Derivatives of piperidine-ketocarboxylic acid

 

(57) Abstract:

The invention relates to new derivatives of piperidine-ketocarboxylic acids of the formula (I), where R1- COR4or SO2R4, R4means of alkenyl, substituted phenyl or pyridine, naphthyl, honokalani, chinoline, benzothiophene, dihydroxyphenyl or pyridyl, substituted with allmineral, R2- C1-C6-alkyl which can be substituted by phenyl or pyridium, R3group-OR6or other6where R6means hydrogen, C1-C6-alkyl, which may be a phenyl, pyridine or morpholinium, their tautomeric and isomeric forms, and salts. The compounds of formula (1) are inhibiting properties with respect to the enzymes, in particular cysteine-proteases, such as calpain, and can find application in medicine. 2 C.p. f-crystals, 2 PL.

The invention relates to new complex ketoesters and ketoamides, which are inhibitors of enzymes, in particular cysteine-proteases, such as calpain (dependent calcium protease cysteine) and its isoenzymes and cathepsins, for example, cathepsins b and L.

Calpain represent intracellular proteolytic enzymes from groups who acidity calcium, and distinguish between Kalpana I or MK-Kalpana, which is activated MK-molar concentrations of calcium ions, and Kalpana II or m-Kalpana, which is activated molyarnye concentrations of calcium ions (see P. Johnson, Int. J. Biochem. 1990, 22(8), 811-22). Currently, there are also other isoenzymes calpain (see K. Suzuki and others, Biol. Chem. Hoppe-Seyler, 1995, 376(9), pp. 523-9.

Assume that calpain play an important role in various physiological processes. This includes the splitting of regulatory proteins, such as, for example, protein kinase C, cytoskeletal proteins, such as MAP 2 and spectrin, muscle proteins, cleavage of proteins in rheumatoid arthritis, neuropeptide metabolism, proteins upon activation of platelets, proteins in mitosis and other calpain, which are listed in the publications of M. L. Barrett and other Life Sci. 1991, 48 p. 1659-69 and K. K. Wang and others, Trends in Pharmacol. Sci. 1994, page 15, 412-9.

In various pathophysiological processes were observed elevated levels of calpain, for example, in the case of ischemia of the heart (e.g., heart attack) kidney or Central nervous system (e.g. stroke), inflammation, muscular dystrophy, cataract eye, damage to the Central nervous system (e.g. the ü these diseases with an increased intracellular calcium level. Consequently dependent calcium processes excessively activated and is no longer amenable to physiological regulation. In accordance with this excessive activity of kalainov can also cause pathophysiological processes.

Therefore, there are allegations that the inhibitors Kalmanovich enzymes can be useful for the treatment of these diseases. Various studies confirm this. For example, Seung-Cial Hong and others, Stroke 1994, 25(3), pages 663-9 and R. T. Bartus and others, Neurological Res. 1995, 17, pp. 249-58 showed a neuroprotective effect of inhibitors of kalainov in acute neurodegenerative disorders, available, for example, after a stroke. Also after experimental brain injury inhibitors calpain helped to mitigate deficits memory function and nerodigital.ini violations (see K. E. Saalman etc. Proc. Natl. Acad. Sci. USA, 1996, 93 p. 3428-3433). Authors K. L. Edelstein and others, Proc. Natl. Acad. Sci. USA, 1995, 92 p. 7662-2, found a protective effect of inhibitors calpain damaged by hypoxia of the kidney. Yoshida, Ken Ishii and others, Jap. Circ. J. 1995, 59 (1), page 40-8 were able to show the beneficial effects of inhibitors calpain after cardiac injuries that were caused by ischemia or reperfusion. Due to the fact that the inhibitors claimer (see, I. Higuchi and other Neuron, 1995, 14 p. 651-59). Secretion of interleukin-1 also suppressed by inhibitors calpain (see N. Watanabe and others, Cytokine 1994, 6(6), pp. 597-601. It was further found that the inhibitors calpain have a cytotoxic effect on tumor cells (see E. Shiba, and other 20th Meeting of the Int. Ass. Breast Cancer Res. , Sendai Jp, 1994, 25.-28th September, Int. J. Oncol. 5 (Suppl.), 1994, page 381).

Other possible applications of inhibitors calpain are presented in the publication Trends in Pharmacol. Sci., 1994, 15, page 412-8 (author: K. K. Wang).

Inhibitors calpain have already been described in the literature. However, the vast majority of this or irreversible or peptide inhibitors. Irreversible inhibitors are usually alkylating means and have the disadvantage that they react in the body selectivity or unstable. For example, these inhibitors often exhibit undesirable side effects, such as toxicity, and therefore they are limited in their application or do not apply. Irreversible inhibitors are, for example, epoxides E 64 (see Biochem. Biophys. Res. Commun. 1989, 158, pp. 432-5), -halogen ketones (see X. Anglican and other J. Med. Chem. 1992, 35, pp. 216-20) and disulfides (see P. of Matsueda and other Chem. Lett. 1990, page 191 -194).

