = 127 [M + H ⁺ ]

Manufacturing examples

Example 1 and Example 2

3- (Naphth-2-ylmethyl) tetrahydropyran-2-one (Example 1) and 3,3-bis (naphth-2-ylmethyl) tetrahydropyran-2-one (Example 2)

(1) (2)

22 ml of a 1 molar solution of lithium bis (trimethylsilyl) amide in THF are added dropwise under argon to a solution of 2 g (20 mmol) of valerolactone in 50 ml of THF precooled to -78 ° C. so that the Temperature of the mixture does not exceed -65 ° C. When the addition is complete, the mixture is stirred at -78 ° C. for 10 min and 4.64 g (21 mmol) of naphth-2-ylmethyl bromide are added. The cooling bath is removed and allowed to warm to room temperature. After 16 h stirring at room temp. the mixture is taken up in water / diethyl ether and the aqueous phase is extracted twice with diethyl ether. The combined organic phases are dried over sodium sulfate and concentrated. The residue was chromatographed on silica gel (eluent: dichloromethane). Yield: Example 1: 2.3 g (47%); Example 2: 0.2 g (<5%)

Example 1 Η-NMR (200 MHz; [d ₆ ] -DMSO): δ [ppm]: 1.37-1.51 (m; lH), 1.65-

1.9 (m; 3H), 2.76 (dd; 1H), 3.03 (m; lH), 3.28 (dd; lH), 4.2 - 4.25 (m; 2H), 7.48-7.55 (m; 3H), 7.73 ( s; lH), 7.81-7.95 (m; 3H)

Example 2 "H-NMR (200 MHz; [d ₆ ] -DMSO): δ [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 3

3-allyl-3 - (naphth-2-ylmethyl) tetrahydropyran-2-one:

1 ml of a 1 molar solution is added dropwise to a solution of 0.24 g (1 mmol) of 3- (naphth-2-ylmethyl) tetrahydropyran-2-one (example 1) in 10 ml of THF, cooled to -78 ° C. Lithium bis (trimethylsilyl) amide in THF so that the temperature of the mixture does not exceed -65 ° C. After the addition is complete, stir

10 min at -78 ° C and add 0.15 g (1.2 mmol) AUyl bromide all at once. The cooling bath is removed and the mixture is left to room temperature. heat. After 16 h stirring at room temp. you take the mixture with sat. Ammonium chloride solution and ethyl acetate and the aqueous phase 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: 53 mg (18%) MS (DCI, NH ₃ ): 298 [M + NH ₄ f 'H NMR (200 MHz; CDC1 ₃ ): δ [ppm]: 1.37-1.51 (m; lH), 1.55 -1.8 (m; lH), 1.9 (m; 2H), 2.3 (dd; lH), 2.78 (m; lH), 2.80 (d; lH), 3.48 (d; lH), 3.89. (m; lH), 4.17 (m; lH),

5.18 (dd; lH), 5.22 (d, lH), 5.7 (m; lH), 7.42 (dd; lH), 7.45-7.49 (br m; 2H), 7.68 (s; lH), 7.88 (m; 3H ). Example 4 and Example 5

3- (2-Naphthylmethyl) -dihydro-fiιran-2-one (Example 4) and 3,3-di- (2-naphthyl-methyl) -dihydro-furan-2-one (Example 5)

(4) (5)

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. The mixture is stirred at 0 ° C. for 15 min, cooled to -78 ° C. and a solution of butyrolactone (4.3 g, 50 mmol) in 10 ml of THF is added dropwise. After the addition has ended, the mixture is stirred for 30 min and then a solution of 2-bromomethylnaphthalene (13.4 g, 60 mmol) in 30 ml of THF is slowly added dropwise. The mixture is stirred at -78 ° C for 2 h, in an ice bath for 1 h and then at room temperature overnight. The mixture is then evaporated and semi-saturated in dichloromethane

Sodium bicarbonate solution added. The organic phase is separated off, dried over magnesium sulfate and evaporated. The components (Example 4) and (Example 5) are purified and separated by column chromatography (eluent cyclohexane: ethyl acetate 3: 1). Yield: Example 4: 4.8 g (35.4%)

Example 5: 1.2 g (2.7%).

