DE4441984A1 - New tri:fluoromethyl-pyrrolidinone derivs. - Google Patents

Abstract

N-Substd. trifluoromethyl-pyrrolidine-2-ones (I) and their salts are new: R1 = H, 1-6 C alkyl or CF3; A = alkylene or alkenylene with up to 6C, and R2 = 1-6C alkoxy, -NR3R4 or -SO2-R5, or A = direct bond, and R<2> = H, 1-8C alkyl, Ar<1> or Ar<1>-1-6C; R3 = 1-8C alkyl, alkoxycarbonyl with up to 10C, Ar<2> or Ar<2>-1-6C alkoxy-carbonyl; R4 = H, Ar<2>, Ar<2>-1-6C alkyl or 1-8C alkyl; R5 = Ar<3>, Ar<3>-1-6C alkyl, CN, 1-8C alkyl, CF3 or -NR6R7; R6, R7 = H, Ph or 1-6C alkyl; Ar<1> = aryl with up to 10C opt. substd. by halo, CN, NO2, CF3, 1-6C alkyl or 1-6C alkoxy; Ar<2> = aryl with up to 10C; Ar<3> = aryl with up to 10C opt. substd. by halo, NO2, 1-6C alkyl or 1-6C alkoxy.

Description

The invention relates to N-substituted trifluoromethyl lactams, processes for their Production and their use, in particular as a medicament for treatment brain disorders.

The invention relates to N-substituted trifluoromethyl lactams of the general Formula (I)

in which
R¹ represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, or
represents trifluoromethyl,
A represents an alkylene or alkenylene chain with up to 6 carbon atoms and
R² stands for straight-chain or branched alkoxyl with up to 6 carbon atoms or for a group of the formula -NR³R⁴ or -SO₂-R⁵,
wherein
R³ denotes straight-chain or branched alkyl with up to 8 carbon atoms or alkoxycarbonyl with up to 10 carbon atoms, aryl or aralkyloxycarbonyl with up to 10 carbon atoms in the aryl part and up to 6 carbon atoms in the alkyl part,
R⁴ is hydrogen or aryl with up to 10 carbon atoms or aralkyl with up to 10 carbon atoms in the aryl part and with up to 6 carbon atoms in the alkyl part or straight-chain or branched alkyl with up to 8 carbon atoms and
R⁵ means aryl or aralkyl each having up to 10 carbon atoms in the aryl part and up to 6 carbon atoms in the alkyl part, where the aryl radical can be substituted by halogen, nitro, alkyl or alkoxy having up to 6 carbon atoms, or cyano or straight-chain or branched alkyl having up to to 8 carbon atoms means or trifluoromethyl or means a group of the formula -NR⁷R⁷,
in which
R⁶ and R⁷ are the same or different and represents hydrogen, phenyl or alkyl having up to 6 carbon atoms or
A stands for a direct bond and
R² stands for a group -R⁸,
in which
R⁸ is hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms or aryl or aralkyl each having up to 10 carbon atoms in the aryl part and up to 6 carbon atoms in the alkyl part and where the aryl part can in each case be substituted by halogen, cyano, nitro, trifluoromethyl , Alkyl or alkoxy each with up to 6 carbon atoms,
and their salts.

Compounds of the formula (I) in which
R¹ represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, or
represents trifluoromethyl,
A represents an alkylene chain with up to 4 carbon atoms and
R² represents straight-chain and branched alkoxy having up to 4 carbon atoms or a group of the formula -NR³R⁴ or -SO₂R⁵, wherein
R³ denotes straight-chain or branched alkyl having up to 6 carbon atoms, or alkoxycarbonyl having up to 8 carbon atoms or phenoxycarbonyl or benzyloxycarbonyl,
R⁴ is hydrogen or phenyl, benzyl or straight-chain or ver branched alkyl having up to 6 carbon atoms, or phenyl or benzyl
and
R⁵ denotes phenyl or benzyl, where the phenyl ring can in each case be substituted by fluorine, chlorine, methyl or methoxy, or straight-chain or branched alkyl having up to 3 carbon atoms or trifluoromethyl,
and their salts.