Many well-known reversible inhibitor aptenia aldehydes, as, for example, Z-Val-Phe-H (MDL 28170) see C. Copper, Trends in Biol. Sci. 1991, 16, pp. 150-3) and compounds described in European patent 520336. In physiological conditions the peptide aldehydes have often the disadvantage that due to the existing reactivity they are unstable and can quickly metabolized, prone to non-specific reactions, which can cause toxic effects (see Th.A. Ferentz and B. Castro, Synthesis, 1983, pp. 676-78). The use of peptide aldehydes in the treatment of diseases is thus limited or no sense. There is therefore nothing surprising in the fact that only some aldehydes are used as active principle, namely, first of all, when the aldehyde group is stabilized, for example, through education of Polyacetal.

Progress is the discovery that certain peptide derivatives of ketone are also inhibitors of cysteine-proteases, in particular calpain. So, for example, derivatives of ketone known as inhibitors of serine-proteases, and ketogroup activated electroepitaxy group, for example, trifluoromethyl. When the cysteine-proteases derived ketone, which ketogroup activated Med. hem. 1990, 33, pp. 11-13). Suddenly still as effective inhibitors calpain could only be found ketone derivatives, in which, on the one hand, being in the position of the leaving group cause irreversible inhibition and, on the other hand, carboxylic acid derivative activates ketogroup (see M. P. Angelastro, etc. in the above source, as well as applications WO 92/11850; WO 92/12140; WO 94/00095 and WO 95/00535). However, these ketoamide and complex ketoesters still only peptide derivatives have been described as effective (see Gaogao Lee and others, J. Med. Chem. 1993, 36, pp. 3472-80; C. L. Harbeson etc., J. Chem. 1994, 37, p 2918-29 and M. P. Angelastro in the above source).

The present invention is to develop ones inhibitors, which are produced from more stable ketones and who do not have the common problems of the peptides (metabolic stability, poor passage through the membrane of cells, and so on).

The object of the present invention are derived piperidin-ketocarboxylic acids of the formula (I)

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where R1-CO-R4, -SO2-R4, -CONH-R4, COOR4, -C(=N)-R4, -C(=O)-OTHER4and-C(= S)-other4where R4means a branched or unbranched C5that means a branched or unbranched1-C4-alkyl, -O-C1-C4-alkyl, HE, Cl, F, Br, J, CF3, NO2, NH2, CN, COOH, COO-C1-C4-alkyl, -N-C1-C4-alkyl, NHCOPh, NHSO2-C1-C4-alkyl, NHSO2Ph,

-SO2-C1-C4-alkyl and-SO2Ph, where Ph means phenyl,

R2-a branched or non-branched C1-C6-alkyl, which may have phenyl, pyridine or naphtalene ring which for its part may be substituted up to two radicals R5with the above value,

R3group-OR6and-other6where R6means hydrogen, phenyl ring which may have one or two radicals R5with the above value, branched ILT ring, as, for example, phenyl, naphthalene, pyridine, pyrimidine, piperidine, pyrolidine, morpholine, thiophene, quinoline and isoquinoline ring, and the aromatic ring can have a maximum of two radical-NR7R8where R7and R8independent from each other and denote hydrogen or a branched or non-branched C1-C6-alkyl, or a maximum of two radicals R5with the above value, and their tautomeric and isomeric forms and their possible physiologically tolerated salts

Preferred are derivatives of piperidine-ketocarboxylic acid of General formula (I), in which

R1means the group-C(=O)R4, -SO2R4,

R2branched or non-branched C1-C6-alkyl, benzyl, and-CH2-pyridyl,

R3group-OR6and-other6and

R4, R5and R6have the above values.

Especially preferred are derivatives of piperidine-ketocarboxylic acid of General formula (I), in which

R1means the group-C(=O)R4, -SO2R4,

R2- C1-C4-alkyl and benzyl,

R3- group-other6,
SUP> is hydrogen, C1-C4-alkyl which can be substituted by phenyl, pyridine or morpholine.

The compounds of formula (I) can be used as the racemate or as pure enantiomeric compounds or as diastereomers. If desired pure enantiomeric compounds can be obtained, for example, due to the fact that with suitable optically active bases or acids spend classical splitting of the racemate of compounds of formula (I) or their intermediate products.

The object inventions are the compounds of formula (I) in their maternal or tautomeric form, for example, those in which ketogroup in the formula (I) is contained in the enol tautomer.

The object of the present invention are physiologically acceptable salts of the compounds (I), which can be obtained by reaction of the compounds (I) with appropriate acids or bases.

Preparation of derivatives of piperidine-carboxylic acid (I) can be produced by various methods shown in schemes 1 and 2.

Based on piperidine-carboxylic acid II receive derivative III interaction under normal conditions with "activated" acid derivatives R1-L-falls in anhydrous, inert solvent such as methylene chloride, tetrahydrofuran and dimethylformamide, at temperatures from -20 to +25oAnd usually under normal conditions, set forth in Houben-Weyl, Methods der organischen Chemie, 4th ed. volume 5, section V.

