DE19601938A1 - New phosphodiesterase inhibitors - Google Patents

Abstract

Described are compounds of the formula (I), their preparation and their use in drugs.

Description

The invention relates to the compounds of formula I, the process for their preparation and their use in medicines.

It is known that selective inhibitors of cAMP-specific phosphodiesterase IV (cAMP-PDE IV inhibitor) possess pharmacological properties on the basis of which they represent suitable active ingredients in pharmaceutical preparations. One of the best known Compounds of the inhibitors of cAMP-PDE-IV is rolipram (4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone, USP 4,194,926. To make Rolipram effective improve, numerous modifications have been made to the molecule, but without to achieve the desired increase in effectiveness.

Surprisingly, it has now been found that the compounds of the formula I are very represent potent selective cAMP-PDE IV inhibitors that are metabolically very stable. As the new compounds, the properties known from inhibitors of PDE-IV show how, for example, influencing the central neurotransmission, relaxation of the smooth muscle cells and inhibition of TNF production while prolonged Have a duration of action, they are more advantageous as a drug than rolipram.

The invention relates to the compounds of formula I.

wherein
R1 C _1-4 alkyl,
R² is C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _1-2 alkyl, C _2-6 alkenyl, C _7-8 bicycloalkyl, a heterocycle or C _1-6 Alkyl which is substituted by one or more halogens, hydroxy, carboxy, C _1-4 alkoxy, C _1-4 alkoxycarbonyl or an amino group which is optionally substituted by C _1-4 alkyl,

R⁴ is hydrogen or C _1-6 alkyl,
R⁴ ′ C _1-6 alkyl,
R⁵ is hydrogen, C _1-6 alkyl, C _1-6 alkanoyl, benzoyl, benzyl, mesyl, phenyl, benzethyl,
R⁶ C _1-4 alkyl, hydroxy,
R⁷ hydrogen, hydroxy and
their isomers and mixtures thereof.

The compounds of the formula I can contain one or more chiral centers and also include the racemic diastereomeric mixtures and the individual optical ones Isomers.

Alkyl in each case means straight-chain or branched alkyl groups such as, for example Methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-methyl-butyl, 2,2-dimethylpropyl and hexyl.

Alkenyl means, for example, 1-propenyl, 2-propenyl or 3-methyl-2-propenyl.

Cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or to understand cycloheptyl.

The term "heterocycle" encompasses a 5- or 6-membered saturated heterocycle with an oxygen, sulfur or nitrogen atom such as 2- and 3-tetra hydropyranyl, 2- and 3-tetrahydrofuranyl, dihydropyranyl, pyrrolidinyl, pyrrolinyl, pipe ridinyl and N-alkyl-pyrrolidinyl and N-alkyl-piperidinyl wherein the alkyl radical 1-4 Koh contains atomic atoms. Heterocycles with more than one are also included Heteroatoms such as morpholine, piperazine and N-alkyl-piperazine.

Halogen means chlorine, fluorine, bromine and iodine.

Examples of bicycloalkyls are bicyclo [2.2.1] hept-2-yl, bicyclo [2.2.2] oct-2-yl, Bicyclo [3.2.1] oct-3-yl.

Preferred compounds of the formula I are those in which R 1 is methyl and R 2 is cyclopentyl mean.

The new compounds of formula I and their isomers are inhibitors of Phosphodiesterase IV and influence the targeted intervention in the cAMP metabolism the signaling function of this important intracellular transmitter, which the molecular substrate of information transfer in a variety of biochemical Represents reactions. The different partial aspects of the action profile can be based on this base pharmacological mechanism, which is an explanatory basis  supplies u. a. for the anti-inflammatory effect and the good neuropsychotropic Effectiveness.

Because of their activity profile, the compounds of the formula I are suitable for treatment neurodegenerative diseases such as dementia, Parkinson's disease, depression, inflammatory diseases such as arthritis, shock, sepsis, pulmonary diseases, Bone resorption diseases, HIV infection, cerebral malaria, multiple sclerosis and inflammatory skin diseases. Furthermore, the invention Compounds also bronchospasmolytic, antiproliferative, antiplatelet and tocolytic properties.

