Substituted piperidine-2,6-diones and methods for their production

 

(57) Abstract:

The invention relates to new substituted piperidine-2,6-diones of the formula (I)

where Z is-C(R1R2)-CH2or-C(R1)=CH-; R1- phthalimid, when Z is-C(R1R2)-CH2- or one - or twofold substituted by hydroxy, methoxy or amino groups phtalimide radical when Z represents-C(R1)=CH-, R2is hydrogen or C1-6alkyl group; R3is hydrogen, C1-6an alkyl group or aromatic ring system; R4- C1-6alkyl or aromatic ring. The compounds of formula (I) possess an inhibitory action on the release of TNF-, and induced antigen synthesis of interleukin-2. The compounds of formula (I) can be obtained by condensation of phthalic anhydride with substituted glutamic acid and subsequent cyclization of the resulting product and transfer it to the imide. Another method of preparing compounds of formula (I) is the condensation of phthalic anhydride with substituted 3-aminoglutethimide or 5-substituted 3-aminoglutethimide. 3 S. and 2 C.p. f-crystals, 1 table.

The invention relates to analogs of thalidomide from the class piperidine-2,6-diones, method of their production and their use in lecaros, transplant rejection, aphthous stomatitis, erythema nedaznai lepromatosis, Beck disease, rheumatoid arthritis and many other diseases accompanied by inflammation, excessive formation which is a cytokine factor - tumor necrosis (TNF-, Tumor-Necrosis-Factor) plays a major role. One of the approaches in therapy of these diseases consists in the purposeful suppression of the release of the F - introduction as active agents immunosuppressive agents, or modulators, such as dexamethasone, pentoxifylline or thalidomide.

However, among the indications for use should distinguish between those which require General immunosuppression, and those that require full account of all the advantages and disadvantages of immunosuppression. It was found that in the treatment of aphthous stomatitis thalidomide is superior to classical immunosuppressants. Other examples of diseases in which thalidomide has shown good efficacy without causing General immunosuppression, are cutaneous lupus erythematosus, (H+G 69, 816-822 (1994)), pyoderma gangrenosum and orogenitalnyh ulcers when illness behceta (The Lancet, 20.05.89, 1093-1095). Pathogenic factors of these limited skin and mucous membrane F - and other cytokines adhesiveness of the endothelium against leukocytes focal increases, that decisively contributes to the formation of vasculitides. When the system paintings disease the action of the thalidomide on the skin and mucous membranes is limited to that (optional) requires immunosuppression. Examples of this is systemic lupus erythematosus, which, along with skin phenomena also cause life-threatening changes in the internal vessels, particularly of the kidneys, caprareccia type II with the defeat of the eyes and/or joints, and also Behcet's disease with lesions of the eye and/or joints.

Substance that is similar to thalidomide suppresses the change of the endothelium, but at the same time fully or partially block the reaction of the specific cellular immune defense, can contribute to significant progress in therapy called systematic patterns of disease. Key information the substance of the cellular immune response is interleukin 2 dependent on antigen specific proliferation of lymphocytes.

Therefore, when developing new drugs aim to make full use of anti-inflammatory properties of thalidomide in conjunction with immunosuppressive active components, which thalidomide in his individual clinical application of ridin-2,6-diones, suppressing caused by inflammation of the release of F-, and induced antigen synthesis of interleukin-2.

It was found that meet the specified requirements proposed according to the invention the connection.

Thus, an object of the present invention are substituted in position 3 and 5 of the piperidine-2,6-diones of General formula (I)

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where Z denotes one of the groups:

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moreover, the carbon atom with a substituent R1linked by a carbonyl group, and

where R1means phtalimide radical (when Z represents-C(R1R2)-CH2- or one - or twofold substituted by hydroxy, methoxy or amino groups phtalimide radical (when Z represents-C(R1)=CH-),

R2denotes hydrogen or C1-6alkyl (linear or branched),

R3denotes hydrogen, C1-6alkyl group (linear or branched), or an aromatic or heteroaromatic ring system, and

R4stands WITH1-6alkyl group (linear or branched), or an aromatic or heteroaromatic ring system.

From piperidine-2,6-diones of the formula (I) in which Z represents-C(R1R2)-CH4is phenyl.