Esters piperidine-carboxylic acid III is converted to the acid IV by reaction with acids or bases, such as lithium hydroxide, sodium hydroxide or potassium hydroxide in water or in mixtures of water and organic solvents, such as alcohols or tetrahydrofuran, at room or elevated temperatures, as, for example, when 25-100oC.

These acids IV are subjected to interaction with the derived amino acids, and normal use conditions, which are described above and shown in Houben-Weyl.

Derivatives of V, which are, as a rule, esters, become the same as the above hydrolysis in ketocarboxylic acid VI. Similar reaction get complicated ketoesters VII, and operate according to the method described Gaogao Lee, J. Med. Chem., 1993, 36, pp. 3472-80. According to this method, the carboxylic acid, such as formula (VI), at elevated temperature (50-100o(C) is subjected to interaction with chlorine the obtained product is subjected to interaction with such bases, as methanolate sodium in ethanol at a temperature of 25-80oC obtaining complex keeeper I' according to the invention. Complex ketoesters I' can be, for example, gidrolizirovanny in the manner described above in ketocarboxylic acid according to the invention.

The transformation in ketoamide I' is also similar to the method for Gaogao Lee and others in the presence of a Lewis acid such as, for example, bactritoidea, in inert solvents, such as methylene chloride, at room temperature, and it turns out dition. These derivatives are subjected to interaction with amines R3-N in polar solvents, such as alcohols, at a temperature of 0-80oC. thus receive ketoamide I'.

An alternative method is presented in scheme 2. Piperidine-carboxylic acid IV is subjected to interaction with derivative aminohydrocinnamic acid VII (see C. L. Harbinson and other J. Med. Chem. 1994, 37, p 2918-29) under normal conditions of formation of the peptide bond (see the above-mentioned publication Houben-Weyl) to produce amides VIII. These derivatives VIII can be oxidized to derivatives ketocarboxylic acid I according to the invention. You can use various conventional oxidation reactions will Roll or similar will Roll or similar will Turn oxidation (see T. T. Tidwell, Synthesis 1990, p. 857-70) or sodium hypochlorite/TEMRO (C. L. Harbinson and others, see above).

If the compounds VIII are complex-hydroxyether (X=O-alkyl), they can be gidrolizirovanny to carboxylic acid IX, and operate similarly to the above methods, but preferably with lithium hydroxide in mixtures of water with tetrahydrofuran at room temperature. Other esters or amides X is produced by reacting alcohols or amines under the above described conditions. The derived alcohol X can again be subjected to oxidation to obtain derivatives of the ketocarboxylic acid I' according to the invention.

Obtained in the framework of the present invention ketone derivatives I are inhibitors of cysteine-proteases, such cysteine-proteases, as calpain I and II and cathepsin, respectively L.

The inhibitory effect of derivative ketone I was determined by means known in the literature testing of enzymes, and as the scale of activity was determined by the concentration of inhibitor, which inhibited 50% of enzyme activity (=IC50). Derivatives of ketone I was measured thus to their inhibitory action in Rel
The inhibitory effect on cathepsin In determined similarly to the method by S. Hasnain etc., J. Biol. Chem. 1993, 268, pp. 235-40. To 88 μl of cathepsin b (cathepsin In the liver of a person, product, company Calbiochem), diluted to 5 um. 500 µmol buffer solution was added 2 μl of inhibitor solution in dimethyl sulfoxide (final concentration: 100 µm to 0.01 Microm). This mixture for 60 min at room temperature (25oC) pre-incubated and then initiated the reaction by means of the additive 10 μl, 10 mmol of Z-Arg-Arg-pNA (in buffer with 10% dimethyl sulfoxide). Over the course of the reaction was observed 30 min at 405 nm using a reader microtitre plates. The maximum rises determine the values of the IC50.

Test using calpain I and II

Test the inhibitory properties of the inhibitor calpain produced buffered with 50 mmol Tris-HCl, pH 7.5; 0.1 mol NaCl; 1 mmol of dithiothreitol; 0.11 mmol CaCl; 1 mmol of dithiothreitol, 0.11 mmol CaCl2and used fluorogenic substrate calpain Suc-Leu-Tyr-AMC (25 mmol dissolved in DMSO, product company Bachem, Switzerland) (see Sasaki and others J. Biol. Chem. 1984, volume 259, page 12489-12494). Allocated human MK-calpain from the cells following the methods Croall, Demartino (BBA 1984, volume 788, p is the real diethylaminoethylamine group sepharose, phenyl-sepharose, superdex 200 and Blue-sepharose) received an enzyme with a purity >95%, determined by electrophoresis on polyacrylamide gel using sodium dodecyl sulfate, Western blotting and N-terminal sequencing. The fluorescence of the product splitting, 7-amino-4-methylcoumarin (AMC), was determined using fluorimetry Spex-Fluorolog whenex=460 nm. For a 60-minute measuring cleavage of the substrate is linear and autocatalytic activity calpain small, if the tests were carried out at a temperature of 12o(See Chatterji and others 1996, Bioorg. & Med. Chem. Lett., vol. 6, pp. 1619-1622). Inhibitors and substrate calpain was applied in the test environment as solutions in dimethyl sulfoxide (DMSO) and the final concentration of DMSO should not exceed 2%.