The effectiveness of the compounds of formula I in the known indications can be shown by appropriate pharmacological tests. When connecting the Formula I, which have an asymmetric center, is often at the biological activity one of the stereoisomers larger.

The agents are produced by customary methods by adding the active ingredient suitable carriers, auxiliaries and / or additives in the form of a pharmaceutical Brings preparation that is suitable for enteral or parenteral application. The Application can be oral or sublingual as a solid in the form of capsules or tablets or as a liquid in the form of solutions, suspensions, elixirs, aerosols or Emulsions or rectally in the form of suppositories or in the form of, if appropriate Subcutaneously applicable injection solutions or topically or intrathecally. As Auxiliaries for the desired pharmaceutical formulation are those of ordinary skill in the art known inert organic and inorganic carrier materials such as. B. Water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. If necessary, can also Preservatives, stabilizers, wetting agents, emulsifiers or salts for modification osmotic pressure or buffer.

The pharmaceutical preparations can be in solid form, for example as tablets, Dragees, suppositories, capsules or in liquid form e.g. B. as solutions, suspensions or emulsions are present.

Auxiliary materials such as salts and bile acids can also be used as carrier systems or animal or vegetable phospholipids, but also mixtures thereof as well Liposomes or their components can be used.  

Tablets, coated tablets or capsules with talc are particularly suitable for oral use and / or hydrocarbon carriers or binders, such as. B. lactose, corn or Potato starch, suitable. The application can also be in liquid form, such as. B. as juice, to which sweetener may be added.

For parenteral use, especially injection solutions or suspensions, in particular aqueous solutions of the active compounds in polyhydroxyethoxylated Castor oil, suitable or also implanted mini pumps with delayed active ingredient release.

The pharmaceutical product can be in a single dose or in multiple doses e.g. B. 2, 3 or 4 times a day or by an osmotic pump that enable continuous application. The active ingredients can be used in one single or separate dosing or at different times, for example be administered alternately.

For topical application, the active ingredients are used in a conventional manner Processed using conventional emulsifiers and auxiliaries.

The dosage of the active ingredients can vary depending on the route of administration, age and weight of the Patients, type and severity of the disease to be treated and similar factors vary. The daily dose is 0.001-100 mg, preferably 0.01-40 mg, the Dose as a single dose or divided into 2 or more Daily doses can be given.

The compounds of formula I are prepared by methods known per se, such as they in the literature (e.g. in standard works such as Houben-Weyl, Methods of the Org. Chemistry, Georg Thieme Verlag Stuttgart) are described, under reaction conditions that are known or suitable for the implementations mentioned. It can one also makes use of known variants not mentioned here.

The invention therefore relates to the process for the preparation of the compounds of Formula I and its isomers.

The process for the preparation of the compounds of formula I-a and I-b is thereby characterized in that a compound of formula II

wherein R¹, R² and R⁴ have the above meaning and R⁶ 'is hydrogen or C _1-6 alkyl, decarboxylated. The decarboxylation is carried out thermally by heating to 180 ° C., optionally in an inert solvent such as hydrocarbons.

The compounds of the formula Ia cannot be prepared via the starting materials IIa according to the syntheses known from USP 4.193.626 and USP 4.153.713 but according to the following scheme 1:

Here, the ketone is reacted with nitromethane in inert solvents such as halogenated hydrocarbons, cyclic or acyclic ethers or hydrocarbons such as dichloromethane, tetrahydrofuran, toluene in the presence of organic bases such as triethylamine. The condensation is carried out under pressure. The 2-nitroethanol derivative thus obtained is dehydrated in the usual manner in the presence of p-toluenesulfonic acid. The subsequent reaction of the nitrostyrene derivative with a di- (C _1-5 ) -alkyl-malonic ester is carried out in the presence of bases such as alkali metal alcoholates either at room temperature or under pressure.

The cyclization to the corresponding lactam is achieved reductively with inert Raney nickel Solvents such as cyclic ethers, alcohols and mixtures thereof. Advantageous for the implementation is increased H₂ pressure and temperature. The saponification of the Ester group is made basic by raising the temperature to the boiling point of the reaction mixture with alkali metal hydroxides in aqueous solvents such as alcohols or hydrolyzed cyclic ethers.