From piperidine-2,6-diones of the formula (I) in which Z represents-C(R1)=CH-, R3denotes ethyl and R4denotes phenyl, most preferably a compound in which R1is 3,4-dimethoxytoluene.

The invention further relates to a method for obtaining analogs of thalidomide from the class piperidine-2,6-diones of General formula (I).

Compounds of General formula (I) in which Z represents-C(R1R2)-CH2- can be obtained by condensation of phthalic anhydride with substituted glutamic acids, for example 4-phenylglutaric acid or 4-methylglucamine acid, in an organic solvent, preferably pyridine, the cyclization product acetanhydride and subsequent transfer to the imide. The conversion of the anhydride imide is carried out by melting in the presence of urea.

These target compounds of formula (I) can be obtained also by the interaction of phthalic anhydride with 5-substituted 3-aminoglutethimide, preferably by heating in acetic acid.

Compounds of General formula (I) in which Z represents-C(R1)=CH-, can be obtained by condensation of substituted phthalic the s, such as, for example 3-amino-5-ethyl-5-phenylphthalimide, in an organic solvent, for example, acetic acid.

Example 1. 2-(5-Methyl-2,6-dioxopiperidin-3-yl)-1,3-dihydro-2H-isoindole-1,3-dione (1)

a 2.00 g (11 mmol) of 4-Methylglucamine acid and 1.95 g (13 mmol) of phthalic anhydride is heated under reflux in 15 ml of dry pyridine for 6 hours After removal of the solvent the residue is heated for 1 h in 10 ml of acetanhydride to a boil. Fallen precipitates upon cooling, the solid is subjected to vacuum filtration and the filtrate concentrated. After mixing the filtrate with simple ether, the precipitate is subjected to vacuum filtration and the combined precipitates is recrystallized from absolute toluene. a 2.00 g (7 mmol) of kristalliset and 0.23 g (3.8 mmol) of urea are thoroughly mixed and melted in an oil bath at approximately 200oC for 30 minutes Frozen melt quickly heated to boiling sequentially with 4 ml of acetanhydride and 6 ml of ethanol. Precipitated precipitated solid is subjected to vacuum filtration and recrystallized from a mixture of DMF/water. This way obtain 1.35 g (67% of theory) of 2-(5-methyl-2,6-dioxopiperidin-3-yl)-1,3-dihydro-2H-isoindole-1,3-dione (1) with temperature plavini (12 mmol) of 4-Phenylglutaric acid and 2.12 g (14 mmol) of phthalic anhydride is heated under reflux in 40 ml of dry pyridine for 6 hours After removal of the solvent the residue is dissolved in 50 ml of 5% model HC1 and extracted with ethyl acetate. The organic phase is washed with water, discolor activated charcoal and dried over sodium sulfate. After removal of the solvent the residue is heated under reflux for 1 h in 40 ml of acetanhydride. Then the solution is concentrated and mixed with simple ether. The precipitation is subjected to vacuum filtration and recrystallized from dry toluene. a 2.00 g (6 mmol) of kristalliset and 0,19 g (3 mmol) of urea is melted in an oil bath at approximately 200oC for 30 minutes Frozen melt quickly heated to boiling sequentially with 4 ml of acetanhydride and 8 ml of ethanol. Precipitated precipitated solid is recrystallized from a mixture of DMF/water. In this way receive 0,80 g (40% of theory) of 2-(5-phenyl-2,6-dioxopiperidin-3-yl)-1,3-dihydro-2H-isoindole-1,3-dione (2) with a melting point 228-231oC.

Example 3. 2-(5-Ethyl-5-phenyl-2,6-dioxopiperidin-3-yl)-1,3-dihydro-2H-isoindole-1,3-dione (3)

to 1.00 g (4 mmol) of 3-Amino-5-ethyl-5-phenylphthalimide dissolved in 40 ml of anhydrous ethanol, the solution is mixed with 0.1 g of palladium on coal (10% Pd/C and stirred under hydrogen atmosphere for 8.5 hours and Then the catalyst otfiltrovana in 40 ml ice-cold vinegar for 4 hours After removal of the solvent the residue is recrystallized from ethanol. In this way receive 0,99 g (63% of theory) of 2-(5-ethyl-5-phenyl-2,6-dioxopiperidin-3-yl)-1,3-dihydro-2H-isoindole-1,3-dione (3) with a melting point 174-177oC.