Compounds of the formula (I) in which
R¹ represents hydrogen, methyl or trifluoromethyl,
A represents a methylene or ethylene chain
and
R² represents straight-chain or branched alkoxy having up to 3 carbon atoms, or a group of the formula -NR³R⁴, wherein
R³ means straight-chain or branched alkyl with up to 4 carbon atoms or alkoxycarbonyl with up to 6 carbon atoms and
R⁴ is hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms
and their salts.

In the context of the present invention are physiologically acceptable salts prefers. Physiologically acceptable salts are generally salts of the invention uses according to the invention with inorganic or organic acids. Before salts with inorganic acids such as hydrochloric acid, bromine are added hydrochloric acid, phosphoric acid or sulfuric acid or salts with organic Carbon or sulfonic acids such as acetic acid, malonic acid, malein acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid  or methanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.

In addition, a process for the preparation of the compounds (1) was found in which
R¹, A and R² have the meaning given above,
characterized in that pyrrolidinone derivatives of the formula

in which
R¹ has the meaning given
with compounds of the formula

Z-A-R² (III),

in which
Z is halogen, in particular bromine or chlorine or Z is another suitable leaving group and
A and R² have the meaning given,
if appropriate in the presence of a diluent and if appropriate in the presence of an acid-binding agent.

The preparation of the compounds of the invention can follow, for example the formula scheme explains:

The substances of the formula (I) according to the invention can be prepared in the presence a diluent. All inert come as diluents organic solvents in question. These include in particular aliphatic, alicyclic and aromatic, optionally halogenated hydrocarbons such as Gasoline, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride substance, chlorobenzene or orthodichlorobenzene, ethers such as diethyl ether, diisopro pylether, dioxane or tetrahydrofuran, ketones such as acetone, butanone, Methyl isopropyl ketone, methyl isobutyl ketone, nitriles such as acetonitrile, propionitrile or benzonitrile; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N- Methylformanilide, N-methylpyrrolidone or hexamethylphosphoric triamide; Esters such as methyl acetate or ethyl acetate or bases such as pyridine or organic acids such as formic acid or acetic acid.

The process according to the invention for the preparation of the compounds of the formula (I) is preferably carried out in the presence of a suitable acid-binding agent leads. As such, all commonly used inorganic or organic bases in question. Alkali metal alcoholates are preferably used, such as sodium or potassium methanolate or ethanolate or tert-butoxide or Alkali metal carbonates, such as sodium carbonate, potassium carbonate or Sodium bicarbonate, also lower tert-alkylamines, cycloalkylamines or Arylalkylamines such as triethylamine, N, N-dimethylbenzylamine, also pyridine.

The reaction temperatures can be in the process according to the invention Preparation of the compounds of general formula (I) in a larger Be  be varied widely. Generally one works at temperatures between -30 ° C and + 200 ° C, preferably at temperatures between 0 ° C and + 130 ° C.

When carrying out the method according to the invention, the implementation of Compounds (II) with (III) using an acid binding agent such as the bases mentioned above.

The method according to the invention can optionally also be carried out in a two phase system, such as water / toluene or water / dichloromethane, optionally in the presence of a suitable phase transfer catalyst be performed. Examples of such catalysts are: tetrabutyl ammonium iodide, tetrabutylammonium bromide, tetrabutylammonium chloride, tri butyl-methylphosphonium bromide, trimethyl-C₁₃-C₁₅-alkylammonium chloride, tri methyl-C₁₃-C₁₅-alkylammonium bromide, dibenzyl-dimethyl-ammonium methylsul fat, dimethyl-C₁₂-C₁₄-alkylbenzylammonium chloride, dimethyl-C₁₂-C₁₄-alkyl-ben cylammonium bromide, tetrabutylammonium hydroxide, triethylbenzylammonium chloride, methyltrioctylammonium chloride, trimethylbenzylammonium chloride, 15- Krone-5, 18-Krone-6 or tris- [2- (2-methoxyethoxy) ethyl] amine.