All reactions are expediently carried out under inert gas.

The preparation of the starting materials of the formula II, in which R⁶ is C _1-6 alkyl, is carried out analogously to scheme 1, by reacting the ketone or the aldehyde with nitroethane and working up as described above.

The process for the preparation of the compounds of formula I, wherein R³ den Heterocycle (c) means is characterized in that a compound of Formula III

wherein R¹ and R² have the above meaning, RC _1-5 alkyl and Hal is halogen, cyclized with ammonia to a compound of formula Ic '

and, if desired, subsequently hydroxylated to a compound of the formula I-c ′ ′

and then, if desired, hydrogenated to a compound of formula I-b ′ ′

The cyclization of the compounds of formula III takes place by using the halogen derivative, especially the bromide or iodide, with ammonia in protic solvents such as Alcohols. The reaction is generally carried out at temperatures from 0 ° C to Room temperature.

The hydroxylation can be carried out in the presence of Cu (I) and Cu (II) halides, such as Bromides, in aqueous solvent mixtures, such as dimethyl form amide / water by introducing air.  

The hydrogenation to compounds of formula I-b '' is carried out catalytically in polar Solvents at room temperature or elevated temperature. As catalysts are Precious metal catalysts such as platinum, palladium or Pd / BaSO₄ suitable.

The process for the preparation of the compounds of formula I, wherein R³ den Heterocycle (d) is characterized in that a compound of Formula IV

wherein R¹ and R² have the above meaning and R is each C _1-5 alkyl, intramolecularly condensed to a compound of formula Id.

The condensation to the lactone of formula I-d succeeds by the compound of Formula IV in inert solvents such as high-boiling hydrocarbon substances heated with p-toluenesulfonic acid.

The process for the preparation of the compounds of the formula I-e and I-f is thereby characterized in that a compound of formula V

wherein R¹ and R² have the above meaning, with hydroxylamines to a compound rearranged of the formula I-e and, if desired, then hydrogenated to a Compound of formula I-f.  

The intermediate oxime formed can, for example, with O-mesitylene sulfonyl hydroxyl amine in inert solvents such as halogenated or aromatic hydrocarbons can be obtained at room temperature. The rearrangement occurs in the presence of bases such as for example basic aluminum oxide.

The reduction of the double bond can be carried out in the usual way, for example in the presence of noble metal catalysts such as palladium or platinum, optionally on supports, in polar solvents at room temperature or elevated temperature.

If desired, the compounds of the formula I thus obtained can subsequently be added to are usually alkylated, acylated or arylated or separated into the isomers will.

The introduction of the substituent R⁵ succeeds by the usual methods, for example by the reactive derivative R⁵X, wherein X is halogen or tosylate, in Presence of a base such as alkali metal hydroxide, carbonate or alcoholate or alkali metal hydride implements.

The mixtures of isomers can be prepared using customary methods such as, for example Chromatography, crystallization or conversion into diastereomers such as, for example Salt formation can be separated into the enantiomers. The enantiomer separation can be carried out on the Final stage or in the intermediate stages, optionally the enantiomers can also be synthesized from chiral intermediates or with chiral auxiliaries.

As far as the preparation of the starting compounds is not described, these are known or can be produced analogously to known or described methods.

For example, the compounds of formula V are by the method of M.J. Bestmann et al. Chem. Ber. 118, 2640-2658 [1985].

The following examples are intended to explain the process according to the invention.

example 1 4 (3-cyclopentyloxy-4-methoxypheny) -4-methyl-pyrrolidin-2-one a) 1- (3-Cyclopentyloxy-4-methoxyphenyl) -1-methyl-2-nitroethanol