Typical test mixture was reduced to that in a cell with a capacity of 1 ml, containing buffer, filed 10 μl of substrate (final concentration of 250 μm) and then with 10 μm MK-calpain (final concentration: 2 μg/ml, i.e. 18 nmol). Caused by Kalpana cleavage of the substrate was measured for 15-20 minutes then produced a flow of 10 μl of inhibitor (50-100 μmol dissolved in (DMSO) and measuring the inhibition of cleavage was determined by another 40 min. Value of Kiabout the concentrations of inhibitor, V0= initial feed rate of the inhibitor; V1= reaction rate at equilibrium.

Test with platelets to determine the cellular activity of the inhibitors calpain.

Caused by Kalpana cleavage of proteins in platelets was performed as described Gaogao Lee and others in J. Med. Chem., 1993, 36, pp. 3472-3480. Human trombly was isolated from fresh blood mixed with sodium citrate, and were set to 107cells/ml in a buffer of 5 mmol HEPES, 140 mmol NaCl and 1 mg/ml albumin bovine serum, pH 7,3.

Platelets (0.1 ml) pre-incubated 5 minutes by 1 ál of different concentrations of inhibitor solution in DMSO. After that produced feed ionophore calcium A (1 µmol test) and calcium (5 mmol per test), and incubated for 5 minutes at a temperature of 37oC. After centrifugation, the platelets were placed in a buffer containing polyacrylamide gel, treated with dodecylsulfonate sodium, boiled 5 min at 95oC and proteins were separated on 8% gel. Cleavage of both proteins, actin binding protein Talin, followed by quantitative densitometry, because after the filing of calcium and ionophore these prlog activity of the enzyme.

Induced by glutamate cell death of cortical neurons

The test was similar to the test described D. C. Choi, M. A. Maulucci-Gedda and A. P. Krigstein (1987) "Glutamate neurotoxicity in cortical cell culture", J. Neurosci. 7, pages 357-368.

15-Dnevnik mouse embryos analyzed half of the cerebral cortex and enzymatic (trypsin) were assigned to individual cells. These cells (glia and cortical neurons) were cultivated in microtitre plate with 24 holes. Three days later (when coated with laminin plates) or seven days (in ornithine coated plates) using 5-fluoro-2-dose irradiation on neurogenesis conducted mitotic cell division (mitotic processing). 15 days after preparation of the cells by addition of glutamate (15 min) caused cell death. After removal of glutamate was applied inhibitors calpain. After 24 hours was determined the damage to cells by detection of lactate dehydrogenase in the Packed fluid cell cultures.

There is a statement that calpain also plays a role in apoptotic cell death (see M. K. So Squee and other J. Cell. Physiol. 1994, 159, pages 229-237; T. Patel and others, Faseb Journal, 1996, 590, 587-597). Therefore, another test was caused cell death in human cell lines by calcium TB calpain, to prevent induced cell death.

In the human cell line NT2 can cause cell death by calcium in the presence of ionophore A. 105cells/deepening filed in microtitre plates for 20 hours before the test. Then cells were incubated with different concentrations of inhibitors in the presence of 2.5 mmol of ionophore and 5 mmol of calcium. To the reaction mixture were added after 5 hours of 0.05 ml of XTT (Cell Proliferation Kit II, Boehringer, Mannheim, DE). The optical density was determined in approximately 17 hours in accordance with the manufacturer's instructions using reader Easy Reader EAR 400 firm SLT. The optical density, which killed half of the cells is calculated from both control values with cells without inhibitors, which were incubated in the absence and in the presence of ionophore.

Derivatives of ketone I are inhibitors of cysteine-proteases, such as calpain I and II, as well as cathepsin In and L, and can be used in combating diseases associated with increased activity of enzymes calpain and/or cathepsin. As a consequence, these derivative of the ketone I can be used for the treatment of neurodegenerative diseases, which voznikayet multiple heart attacks, Alzheimer's disease, Huntington's disease (chorea) and, in addition, for the treatment of heart damage after cardiac ischemia, damage to the kidneys after renal ischemia, damage of skeletal muscles, muscular dystrophies, damage caused by proliferation of smooth muscle cells, coronary vasospasm, cerebral vasospasm, eye cataracts and/or restenosis of blood stream after angioplasty.

Moreover, derivatives of ketone I can be useful when hemoterapia tumors and their metastases, and for treatment of diseases in which there is a high level of interleukin-1, for example, inflammation and/or rheumatic diseases.

Dosage forms according to the invention contain, along with the usual auxiliary substances therapeutically effective amount of the compounds I.

For local external use, for example as a powder, ointment or spray, the active substance may be contained in the forms in normal concentrations. Typically, the active principle is contained in an amount of from 0.0001 to 1 wt.%, preferably, from 0.001 to 0.1 wt.%.