The process according to the invention is usually carried out under normal pressure carried out. However, it is also possible under increased or reduced pressure to work.

To carry out the process according to the invention, the starting point is per mole Pyrrolidone derivative of formula (II) generally 1.0 to 5.0 mol, preferably 1.0 to 2.5 mol of compound of formula (III) and optionally 0.01 to 5.0 moles, preferably 1.0 to 3.0 moles of reaction auxiliary.

In a special embodiment, it is also possible to use the pyrrolidine Derivatives of formula (II) initially in a preceding reaction step Using conventional silylation processes, for example with hexamethyldisilazane or Trimethylsilyl chloride, optionally in the presence of a suitable catalyst, such as sulfuric acid, trifluoroacetic acid, ammonium sulfate, imidazole or silylate saccharin at temperatures between -20 ° C and + 150 ° C and the 1-trimethylsilylbenzimidazoles thus obtained in a subsequent second  Step with alkylating agents of formula (II) according to the invention Implement procedures. In this case, it is advantageous as a catalyst for Add alkylation reaction to tin tetrachloride.

Carrying out the reaction, working up and isolating the reaction products takes place according to known methods (see also the production examples).

The end products of the formula (I) are purified using conventional methods drive, for example by column chromatography or by recrystallization.

The characterization takes place with the help of the melting point or at not kri installing compounds - especially with regioisomer mixtures - with Proton nuclear magnetic resonance spectroscopy (1 H-NMR).

The effectiveness of the compounds according to the invention and thus their suitability for the treatment and prevention of cerebral dysfunction was using the model the determination of the shock threshold procedure.  

Experiment description

Individual young adult male Wistar rats were placed in a chamber electrifiable metal grid floor used. After a short while the animals were able to get used to the shock chamber, an initial flow of 0.20 mA, administered to the feet of the rats for a period of 0.5 s. If still no behavioral reaction, such as paw licking, jumping or vocalization, the foot shock was increased by a step of 0.05 mA. This process was repeated until the rat showed a behavioral response to the foot shock. The Shock intensity at which an initial behavioral reaction occurred was considered Shock limit defined.

To see the effect of drug treatment on the shock threshold the rats were divided into groups of 10. Every group was orally or intraperitoneally either with a test substance or with a vehicle in which the test substance was dissolved, treated. 30 minutes after the administration the shock limit of each rat was assessed and the average of the individual groups. The average shock thresholds with a Test-treated rats were treated with the appropriate vehicle treated animals (controls) compared. The percentage increase or decrease in Shock thresholds of the treated rats compared to the controls were determined determined.

It was found empirically that substances with a nootropic and perceptual increasing effect such as piracetam or tetrahydroamino acridin (THA) reduce the shock limit. In contrast, the shock limit worth with substances with an amnestic effect like the scopolamine elevated. Therefore, the shock limit test for the determination of substances with nootropic effect. Examples are listed in Table 1. The compounds of Examples X, Y and Z reduce the shock threshold lower doses than the reference nootropic piracetam and therefore are stronger nootropics or cognitive enhancers than piracetam.  

The invention also relates to pharmaceutical compositions which contain the said Compounds in an effective amount contain their preparation and Use for the treatment and prevention of the aforesaid Diseases.

The new active ingredients can be introduced into the usual formulations in a known manner such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, Suspensions or solutions using inert non-toxic pharmaceutically suitable carriers or solvents are transferred. Here the therapeutically active compound is in each case in a concentration of about 0.5 to 90% by weight of the total mixture is present, d. H. in quantities that are sufficient to achieve the specified dosage range.

The formulations are prepared, for example, by stretching the Active ingredients with solvents and / or carriers, optionally under Use of emulsifiers and / or dispersants, z. B. in the case of Use of water as a diluent, if necessary organic Solvents or auxiliary solvents can be used.

The application is carried out in the usual way, preferably orally or parinterally, especially perlingually or intravenously. A transdermal application is also possible, e.g. B. by plasters.