A solution of 8.0 g (34.1 mmol) of 3-cyclopentyloxy-4-methoxy-acetophenone in 8 ml Dichloromethane is added after adding 10 ml of nitromethane and 8 ml of triethylamine a sealed polytetrafluoroethylene tube (PTFE shrink tube 3/8 ′ ′, Shrinkage rate 4: 1) in a high pressure apparatus 7 days an isostatic pressure from 12 exposed to kbar. The reaction mixture is then placed in a 250 ml round bottom flask transferred and the solvent evaporated in vacuo. The residue is in 400 ml Dichloromethane taken up, the solution is washed four times with 50 ml of water, Dried over sodium sulfate and evaporated in vacuo. The residue of 8.76 g is chromatographed on a preparative HPLC stainless steel column (stationary phase: Kromasil SIL 13 µm, mobile phase: hexane / ethyl acetate = 9: 1, flow: 100 ml / min, pressure: 2.0 MPa). 4.93 g (62%) of starting material and 3.37 g (33% of theory) are eluted 1- (3- Cyclopentyloxy-4-methoxyphenyl) -1-methyl-2-nitroethanol.

b) 3-Cyclopentyloxy-4-methoxy-α-methyl-β-nitrostyrene

A solution of 2.58 g (8.73 mmol) of 1- (3-cyclopentyloxy-4-methoxyphenyl) -1-methyl-2- nitroethanol in 80 ml of benzene is mixed with 120 mg of p-toluenesulfonic acid and 30 min distilled slowly azeotropically. After cooling to room temperature, the Reaction solution washed with 50 ml of saturated sodium bicarbonate solution, over Dried sodium sulfate and evaporated in vacuo. The oily residue of 2.67 g is subjected to flash chromatography on silica gel (mobile phase: 1 l of ethyl acetate, then hexane / ethyl acetate = 9: 1). 2.31 g (95% of theory) of 3-cyclopentyloxy-4-methoxy-4-methyl-β-nitrostyrene are eluted as a yellow oil (E / Z mixture in Ratio 9: 1).

c) 1- (3-Cyclopentyloxy-4-methoxyphenyl) -1-methyl-1-nitromethyl ethane-2,2-dicarboxylic acid dimethyl ester

A. A solution of 562 mg sodium methylate in 12.5 ml methanol is mixed with 2.83 ml Dimethyl malonate was added and the mixture was stirred at room temperature for 10 min under argon. This The reaction mixture is dissolved in a solution of 2.08 g (7.50 mmol) of 3-cyclopentyloxy-4- added methoxy-α-methyl-β-nitrostyrene in 5.0 ml of methanol, which was then taken for 1 h Argon is stirred at room temperature. After adding 1.25 ml more concentrated Acetic acid precipitates the reaction product with water and in diethyl ether  added. The ether phase is washed with water and dried over sodium sulfate and evaporated in vacuo. The residue obtained is 2.27 g, which together with 1.13 g Product from an analogous batch with 1.05 g (3.78 mmol) of 3-cyclopentyloxy-4-methoxy α-methyl-β-nitrostyrene, chromatographed on a preparative HPLC stainless steel column (stationary phase: Kromasil SIL 13 µm, mobile phase: hexane / ethyl acetate = 9: 1 and 4: 1, flow: 100 ml / min, pressure: 0.95 MPa). 230 mg (7%) of starting material is eluted, 1.86 g (59% of theory) 3-cyclopentyloxy4-methoxy-α-nitromethylstyrene and 1.51 g (33% of theory) 1- (3-Cyclopentyloxy-4-methoxyphenyl) -1-methyl-1-nitromethyl ethane-2,2-dicarboxylic acid dimethyl ester.

B. A solution of 1.90 g (6.85 mmol) of 3-cyclopentyloxy-4-methoxy-α-methyl-β-nitrostyrene in 11.9 ml of methanol with 2.45 ml of dimethylmalonate and 487 mg Sodium methylate added. The mixture is sealed Polytetrafluoroethylene tubing (PTFE shrink tubing 3/8 ′ ′, shrinking rate 4: 1) in one High pressure apparatus exposed to an isostatic pressure of 12 kbar for 18 h. Subsequently the reaction solution is added to 1.2 ml of concentrated acetic acid and with stirring 35 ml of water added. The precipitated product is taken up in diethyl ether, which The ether phase is washed with water, dried over sodium sulfate and in vacuo evaporated. The residue obtained 2.61 g, which on a preparative HPLC Edel steel column can be chromatographed (stationary phase: Kromasil SIL 10 µm, mobile Phase: hexane / ethyl acetate = 9: 1 + 4: 1, flow: 59 ml / min, pressure: 2.77 MPa). You elute 190 mg (10%) starting material and 1.17 g (42% of theory) 1- (3-cyclopentyloxy-4- methoxyphenyl) -1-methyl-1-nitromethyl-ethane-2,2-dicarboxylic acid dimethyl ester as an oil.