Example 4. 2-(5-Ethyl-5-phenyl-2,6-dioxo-1,2,5,6-tetrahydropyridine-3-yl)-4,5-dimethoxy-1,3-dihydro-2H-isoindole-1,3-dione (4)

0.45 g (2 mmol) 3-amino-5-ethyl-5-phenylphthalimide and 0.45 g (2 mmol) of 4,5-dimethoxyflavone anhydride is heated under reflux in 15 ml ice-cold vinegar for 5 hours Then concentrated to dryness and the residue is recrystallized from ethanol. This way obtain 0.55 g (67% of theory) of 2-(5-ethyl-5-phenyl-2,6-dioxo-1,2,5,6-tetrahydropyridine-3-yl)-4,5-dimethoxy-1,3-dihydro-2H-isoindole-1,3-dione (4) with a melting point 203-205oC.

Compounds according to the invention is safe from a Toxicological point of view and therefore suitable for use as pharmaceutically active substances. Accordingly, the invention also relates to the use of analogs of thalidomide from the class piperidine-2,6-diones of the formula (I) as active substances in medicinal products, preferably as suppressants for caused by inflammation of the release of F-, as well as induce the necks least one compound of General formula (I) contain media fillers, solvents, diluents, dyes and/or binders. The choice of auxiliary substances, as well as the applied quantities depend on the method of introduction, namely whether the drug is used orally, intravenously, intraperitoneally, intradermally, intramuscularly, nasal, buccal or locally. For oral administration suitable preparations in the form of tablets, chewable tablets, pills, capsules, granules, drops, mixtures or syrups, for parenteral, local, and inhalation use suitable solutions, suspensions, easily reconstituirea dry preparations as well as sprays. Examples of suitable forms for percutaneous applications are proposed connection at the depot in dissolved form, in the film carrier or plaster, optionally with the addition of tools to facilitate penetration through the skin. The release of the proposed compounds in the body of the preparative forms used oral or percutaneous, can occur prolongirovanne.

Assign the patient a dose of the active substance depends on the weight of the patient, method of administration, the indication and the severity of the disease. Commonly used dose is from 1 to 150 mg/kg of at least one analogue of thalidomide formulary cells in human peripheral blood T-lymphocytes, B-lymphocytes and monocytes) after stimulation by lipopolysaccharide (LPS). LPS is a component of the bacterial cell wall and stimulates monocytes and macrophages.

Along with the stimulation with LPS release F - can also be brought on by stimulation of mononuclear cells in human peripheral blood specific in relation to T-cell monoclonal antibodies to activating antigens (D2-D28) or bacterial superantigen toxin-1, produced in toxic shock (Toxic Shock Syndrome Toxin-1 or TSST-1). In addition to the release of F - these stimulants cause, in particular, to the formation of interleukin-2 (IL-2).

The LPS stimulation of mononuclear cells: effect on F-

The release of F - can be studied in vitro in mononuclear cells of peripheral blood, i.e., T-lymphocytes, B-lymphocytes and monocytes after stimulation with lipopolysaccharide (LPS). LPS is a component of the bacterial cell wall and stimulates monocytes and macrophages.

Mononuclear cells were obtained from heparinized blood at least three voluntary donors. With this purpose, 20 ml of blood was fractionally by well-known methods in density gradients to use ishema cell culture medium consisted of RPMI medium 1640, supplemented with 2 mm glutamine (firm Life Technologies, Eggenstein), 10% fetal calf serum (firm Life Technologies), 50 µg/ml streptomycin (firm Sigma, Deisenhofen), 50 IU/ml penicillin (firm Sigma) and 100 mm-mercaptoethanol (Merck, Darmstadt). Then mononuclear cells were added into 15 ml of cell culture medium and the resulting mixture was distributed in portions of 1 ml sterile incubation 24-well plates (firm Sigma). To a 1-ml portions of the mixture were added, respectively, 1 μl of dimethyl sulfoxide (DMSO, Merck) or 1 μl of a solution of test substance (in DMSO; final concentration in the test: 0,5; 5; 12.5 and 50 μg/ml) and the mixture incubated for one hour in an incubator Cabinet in an atmosphere of CO2(5% CO2, 90% humidity). Then he added, with the exception of the control, respectively, 2.5 μg LPS (E. coli 0127: B8; firm Sigma, Deisenhofen). Incubation of the cultures continued for another 20 hours the Concentration of F - in over sedimentary liquid cell culture was determined after incubation using a commercial kit enzyme-linked immunosorbent assay (ELISA analysis; firm Boehringer-Mannheim). Based on the data obtained for the non-treated active substance control mixtures and innumerabiles concentration, providing 50% inhibition of release of F - values (IC50).