Example 4 R, (II) = 0.28

MS (CI): mz = 227 [M + H ⁺ ] Example 5 R, (II) = 0.49

MS (CI): m / z = 367 [M + H ⁺ ]

Example 6

3-allyl-3-benzyl-dihydro-furan-2-one

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. After the addition has ended, the mixture is stirred for a further 30 min and then a solution of AUyl bromide (4.23 ml, 60 mmol) in 10 ml of HMPA is slowly added dropwise: The mixture is then stirred at -30 ° C for 3 h. The mixture is then evaporated and taken up in dichloromethane semi-saturated sodium hydrogen carbonate solution. The organic phase is separated off

Magnesium sulfate dried and evaporated. The purification is carried out by column chromatography (eluent cyclohexane ethyl acetate 3: 1). Yield: 5.1 g (47.2%). R _f (cyclohexane / ethyl acetate 3: 1) = 0.54 MS (CI): m / z = 217 [M + H ⁺ ]

The compounds listed in Table 1 are prepared in analogy to the regulations listed above. Table 1:

Example 40

3- (4-biphenylmethyl) dihydro-furan-2-one

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. The

The mixture is stirred at 0 ° C. for 15 min, cooled to -78 ° C. and then a solution of butyrolactone (4.3 g, 50 mmol) in 10 ml of THF is added dropwise. After the addition has ended, the mixture is stirred for a further 30 min and then a solution of 4-Bromomethyl-biphenyl (14.8 g, 60 mmol) in 30 ml THF was slowly added dropwise. The mixture is then stirred at -78 ° C. for a further 2 h, then in an ice bath for 1 h and then overnight at room temperature. The mixture is then evaporated and taken up in dichloromethane semi-saturated sodium bicarbonate solution. The organic phase is separated off, dried over magnesium sulfate and evaporated. The purification is carried out by column chromatography (eluent cyclohexane / ethyl acetate 3: 1). Yield: 8.1 g (64.2%). R _f (cyclohexane / ethyl acetate 3: 1) = 0.28 MS (CI): m / z = 253 [M + H ⁺ ]

Claims

claims

1. Compounds of the general formula (I)

in which

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 (C ₆ -C ₁₀ ) aryl or cyano is substituted,

Phenyl, phenoxy and benzoyl, these ring systems optionally being substituted by halogen, and

(C, -C ₆ ) alkyl, which in turn by carboxyl or (C, -C ₆ ) -

Alkoxycarbonyl can be substituted,

or for a rest of the formula

and

a represents a number 1 or 2,

with the exception of 3-benzyl-3-methyltetrahydropyran-2-one, 3-benzyl-3-methyldihydrofuran-2-one and 3-3-dibenzyldihydrofuran-2-one,

and their pharmaceutically acceptable salts.

Compounds of formula (I) according to claim 1, wherein

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 Cyano is substituted,

Fluorine, chlorine, bromine, trifluoromethyl, cyano, (C, -C ₄ ) alkoxy, Phenyl, phenoxy and benzoyl can be substituted, these 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,

or

for a rest of the formula

stands,

and

a represents a number 1 or 2,

and their pharmaceutically acceptable salts.

3. Compounds of formula (I) according to claim 1 or 2, wherein

R ^{1 represents} 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 is R ^{2 represents} (C, -C ₃ ) alkyl or (C, -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, it consists of:

Fluorine, chlorine, bromine, trifluoromethyl, cyano, (C, -C ₃ ) alkoxy,

Phenyl, phenoxy and benzoyl can be substituted, these ring systems optionally being substituted by fluorine, chlorine or bromine, or

(C, -C ₃ ) alkyl which in turn can be substituted by carboxyl or (C _r C ₃ ) alkoxycarbonyl,

or

for a rest of the formula

stands,

and

a represents a number 1 or 2,

and their pharmaceutically acceptable salts.

4. Compounds according to any one of claims 1 to 3 selected from the group consisting of

3-allyl-3- (naphth-2-ylmethyl) tetrahydropyran-2-one; 3-allyl-3-benzyldihydrofuran-2-one;

3 - allyl-3 - (naphth-2-ylmethyl) dihydrofuran-2-one;

3 - allyl-3 - (1,3-dioxaindan-5-ylmethyl) dihydrofuran-2-one;

3-allyl-3- (6-t-butylnaphth-2-ylmethyl) dihydrofuran-2-one.

5. A process for the preparation of the compounds of formula (I) according to any one of claims 1 to 4 by

Compounds of the general formula (II)

in which

a has the meaning given above,

either first by reaction with compounds of the general

Formula (III) or (IV)

R ¹ halogen (III) or R ² halogen (IV),

in which

R '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,

in which

a, R ¹ and R ^{2 have} the meaning given above,

Compounds of the general formula (! ')

in which

R ^{1 represents} hydrogen, (C, -C ₆ ) acyl, (C ₂ -C ₆ ) alkenyl, cycloalkenyl having 3 to 7 carbon atoms, (C, -C ₆ ) alkyl, which is optionally replaced by (C ₆ - Cι ₀ ) 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 one or more times, identical or different, by substituents can be substituted, selected from the group consisting of:

(C _] -C ₆ ) alkyl, which in turn can be substituted by carboxyl or (C, -C ₆ ) alkoxycarbonyl,

or

for a rest of the formula

stands,

and a represents a number 1 or 2,

and their pharmaceutically acceptable salts, for use as medicaments in the treatment of humans and animals.

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. 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. Use of the compounds according to claim 6 for the manufacture of a medicament for the prevention and / or treatment of cerebral ischemia, damage / brain trauma, pain conditions or CNS-mediated cramps.