d) 4- (3-cyclopentyloxy-4-methoxyphenyl) -4-methyl-2-oxo-pyrrolidine 3-carboxylic acid methyl ester

1.50 g (3.66 mmol) of 1- (3-cyclopentyloxy4-methoxyphenyl) -1-methyl-1-nitromethyl ethane-2,2-dicarboxylic acid dimethyl ester, dissolved in a mixture of 14 ml Tetrahydrofuran and 6 ml of methanol are mixed with 300 mg of Raney nickel (B115Z) and in an autoclave for 2 hours at a hydrogen pressure of 20 bar and a temperature of 70 ° C hydrogenated (3 bar hydrogen uptake). After cooling, another 300 mg Raney nickel is added and the reaction is carried out at 110 bar of hydrogen and 90 ° C. for 2.5 h maintained (15 bar hydrogen uptake). After cooling, the catalyst suctioned off, the filtrate is mixed with activated carbon, suctioned off hot and in vacuo evaporated. The residue is dried in a high vacuum. Yield: 1.12 g (88% of Theory) 4- (3-cyclopentyloxy-4-methoxyphenyl) -4-methyl-2-oxo-pyrrolidin-3- carboxylic acid methyl ester.  

e) 4- (3-Cydopentyloxy-4-methoxyphenyl) -4-methyl-2-oxo-pyrrolidine-3-carboxylic acid

A solution of 1.1 g (3.16 mmol) of 4- (3-cyclopentyloxy-4-methoxyphenyl) -4-methyl-2- oxo-pyrrolidine-3-carboxylic acid methyl ester in 10 ml of methanol is made under argon with 180 mg of sodium hydroxide, dissolved in 2.5 ml of water, added and then heated to boiling for 2 h. The reaction solution is evaporated in vacuo, the residue is washed with 50 ml of water added and extracted twice with 50 ml of ethyl acetate. The aqueous phase is in Vacuum removed from the remaining ethyl acetate and carefully after cooling with ice acidified concentrated hydrochloric acid. The resulting precipitate is in ethyl acetate added, the solution is dried over sodium sulfate and in vacuo evaporated. 933 mg (88% of theory) of 4- (3-cyclopentyloxy- 4-methoxyphenyl) -4-methyl-2-oxo-pyrrolidine-3-carboxylic acid as a viscous oil.

f) 4- (3-Cyclopentyloxy-4-methoxyphenyl) -4-methyl-pyrrolidin-2-one (4-methylrolipram)

933 mg (2.79 mmol) of 4- (3-cyclopentyloxy-4-methoxyphenyl) -4-methyl-2-oxo-pyrrolidin-3-car-bonic acid are slowly in a 250 ml round bottom flask in an oil bath Room temperature heated to 160 ° C. During this time the flask is filled with argon rinsed. Between 117 and 155 ° C a clear development of Carbon dioxide. After cooling, there are 810 mg of oil in the flask. This is on chromatographed on a preparative HPLC stainless steel column (stationary phase: Kromasil SIL 10 µm, mobile phase: pentane / ethyl acetate = 4: 1 + 7: 3 + 6: 4, flow: 100 ml / min, pressure: 1.26 MPa). 740 mg of crystalline product is eluted. After recrystallization Dichloromethane diisopropyl ether gives 488 mg (60% of theory) 4- (3-Cyclopentyloxy4-methoxyphenyl) -4-methyl-pyrrolidin-2-one with one Melting point of 110.4 ° C. UV: ε₂₂₈ = 9870, ε₂₇₉ = 4200.  