In the case of parciteral use, solutions of the active ingredients can be found below Use of suitable carrier materials can be used.

In general, it has proven to be advantageous for intravenous administration Amounts from 0.1 to 100 mg / kg, preferably from 1 to 10 mg / kg body weight To achieve the desired results, administer and oral Application is advantageously about 0.1 to 1000 mg / kg, preferably 1 to 100 mg / kg body weight.

Nevertheless, it may be necessary from the amounts mentioned deviate, depending on body weight or the type of Application route of individual behavior towards the drug, the  Kind of its formulation and the time or interval at which the Administration takes place. So in some cases it may be enough with less than the specified minimum quantity, while in other cases the mentioned upper limit must be exceeded. In the case of the application Larger quantities, it may be advisable to use these in several single doses spread over the day.

Manufacturing examples example 1

To a solution of 6.7 g (0.04 mol) of 5- (trifluoromethyl) -5-methyl-pyrrolidin-2-one in 200 ml of dichloromethane, to which 7 ml of triethylamine have been added Room temperature with stirring 5 ml of chloromethyl ethyl ether in 10 ml of dichlorme than dropped. The reaction mixture is heated to reflux for 16 hours then washed three times with water and the organic phase over magne dried sodium sulfate. After filtration, the volatile components in Vacuum removed and the crude product obtained on silica gel with dichlor Filtered methane as eluent by chromatography.

3.5 g (39% yield of the product) are obtained in the form of colorless crystals Theory) with a melting point of 84 ° C.  

Example 2

To a solution of 3.34 g (0.02 mol) of 5- (trifluoromethyl) -5-methyl-pyrrolidin-2- on in 100 ml of dichloromethane, to which 7 ml of triethylamine are added Room temperature with stirring 3.8 g (0.025 mol) of N-methyl-N-chloromethyl-N- ethoxycarbonylamine added dropwise in 10 ml dichloromethane. It turns into 16 hours Heated to reflux, the reaction mixture was then washed three times with water and the organic phase dried over magnesium sulfate. After filtration, the volatile constituents removed in vacuo and the crude product obtained over Chromatographically filtered silica gel with dichloromethane as the eluent.

3.0 g of product are obtained (53.1% yield of theory)
1 H-NMR (in CDCl₃ / TMS):
δ = 0.88 ppm, 1.22 ppm, 2.12 ppm, 2.32 ppm, 2.95 ppm, 4.20 ppm, 4.45 ppm

Example 3

Analogously to Preparation Example 2, the reaction of 5- (trifluoromethyl) 5-methyl-pyrrolidin-2-one with N-propyl-N-chloromethyl-N-ethoxycarbonylamine derivative

produced in a yield of 66% of theory.
1 H-NMR (in CDCl₃ / TMS):
δ = 0.91 ppm, 1.03-1.45 ppm, 2.40 ppm, 3.32-3.70 ppm, 4.25 ppm, 5.13 ppm

Example 4

6.7 g (0.04 mol) of 5- (trifluoromethyl) -5-methyl-pyrrolidin-2-one are mixed with 7.2 g Potassium carbonate and 0.5 g tetrabutylammonium bromide in 100 ml toluene suspended. After adding 8.24 g (0.05 mol) of N-ethyl-N-chloromethyl-N- ethoxycarbonylamine is heated to reflux for 16 hours. Then will the reaction mixture washed three times with water and the organic phase dried over magnesium sulfate. After filtration, the volatile Components removed in vacuo and the crude product obtained on silica gel Filtered chromatographically with dichloromethane as the eluent.