The table shows the inhibitory effect of the compounds according to the invention on lipopolysaccharide-induced release of F-.

Stimulation of T-lymphocytes: inhibition of IL-2

The release of interleukin-2 may be investigated by stimulation in vitro mononuclear cells of peripheral blood, containing, along with T-lymphocytes In lymphocytes and monocytes. Due to stimulation of polyclonal continuous epitopes of the receptor of T-cells or so-called incremental signal molecules on the cell surface receive more indicative of measurement data is compared with stimulation by antigens of some small populations of T-lymphocytes. Apply a combination of the two incremental signals, namely those effects are mediated surface molecules CD2 and CD28.

Mononuclear cells were obtained from heparinized blood at least three voluntary donors. With this purpose, 20 ml of blood was fractionally by well-known methods in density gradients using ficoll-Pak (Ficoll-Paque). Then the cells were collected and washed three times in cell culture media the hub, Eggenstein), 10% fetal calf serum (firm Life Technologies), 50 µg/ml streptomycin (firm Sigma, Deisenhofen), 50 IU/ml penicillin (firm Sigma) and 100 mm-mercaptoethanol (Merck, Darmstadt). Then mononuclear cells were added into 15 ml of cell culture medium and the resulting mixture was distributed in portions of 1 ml sterile incubation 24-well plates (firm Sigma). To a 1-ml portions of the mixture were added, respectively, 1 μl of dimethyl sulfoxide (DMSO, Merck) or 1 μl of a solution of test substance (in DMSO; final concentration in the test: 0,5; 5; 12.5 and 50 μg/ml) and the mixture incubated for one hour in an incubator Cabinet in an atmosphere of CO2(5% CO2, 90% humidity). Then he added, with the exception of the control, respectively at 0.1 µg/ml of monoclinal antibodies (Clone AICD2.M1 provided by Professor Dr. Moyer; anti-D28 obtained from CLB, Amsterdam). Incubation of the cultures continued for another 20 hours the Concentration of IL-2 in the supernatant of the cell culture was determined after incubation with the set for ELISA analysis (firm Boehringer-Mannheim). Based on the data obtained for the non-treated active substance control mixtures and incubated under test compounds is then 50 µg/ml inhibits stimulated CD2/CD28 synthesis of IL-2 866%. When applying staphyloccocal superantigen (E. coli 0127: B8; Sigma, Deisenhofen) TSST-1 (0.1 µg/ml) as a stimulator of T-cell synthesis of IL-2 is suppressed on 7720%.

The above studies show that the analogues of thalidomide from the class piperidine-2,6-diones of the formula (I) inhibit both caused by inflammation of the release of F-and induced antigens synthesis of interleukin-2.

1. Substituted piperidine-2,6-diones of the formula (I)

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in which Z is-C(R1R2)-CH2- or-C(R1)= CH-;

R1- phthalimid, when Z Is-C(R1R2)-CH2- or one - or twofold substituted by hydroxy, methoxy or amino groups phtalimide radical when Z is-C(R1)= CH-;

R2is hydrogen or C1-6alkyl group;

R3is hydrogen, C1-6an alkyl group or aromatic ring system;

R4- C1-6alkyl or aromatic ring.

2. Substituted piperidine-2,6-diones of the formula (I) under item 1, wherein Z Is-C(R1R2)-CH2-; R1- phthalimide; R2is hydrogen; R3is hydrogen or ethyl and R4is methyl or phenyl.

3. Substituted piperidine-2,6-diones of the formula (I) under item 1, wherein Z Is-C(R1)= displaced piperidine-2,6-diones of the formula (I) PP. 1 and 2, characterized in that condense phthalic anhydride substituted with glutamic acid, the product cyclist up anhydride and the latter transferred to the imide.

5. The method of obtaining substituted piperidine-2,6-diones of the formula (I) PP. 1-3, characterized in that the phthalic anhydride condensed with substituted 3-aminoglutethimide or 5-substituted 3-aminoglutethimide.

 

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