Example 2 4- (3-Cyclopentyloxy-4-methoxyphenyl) -Δ³-pyrrolin-2-one

• a) Sodium hydride (4.0 g, 166 mmol) is stirred in dimethoxyethane (160 ml) registered. At 0 ° C then phosphonoacetic acid ethyl ester (33 ml, 166 mmol) in Dimethoxyethane (50 ml) dissolved, slowly added dropwise and 1 hour at room temperature stirred. Then a solution of (3-cyclopentyloxy4-methoxyaceto phenone (15 g, 64 mmol) in dimethoxymethane (50 ml) was added and until complete reaction (DC control) heated to 80 ° C (about 6 hours). After this Evaporation of the solvent, the residue is taken up in ethyl acetate with Washed water and saturated saline, dried with Siccon and evaporated. After chromatography on silica gel, the residue also gives Methylene chloride 16 g of ethyl 3- (3-cyclopentyloxy-4-methoxyphenyl) but-2-ene (82% of theory) as an oil.
• b) The ethyl 3- (3-cyclopentyloxy-4-methoxyphenyl) butenate (15 g, 49 mmol) in carbon tetrachloride (200 ml) with bromosuccinimide (9.2 g, 52 mmol) and Azobisisobutyronitrile (0.2 g, 12 mmol) heated to boiling under reflux for 2.5 hours. After cooling, it is filtered, the organic phase washed with water, with Siccon dried, evaporated and the oily residue with methylene chloride on silica gel chromatographed. 11.5 g of the bromosester are obtained as a colorless oil (61.2% of the Theory).
• c) 4-Bromo-3- (3-cyclopentyloxy-4-methoxy-phenyl) -butene-2-acid ethyl ester- (10 g, 26 mmol) are dissolved in ethanol saturated with ammonia at 0 ° C and at 18 hours Room temperature stirred. After the solvent has been distilled off, between Ethyl acetate / water distributed, the ethyl acetate phase dried with Siccon and evaporated. The 4- (3-cyclopentyloxy-4-methoxy-phenyl) -Δ³pyrrolin-2-one is obtained (4.83 g, 68% of the Theory), melting point 201-203 ° C.

Example 3 4- (3-Cyclopentyloxy-4-methoxyphenyl) -5-hydroxy-Δ ^3- pyrrolin-2-one

4- (4-methoxy-3cyclopentyloxy-phenyl) -Δ ^3- pyrrolin-2-one (5 g, 18.3 mmol) are dissolved in 100 ml of dimethylformamide, with a solution of copper (I) bromide (1, 5 g) in water (100 ml) and heated for 5 hours while passing air through on the steam bath. It is filtered, the solvents are evaporated, the residue is partitioned between ethyl acetate / water, the organic phase is washed with saturated sodium chloride solution, dried with Siccon and concentrated. After chromatography on silica gel with ethyl acetate-acetone (3: 1), the solid residue gives the desired 5-hydroxy-Δ³-pyrrolin-2-one with a melting point of 215-217 ° (2.1 g, 39.7% of theory) .

Example 4 4- (3-Cyclopentyloxy-4-methoxyphenyl) -5-hydroxy-Δ ^3- pyrrolidin-2-one

The 4- (3-cyclopentyloxy-4-methokyphenyl) -5-hydroxy-Δ ^3- pyrrolin-2-one (2.6 g, 9.5 ml) is in ethanol in the presence of Pd / BaSO₄ until the theoretical Amount of hydrogen hydrogenated. After filtering and evaporating, a crystalline mixture of the cis and trans compound (∼2: 1) is obtained. Chromatography on silica gel with methylene chloride: ethanol (10: 1) gives 0.9 g of the cis compound (from ethyl acetate, melting point 143-146 ° C., 34.4%) and 0.5 g of the trans compound (from Ethyl acetate, melting point 151-153 ° C, 9.1%) and 0.4 g of a mixed fraction (15.3%) of 4- (3-cyclopentyloxy-4-methoxyphenyl) -5-hydroxy-Δ ^3- pyrrolidin-2 -on.