In internal administration dosage forms are given in separate doses. In a single dose given per kg weight of 0.1-100 mg Drug fo the P CLASS="ptx2">

In accordance with the desired application of the dosage form according to the invention contain along with the active start common in Galenika fillers and solvents. For local external use can be used farmatsevticheskii-technical auxiliary substances, such as ethanol, isopropanol, ethoxylated castor oil, ethoxylated gidrirovannoe castor oil, polyacrylic acid, polyethylene glycol, polietilenglikolya, the ethoxylated fatty alcohols, paraffin oil, vaseline and lanolin. For internal use are suitable, for example, lactose, propylene glycol, ethanol, starch, talc and polyvinylpyrrolidone.

In addition, the dosage form may contain antioxidants, such as tocopherol and bottled oxyanion and bottled oxytrol, and also improves the taste of substances, stabilizers, emulsifiers and lubricants.

Contained along with active starting substances, and substances used in the manufacture of pharmaceutical dosage forms, must be toxicologically acceptable and joint with the corresponding active early. The manufacture of dosage forms occur is the teli.

Getting the dosage forms is realized by means known in the art methods (see, for example, X. Sucker and other Pharmazeutische Technologie, ed. Thieme Verlag, Stuttgart, 1991).

Drugs may be given in various ways, for example, orally, parenterally, intravenously by infusion, subcutaneously, intraperitoneally or locally. Such dosage forms as tablets, emulsions, solutions for infusion and injection, pastes, ointments, gels, creams, lotions, powder and spray.

Examples

Example 1

Complex ethyl ester 4-methyl-2-oxo-3-(1-(E-3-phenyl-1-acryloyl)piperidine-4-yl)aminovaleric acid

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a) 1-(S-phenyl-1-acryloyl)piperidinyl-4-carboxylic acid

32,0 g (0,248 mol) piperidine-4-carboxylic acid are dissolved in 500 ml of pyrimidine and after that portions mixed with a 43.3 g (0.26 mol) of acid chloride of cinnamic acid. The resulting mixture is stirred for 16 hours at room temperature. Then the reaction mixture is concentrated under vacuum and the residue partitioned between 2 M hydrochloric acid and ethyl ester of acetic acid. The organic phase is separated, concentrated and concentrated under vacuum. Get of 47.0 g (76%) of product. So pl.: 178-179oC.

b) Complex Mustadio a) and 12.5 g (77,1 mmol) of the hydrochloride difficult methyl ester L-valine served in 350 ml of methylene chloride and, while cooling with ice mixed dropwise with 25.6 ml (185,1 mmol) of triethylamine. The mixture is stirred for 1 hour and then added 3.1 g (23,1 mmol) 1-hydroxy-1H-benzotriazole. The reaction mixture was cooled to 0oAnd after that portions mixed with 14.8 g (77,1 mmol) of N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide. The resulting mixture is stirred for 16 hours at room temperature. After that, the organic phase is washed with water, aqueous sodium hydrogen carbonate solution, 5% citric acid solution and again with water, concentrated and concentrated under vacuum. Get 27,3 g (96%) of product.

1H-NMR (CDCl3): = 0,9(6N), 1,6-2,0(3H), 2,2(1H), 2,5(1H), 2,8(1H), AND 3.2(1H), AND 3.8(3H) AND 4.2(1H), 4,6(1H), 4,7(1H), 6,0(1H) AND 6.9(1H), AND 7.3 AND 7.6(5H) and 7.6(1H) million dollars.

C) 4-methyl-3-1-(E-3-phenyl-1-acryloyl) piperidine-4-yl)aminomalonate acid

of 27.0 g (72,5 mmol) of the product of stage b) is dissolved in 200 ml of tetrahydrofuran and mixed with 3.5 g (145 mol) of lithium hydroxide dissolved in 250 ml of water. The resulting mixture is stirred for 1 hour at room temperature. Then remove the tetrahydrofuran under vacuum and the resulting aqueous solution extracted with ethyl acetate. Then it is neutralized 1 M hydrochloric acid and again extracted. The organic phase is dried and concentrated under vacuum, thus obtain 26 g (100%) of product.

1
26,0 g (72,5 mmol) of the product of stage C) 0.9 g (of 7.25 mmol) of 4-dimethylaminopyridine and 23.4 ml (0.29 mol) of pyridine are dissolved in 150 ml of anhydrous tetrahydrofuran. Then added dropwise to 16.2 ml (0.15 mol) of acid chloride of monoethylene ester of oxalic acid so that the temperature rises to approximately the 50oC. over the next three hours, refluxed. The reaction mixture is stirred for 16 hours at room temperature. Then carefully add 100 ml of water and stirred again for about 30 minutes. The mixture is partitioned between water and ethyl acetate. The organic phase is washed several times with water, dried and concentrated under vacuum.

Thus obtained complex enol ether was dissolved in 200 ml of ethanol, mixed with 0,47 g (5.6 mmol) of ethanolate potassium and stirred for 16 hours at room temperature. After that, the mixture is concentrated under vacuum and the residue is subjected to chromatographic purification (solvent: methylene chloride/methanol =20/1), and thus obtain 10.8 g (36%) of product.

MS (fast atom bombardment): m/e=414 (M+).