10.5 g of product are obtained (89% yield of theory).
1 H-NMR (in CDCl₃ / TMS):
δ = 0.89 ppm, 1.05-1.31 ppm, 2.40 ppm, 3.30 ppm, 4.18 ppm, 4.91 ppm

Claims (8)

1. N-substituted trifluoromethyl lactams of the general formula (I) in which
R¹ is hydrogen or
stands for straight-chain or branched alkyl having up to 6 carbon atoms, or
represents trifluoromethyl,
A represents an alkylene or alkenylene chain with up to 6 carbon atoms and
R² stands for straight-chain or branched alkoxyl with up to 6 carbon atoms or for a group of the formula -NR³R⁴ or -SO₂-R⁵,
wherein
R³ means straight-chain or branched alkyl with up to 8 carbon atoms or alkoxycarbonyl with up to 10 carbon atoms, aryl or aralkyloxycarbonyl with up to 10 carbon atoms in the aryl part and up to 6 carbon atoms in the alkyl part,
R⁴ is hydrogen or aryl with up to 10 carbon atoms or aralkyl with up to 10 carbon atoms in the aryl part and with up to 6 carbon atoms in the alkyl part or straight-chain or branched alkyl with up to 8 carbon atoms and
R⁵ means aryl or aralkyl, each with up to 10 carbon atoms in the aryl part and up to 6 carbon atoms in the alkyl part, where the aryl radical can be substituted by halogen, nitro, alkyl or alkoxy with up to 6 carbon atoms, or cyano or straight-chain or branched alkyl having up to 8 carbon atoms or tri fluoromethyl or a group of the formula -NR⁶R⁷,
in which
R⁶ and R⁷ are the same or different and represents hydrogen, phenyl or alkyl having up to 6 carbon atoms or
A stands for a direct bond and
R² stands for a group -R⁸,
in which
R⁸ denotes hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms or aryl or aralkyl each having up to 10 carbon atoms in the aryl part and up to 6 carbon atoms in the alkyl part and where the aryl part can in each case be substituted by halogen, cyano, nitro, Trifluoromethyl, alkyl or alkoxy, each with up to 6 carbon atoms, and their salts. 2. Compounds of general formula (I) according to claim 1, in which
R¹ represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, or
represents trifluoromethyl,
A represents an alkylene chain with up to 4 carbon atoms and
R² stands for straight-chain and branched alkoxy with up to 4 carbon atoms or for a group of the formula -NR³R⁴ or -SO₂R⁵, wherein
R³ denotes straight-chain or branched alkyl having up to 6 carbon atoms, or alkoxycarbonyl having up to 8 carbon atoms or phenoxycarbonyl or benzyloxycarbonyl,
R⁴ is hydrogen or phenyl, benzyl or straight-chain or branched alkyl having up to 6 carbon atoms, or phenyl or benzyl
and
R⁵ is phenyl or benzyl, where the phenyl ring can be substituted by fluorine, chlorine, methyl or methoxy, or straight-chain or branched alkyl having up to 3 carbon atoms or trifluoromethyl. 3. Compounds of general formula (I) according to claim 1, in which
R¹ represents hydrogen, methyl or trifluoromethyl,
A represents a methylene or ethylene chain
and
R² stands for straight-chain or branched alkoxy with up to 3 carbon atoms, or for a group of the formula -NR³R⁴, wherein
R³ means straight-chain or branched alkyl with up to 4 carbon atoms or alkoxycarbonyl with up to 6 carbon atoms and
R⁴ is hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms. 4. A process for the preparation of compounds of general formula (I) according to claim 1, characterized in that pyrrolidone derivatives of the formula (II) in which
R¹ has the meaning given
with compounds of the formula Z-A-R² (III), in which
Z is halogen, in particular bromine or chlorine or Z is another suitable leaving group and
A and R² have the meaning given,
if appropriate in the presence of a diluent and if appropriate in the presence of an acid-binding agent. 5. Medicament containing at least one compound of the general Formula (I) according to claim 1. 6. A process for the manufacture of medicaments, characterized in that at least one compound of the general formula (I) according to An saying 1 if necessary using conventional auxiliaries and carriers substances transferred into a suitable application form. 7. Use of compounds of general formula (I) according to An Proverb 1 in the manufacture of drugs to treat brain performance disorders. 8. Compounds of general formula (I) according to claim 1 for use in fighting diseases.