Example 5 a) 3- (3-Cyclopentyloxy-4-methoxy-phenyl) -4-ethoxy-buten-2-carboxylic acid, ethyl ester

Ethyl 4-bromo-3- (3-cyclopentyloxy-4-methoxy-phenyl) -butene-2-carboxylate (7.66 g, 20 mmol) is in 90 percent. Dissolved ethanol (55 ml) and after adding potassium hydroxide (1.2 g, 21.4 mmol) refluxed for 4 hours. You evaporate and get through Chromatography of the residue on silica gel with acetone / methylene chloride 1: 1 Title compound as a colorless oil (2.8 g, 40.2%).

b) 3- (3-Cyclopentyloxy-4-methoxy-phenyl) -butene (2) -4-olide

3- (3-Cyclopentyloxy-4-methoxy-phenyl) -4-ethoxy-buten-2-acid ethyl ester (700 mg, 2nd mmol) in xylene (20 ml) with p-toluenesulfonic acid hydrate (100 mg) for 1.5 hours cooked under reflux. After cooling with saturated sodium bicarbonate solution and washed with saturated saline, dried over Siccon and in Vacuum concentrated. The residue is on silica gel with cyclohexane-ethyl acetate 1: 1  chromatographed. The main fractions are evaporated and the crystalline Crystallized residue from ethyl acetate-diisopropyl ether. You get that Title compound (130 mg, 23.7%) with a melting point of 132 ° C.

Example 6 4- (3-cyclopentyloxy-4-methoxyphenyl) -5,6-dihydropyridine [1H] -2-one

3- (3-cyclopentyloxy-4-methoxy) phenyl-cyclopenten-2-one (544 mg, 1.4 mmol) and O-Mesitylenesulfonyl-hydroxylamine (Y. Tamura, J. Minamikawa, M. Ikeda, Synthesis 1977, 1) (500 mg, 2.3 mmol) are dissolved in methylene chloride (10 ml). After 16 hours at The solvent is evaporated at room temperature, the residue in a little toluene dissolved, drawn up on a column with basic aluminum oxide (30 g) and with methanol eluted. When the eluate is concentrated, the unrearranged mesitylene sulfonyl crystallizes oxime (400 mg). It is filtered, the mother liquor evaporated and chromatographed on Silica gel / acetone methylene chloride (1: 1). 93 mg (59%) of the title compound are obtained, Melting point 99 ° C.

Example 7 4- (3-cyclopentyloxy-4-methoxyphenyl) piperidin-2-one

4- (3-cyclopentyloxy-4-methoxy-phenyl) -5,6-dihydropyridine [1H] -2-one (60 mg, 0.2 mmol) are hydrogenated in Ethanok (10 ml) in the presence of 10 mg palladium-carbon (10 mg). The catalyst is filtered off and the filtrate is concentrated. This crystallizes when cooling Piperidone from (40 mg: 69%), melting point 140-142 °.

Example 8

• a) 3-Cyclopentyloxy-4-methoxy-benzaldehyde (429.5 g; 1.95 mmol) are in Acetic acid (840 ml) dissolved and after addition of ammonium acetate (73 g) and nitroethane (420 ml; 5.9 mmol) until the reaction is complete (TLC control) (approx. 6 hours) 95 ° C warmed. Dilute with water (4 l) and take in the oil which has separated out Methylene chloride (2 + 0.5 l). The methylene chloride phases are with water and saturated sodium bicarbonate solution, washed for 30 minutes with sodium sulfate and stirred coal, suction filtered and evaporated in vacuo. The resulting crystal mash is stirred with ethanol: water (2: 1; 1.6 l) for 1 hour, suction filtered and with ethanol  Washed water (2: 1; 420 ml). 262 g of the title compound (48% of the Theory). Melting point after recrystallization from acetic acid 82-84 °.
• b) Sodium methylate (47 g; 1.12 mmol) is dissolved in methanol (1.2 l) and under Stirring and cooling to 15 ° C dimethyl malonate (91 ml; 0.77M) and (3-Cyclopentyloxy-4-methoxy) -1-methyl-nitrostyrene (200 g; 0.72M) added. After 15 Minutes, the clear solution is carefully mixed with acetic acid (120 ml) while cooling, whereby crystallization takes place. It is diluted with water (2.3 l) and suction filtered after 1 hour. The crystals are washed with water and dried. Yield 293.3 g (99% of Theory), melting point 110-111 ° C.
• c) 2- (3-Cyclopentyloxy-4-methoxyphenyl) -3-nitro-butane1,1-dicarboxylic acid dimethyl ester 90 g; 0.22 mmol) in tetrahydrofuran / methanol (7: 3, 450 ml) in the presence from Raney nickel (18 g) at 60 ° C and 20 bar until the hydrogen uptake stops hydrated. It is filtered from the catalyst, washed with tetrahydrofuran / methanol (7: 3) and concentrated to 60 ml. After dilution with methyl t-butyl ether (270 ml) to approx. 60 ml concentrated and this process repeated. This crystallizes on cooling to 15 ° C Product out. (44.1 g; 53.5%), melting point 164-166 ° C.
• d) 4- (3-Cyclopentyloxy4-methoxy-phenyl) -5-methyl-pyrolidin-2-one-carboxylic acid methyl ester-1 (38.2 g; 0.11M) are suspended in methanol (245 ml) and after adding sodium hydroxide (6.4 g; 0.16 mmol) dissolved in water (160 ml) for 2 hours heated under reflux with stirring. The aqueous phase is cooled with acetic acid acidified, the crystalline precipitate filtered off and washed with water. After this Drying gives the carboxylic acid (34.3 g, 98% of theory), melting point 114-119 ° C.
• e) 4- (Cyclopentyloxy 4-methoxy-phenyl) -5-methyl-pyrrolidin-2-one-carboxylic acid-1 (24.6 g; 0.074 mmol) are stirred until the CO₂ development has ended Heated 180 ° C. The mixture is then kept at 180 ° C. for 30 minutes, cooled and dissolved in 380 ml of ethyl acetate with heating and addition of activated carbon. The hot filtered solution is concentrated to 1/3 of the volume and cooled to -5 ° C. with stirring. You suck it Crystal porridge and receives 14.2 g of 5-methyl-rolipram (66% of theory) with the Melting point 129-130 ° C.