Example 2

Amide 4-methyl-2-oxo-3-(1-(E-3-phenyl-1-acryloyl)piperidine-4-yl)aminovaleric the l)aminovaleric acid

6.0 g (14.6 mmol) of the product of example 1 g) and 1.5 ml (17.5 mmol) of 1,2-identicial dissolved in 20 ml of anhydrous methylene chloride and mixed with 4 ml of bothrideridae. The mixture is stirred for 16 hours at room temperature. Then diluted with 10 ml of methylene chloride and washed 3 times with saturated solution of sodium chloride. The organic phase is dried and concentrated in vacuo, you get to 7.3 g of crude product, which without treatment served on phase b).

b) Amide 4-methyl-2-oxo-3-(E-1-(3-phenyl)-1-acryloyl)piperidine-4-yl)-aminovaleric acid

1.7 g (3.6 mmol) of the product of stage a) is served in 20 ml of 2 M ethanolic ammonia solution and stirred for 16 hours at room temperature. After that, the mixture is concentrated under vacuum and subjected to chromatographic purification (solvent: methylene chloride/methanol =40/3), you get to 0.22 g of the product.

MS (fast atom bombardment): m/e=385 (M+).

Example 3

Amide N-ethyl-4-methyl-2-oxo-3-(1-(E-3-phenyl-1-acryloyl)piperidine-4-yl) aminovaleric acid

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1.7 g (3.6 mmol) of the product of example 2A) is subjected to interaction with ethanolic ethylamine in the conditions of example 2B. Thus obtain 0.15 g of product.

M is sawdust)-2-oxo-3-(1-(E-3-phenyl-1-acryloyl)piperidine-4-yl)-aminovaleric acid

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1.3 g (3.6 mmol) of the product of example 2A) is subjected to interaction with 0.8 g (5.4 mmol) of 3-(morpholine-1-yl)-Propylamine in the conditions of example 2B). Obtain 1.1 g of product.

MS (fast atom bombardment): m/e=512 (M+).

Example 5

Amide 4-methyl-2-oxo-3-(1-(E-3-phenyl-1-acryloyl)piperidine-3-yl)-amido-N-2-(pyrimid-2-yl)acylalanines acid.

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1.3 g (2.8 mmol) of the product of example 2A) is subjected to interaction with 0.7 g (5.5 mmol) of 2-(2-amino-ethyl)pyridine analogously to example 2B). You get to 0.85 g of the product.

MS (fast atom bombardment): m/e=490 (M+).

Example 6

Complex ethyl ester 2-oxo-4-phenyl-3-(1-(E-3-phenyl-1-acryloyl)-piperidine-4-yl)-aminomethane acid

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a) methyl ester of 3-phenyl-3-(1-(E-3-phenyl-1-acryloyl)-piperidine-4-yl)-aminopropionic acid

The product is obtained analogously to example 1B) from the intermediate product of example 1A) and compound methyl ester of phenylalanine.

1H-NMR (CDCl3): =1,6-2,0(3H), 2,35(1H), 2,9(1H), 3,0-3,3(4H), AND 3.7(3H), 4,1(1H), 4,6(1H), 4,9(1H) and 6.9(1H), AND 7.1(2H) and 7.2 to 7.7(M) million dollars.

b) 3-phenyl-3-(1-(E-3-phenyl-1-acryloyl)-piperidine-4-yl)-aminopropionic acid

The product is obtained analogously to example 1B) from the ex is, ,2(1H), 6,8(1H), 7,0-7,8(11N) and OK. 8,2(lat.) million.

in Complex ethyl ester 2-oxo-4-phenyl-3-(1-(E-3-phenyl-1-acryloyl)-piperidine-4-yl)-aminomethane acid

The product is obtained analogously to example 1G) of the intermediate product of example 6b).

MS (fast atom bombardment): m/e=462 (M+).

Example 7

Amide N-(3-morpholine-1-yl)propyl)-2-oxo-4-phenyl-3-(1-(E-3-phenyl-1-acryloyl)-piperidine-4-yl)-aminomethane acid

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The product is obtained analogously to example 2B) of the product of example 6 and 1-(3-aminopropyl)-the research.

1H-NMR (CDCl3): = 1,4-1,9(6N), 2,3-2,6(6N), 2,8(1H), 3,3(2H), 3,3-3,5(3H), AND 3.6 TO 3.8(4H), 4,1(2N), 4,6(1H), AND 5.5(1H), 6,1(1H) AND 6.9(1H), AND 7.1(1H), A 7.2 TO 7.7(10H) and 8.9(1H) million dollars.

Example 8

Amide 2-oxo-4-phenyl-3-(1-(E-3-phenyl-1-acryloyl)-piperidine-4-yl)-aminomethane acid.

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The product is obtained analogously to example 2B) of the product of example 6 and ethanolic ammonia solution.

1H-NMR (D6-DMSO): = 1.2 to 1.9(4H), 2,4(1H), 2,7-2,9(2N), to 3.0-3.2(2H), 4,1-4,3(3H), 5,1(1H) and 7.0 to 8.2(14N) million dollars.

Example 9

Amide 4-methyl-N-(2-(morpholine-1-yl)ethyl)-2-oxo-3-(1-(E-3-phenyl-1-acryloyl)-piperidine-4-yl)aminovaleric acid

< / BR>
The product is obtained analogously to example 2B) of the intermediate product of example 2A) and 1-(-(1-(E-3-phenyl-1-acryloyl)-piperidine-4-yl)aminovaleric acid

< / BR>
a) Complex ethyl ester of 3-(1-(E-3-phenyl-1-acryloyl)-piperidine-4-yl)-aminomethane acid

The product is obtained analogously to example 1B) from the intermediate product of example 1A) and compound ethyl ester 2-aminobutyric acid.

1H-NMR (CDCl3): = 0,9(3H), 1,6-2,0(6N), 2,5(1H), 2,9(1H), AND 3.2(1H), AND 3.8(3H) AND 4.2(1H), 4,5-4,7(2H), and 6.3(1H) and 6.9(1H), and 7.4(3H), AND 7.6(2H), 7.7(1H) million dollars.

b) 3-(1-(E-3-phenyl-1-acryloyl)-piperidine-4-yl)-aminomalonate acid

The product is obtained analogously to example 1B) from the intermediate product of example 10A).

1H-NMR (D6-DMSO): = 0,9(3H), 1,3-1,9(6N), 2,6(1H), 2,7(1H), AND 3.1 (1H), 4,1(1H), 4,3(1H), 4,5(1H), 7,2-7,6(5H), AND 7.7(2H), AND 8.0(1H) and 12.5 (width) million.

in Complex ethyl ester 2-oxo-3-(1-(E-3-phenyl-1-acryloyl)-piperidine-4-yl)-aminovaleric acid

The product is obtained analogously to example 1G) of the intermediate product of example 10B).

1H-NMR (CDCl3): = 0,9(3H), 1,4(3H), 1.8-to 2.2(6N), 2,5(1H), 2,8(1H), 3,2(1H) AND 4.2(1H), 4,4(2H), 4,6(1H), 5,1(1H), 6,7(1H) AND 6.9(1H), AND 7.4(3H), 7.5(A 2H), 7.7(1H) million dollars.

Example 11

Amide 2-oxo-3-(1-(E-3-phenyl-1-acryloyl)-piperidine-4-yl)-aminovaleric acid

< / BR>
The product is obtained analogously to example 2A) and 2B) of the product of example 10 and ethanolic ammonia solution.

MS: m/e=371 (M+).


< / BR>
a) 1-(2-naphthylmethyl)-piperidine-4-carboxylic acid

26,0 g (0.2 mol) piperidine-4-carboxylic acid are dissolved in 250 ml of pyridine and at room temperature portions are mixed from 47.6 g (0.2 mol) of acid chloride of 2-aftershool acid. The resulting mixture is stirred for about 5 hours at room temperature. The reaction mixture was concentrated in vacuo and the residue distributed between ethyl acetate and 2 M hydrochloric acid. The organic phase is dried and concentrated in vacuo. Get to 48.5 g (75%) of product.

b) Complex ethyl ester of 3-(1-(2-naphthylmethyl)-piperidine-4-yl)-amido-2-oxo-4-phenylpropionic acid

The product is obtained analogously to example 1B) from the intermediate product of example 12A).

1H-NMR (D6-DMSO): = 1,1(3H), 1,4-1,8(5H), 2,3-2,6(2N), 2,7-3,2(M), 3.5 to 3.8(2H), 4,0(2N), 4,5(1H), 7,2(4H), AND 7.7(3H), 8,1-8,3(3H) and 8.5(1H) million dollars.

C) 3-(1-(2-naphthylmethyl)-piperidine-4-yl)-amido-2-oxo-4-phenylpropionate acid

The product is obtained analogously to example 1B) from the intermediate product of example 12B).

1H-NMR (D6-DMSO): =1,3-1,8(5H), 2,3-2,6(3H), is 2.8-3.2(2H), 3,4-3,8(2H), and 4.4(1H), 7,2(4H), AND 7.7(3H), OF 8.0 TO 8.3(4H) and 8.4(1H) million dollars.

d) Complex ethyl ester of 3-(1-(2-naphthylmethyl)-piperidine-4-yl)-amido-2-oxo-4-Penelas the>SUP>1
H-NMR (D6-DMSO): =1,2(3H) AND 1.3 TO 1.9(4H), 2,2(1H), of 2.3-2.5(2H), 2,8(1H), AND 3.1(1H), 3,6(2H) AND 4.2(2H), AND 4.4(1H), 7,0 IS 7.3(5H), AND 7.7(3H), OF 8.0 TO 8.3(3H) and 8.4(2H) million dollars.

Example 13

Amide 3-(1-(2-naphthylmethyl)-piperidine-4-yl)-amino-2-oxo-4-phenylalkanoic acid

< / BR>
The product is obtained analogously to example 2A) and 2B) of the product of example 12.

MS (fast atom bombardment): m/e=493 (M+).

Example 14

Amide N-(3-(morpholine-1-yl)Strait-1-yl)-3-(1-(2-naphthylmethyl)-piperidine-4-yl)-amido-2-oxo-4-phenylalkanoic acid

< / BR>
The product is obtained analogously to example 2A) and 2B) of the product of example 12 and 1-(3-amino-I-1-yl)-the research.