Claims (6)

1. Compounds of formula I. wherein
R1 C _1-4 alkyl,
R² is C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _1-2 alkyl, C _2-6 alkenyl, C _7-8 bicycloalkyl, a heterocycle or C _1-6 alkyl which C _1- 4 alkoxycarbonyl or optionally substituted with C _1-4 alkyl stubstituierten amino group with one or more halogens, hydroxy, carboxy, C _1-4 alkoxy, substituted,
R³ R⁴ is hydrogen or C _1-6 alkyl,
R⁴ ′ C _1-6 alkyl,
R⁵ is hydrogen, C _1-6 alkyl, C _1-6 alkanoyl, benzoyl, benzyl, mesyl, phenyl, benzethyl,
R⁶ C _1-4 alkyl, hydroxy,
R⁷ is hydrogen or hydroxy and
their isomers and mixtures thereof. 2. Medicament containing a compound of formula I and pharmaceutical applicable carrier. 3. Process for the preparation of the compounds of formula Ia and Ib ' wherein R¹, R², R⁴ and R⁵ have the above meaning and R⁶, hydrogen or C _1-6 alkyl, characterized in that a compound of formula II wherein R¹, R² and R⁴ have the above meaning and R⁶, hydrogen or C _1-6 alkyl, decarboxylated and, if desired, then the isomers are separated, alkylated, acylated or arylated. 4. Process for the preparation of the compounds of formula Ic wherein R¹, R², R⁵ and R⁷ have the above meaning, characterized in that a compound of formula III wherein R¹ and R² have the above meaning, RC _1-5 alkyl and Hal is halogen, cyclized with ammonia to a compound of formula Ic ' and, if desired, subsequently hydroxylated to a compound of the formula Ic ′ ′ and then, if desired, hydrogenated to a compound of formula Ib ′ ′ and, if desired, each separates, alkylates, arylates or acylates. 5. Process for the preparation of the compounds of formula Id wherein R¹ and R² have the above meaning, characterized in that a compound of formula IV wherein R¹ and R² have the meaning given above and R is in each case C _1-5 alkyl, condenses intramolecularly and, if desired, subsequently separates the isomers. 6. Process for the preparation of the compounds of formula Ie and If wherein R¹, R² and R⁵ are as defined above and represent a double or single bond, characterized in that a compound of formula V wherein R¹ and R² have the above meaning, rearranged with hydroxylamines to a compound of the formula Ie and, if desired, then hydrogenated to a compound of the formula If or the isomers are separated, alkylated, arylated or acylated.