MS (fast atom bombardment): m/e=620 (M+).

Example 15

Amide 3-(1-(2-naphthylmethyl)-piperidine-4-yl)-amido-2-oxo-4-phenyl-N-(2-(2-pyridyl)-ethyl) - butyric acid

< / BR>
The product is obtained analogously to example 2A) and 2B) of the product of example 12 2-(2-amino-ethyl)-pyridine.

MS (fast atom bombardment): m/e=598 (M+).

Example 16

Amide 3-(S)-(1-(2-naphtol)-piperidine-4-yl)-amido-2-oxo-4-phenylalkanoic acid

< / BR>
(a) Amide 3-(S)-(N-tert. -butoxycarbonyl-amino)-2-(R, S)-hydroxy-4-phenylalkanoic acid

of 17.7 g (60 mmol) of 3-(S)-N-tert.-butoxycarbonyl-amino)-2-(R, is oxibendazole dissolved in 150 ml of anhydrous dimethylformamide. When -5oWith successively added to 12.6 g (66 mmol) of hydrochloride (N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide and 48 ml (approximately 2 molar) ethanolic ammonia solution and stirred for about one hour at this temperature. After that, the mixture is stirred for another 16 hours at room temperature. Then add 500 ml of water and extracted with ethyl acetate. The organic phase is washed with diluted aqueous sodium hydroxide and water, dried and concentrated in vacuo. The residue is treated more n-heptane and the precipitate is sucked off. Obtain 13.5 g (76%) of product.

1H-NMR (D6-DMSO): = 1,3(9H), 2,6-2,9(2H), and 3.7(1H), 5,7(1H) and 6.2(1H) and 7.3(5H) million dollars.

b) Amide 3-(S)-amino-2-(R, S)-hydroxy-4-phenylalkanoic acid

13,4 g (46 mmol) of the product of stage a) is dissolved in 300 ml of methylene chloride and mixed with 100 ml triperoxonane acid. The resulting mixture is stirred for 1 hour at room temperature and then concentrated in vacuo. The residue is partitioned between water and simple diethyl ether and then the aqueous phase was concentrated in vacuo. Obtain 12.3 g (88%) of product as trifenatate.

in) Amide and 2-(R, S)-hydroxy-3-(S)-(1-(2-naphtol)-piperidine-4-yl)-amido-4-phenylalkanoic acid

Similarly, stage b) 1.1 g (3.6 mmol) prod,0 g (61%) of product.

1H-NMR (D6-DMSO): = 1.2 to 1.9(6N), of 2.6-3.2(4H), 3,6(1H), 3,6(1H), 3,7-4,0(1H), 4,0(1H), 4,2-4,6(2H) and 7-8,2(14N) million dollars.

g) Amide 3-(S)-(1-(2-naphtol)-piperidine-4-yl)-amido-2-oxo-4-phenylalkanoic acid

and 0.46 g (1 mmol) of the product of stage b) and 0.4 g (4 mmol) of triethylamine dissolved in 10 ml of dimethyl sulfoxide and at room temperature is mixed with 0,48 g (3 mmol) of a complex of pyridine and sulfur trioxide dissolved in 5 ml of dimethylsulfoxide. The resulting mixture is stirred for 16 hours. Then add 150 ml of water and the precipitate is sucked off. Obtain 0.33 g (72%) of product.

MS: m/e=457 (M+).

Analogously to example 16, you can get more of the compounds of General formula (I), summarized in table 1, where the conditional reduction in PH means phenyl.

The applicant is providing the totality of symptoms following activity derived piperidin-ketocarboxylic acids of the formula I in table 2. These data are obtained by testing calpain I.

In addition, the applicant reports that the derivatives of piperidine-ketocarboxylic acids of the formula (I) according to the invention belong to the category of low-toxic substances.

1. Derivatives of piperidine-ketocarboxylic acids of the formula (I)

< / BR>
where R1-CO-R, chinoline, benzothiophene, dihydroxyphenyl or pyridyl, substituted with allmineral;

R2- a branched or non-branched C1-C6-alkyl which can be substituted by phenyl or pyridium;

R3group-OR6or other6where R6means hydrogen, a branched or unbranched C1-C6-alkyl which can be substituted by phenyl, pyridine or morpholinium,

and their tautomeric and isomeric forms and their possible physiologically tolerated salts.

2. Derivatives of piperidine-ketocarboxylic acids of the formula (I) under item 1, where R1means C(= O)R4, -SO2R4; R2branched or non-branched C1-C6-alkyl; R3group-OR6or other6; R4, R5and R6are specified in paragraph 1.

3. Derivatives of piperidine-ketocarboxylic acids of the formula (I) under item 1 or 2, where R1means C(= O)R4, -SO2R4; R2- C1-C4-alkyl; R3- group-other6where R6means hydrogen, C1-C4-alkyl which can be substituted by phenyl, pyridium or morpholinium, R4naphthyl or chinoline or the group-CH= CH-R9where R9can the

 

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