Derivatives propanolamine, methods for their production and tool based on them

 

(57) Abstract:

The invention relates to the derivatives of propanolamine formula (I) and their pharmaceutically acceptable salts, where R1and R2means phenyl, naphthyl, pyridyl, thienyl, pyrimidyl, thiazolyl, hinely, piperazinil, oxazolyl, which may be substituted with halogen, HE, NO2, NH2, COOH, etc., R3-R8mean hydrogen, hydroxyl, (C1-C8-alkoxy, NH2-THE OTHER9, -N(R9R10, R9-R10mean hydrogen or (C1-C8)alkyl, X is CH or N, Y represents CH or N, provided that the residues R1, R2X and Y are not simultaneously mean R1- phenyl, R2is phenyl, X is CH, Y is CH. The compounds of formula (I) have inhibitory receipt of [3H] taurocholate activity and can find application in medicine. 3 S. and 3 C.p. f-crystals, 7 PL.

The invention relates to substituted derivatives of propanolamine and their salts.

Already describes the different classes of biologically active substances for the treatment of obesity and lipid disorders:

polymer adsorbers, such as cholestyramine;

- benzothiazepine (international application WO 93/16055);

- dimers and conjugates of bile sour the EP 00557879).

The basis of the invention is the provision of other compounds which are therapeutically suitable Hypo-lipidemias action.

The invention relates therefore to a derivative of propanolamine formula (I)

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where R1and R2independently from each other, means cycloalkyl with 3-8 carbon atoms in the cycle, phenyl, naphthyl, tenantry, pyridyl, thienyl, furyl, pyrimidyl, indolyl, thiazolyl, imidazolyl, coumarinyl, talimini, Chinois, piperazinil, tetrazolyl, triazolyl, oxazolyl and their thieno-, pyridine or Antonelliana derivatives, and cycloalkene ring, aromatic ring or heteroaromatic ring can be from once to three times substituted by fluorine, chlorine, bromine, iodine, hydroxyl, CF3, -NO2CN, (C1-C8-alkoxyl, (C1-C8)-alkyl, amino, -NH-R9, -N(R9R10, CHO, -COOH, -COOR11, -(C=O)-R12, (C1-C6)-alkyl, (C1-C6)-alkyl-(OH)-phenyl, (C1-C6-alkyltrimethyl, (C1-C6-alternatinggroup, (C1-C6) -alkyl-CN,

(C1-C6-alkylaminocarbonyl, (C1-C6)-alkyl-NH-R9, (C1-C6)-alkyl-N (R9R10<(C1-C6)-alkyl-(C=O)-R12, -O-(C1-C6)-alkyl-OH, -O-(C1-C6)-alkyl-CF3, -O-(C1-C6-alternatinggroup, -O-(C1-C6)-alkyl-CN, -O-(C1-C6-alkylamino, -O-(C1-C6)-alkyl-NH-R9, -O-(C1-C6)alkyl-N(R9R10,

-O-(C1-C6)-alkyl-Cho, -O-(C1-C6) -alkyl-COOH, -O-(C1-C6) -alkyl-COOR11, -O-(C1-C6)-alkyl-(C=O)-R12, -N-SO3N, SO2-CH3, -O-(C1-C6)-alkyl-O-(C1-C6-alkylphenyl, and in the alkyl residues of one or more hydrogen atoms may be replaced by fluorine;

R3-R8, independently of one another denote hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, CF3, -NO2CN, (C1-C8-alkoxy, (C1-C8)-alkyl, amino, -NH-R9, -N(R9R10CHO, -COOH, -COOR11, -(C=O)-R12and in the alkyl residues of one or more hydrogen atoms may be replaced by fluorine;

R9-R12, independently of one another, mean hydrogen, (C1-C8)-alkyl,

X is CH, N;

Y represents CH, N;

provided that the residues R1, R2X and Y are not simultaneously mean: Ractualname are the compounds of formula (I), in which one or more residues have the following meaning:

R1and R2independently from each other, means cycloalkyl with 3-8 carbon atoms in the cycle, phenyl, naphthyl, thienyl, furyl, pyrimidyl, thiazolyl, imidazolyl, talimini, Chinois, piperazinil, tetrazolyl, triazolyl, oxazolyl or their thieno-, pyridine-or Antonelliana derivatives, and cycloalkene ring, aromatic ring or heteroaromatic ring can be from once to three times substituted by fluorine, chlorine, bromine, hydroxyl, CF3, -NO2CN, (C1-C8-alkoxyl, (C1-C8)-alkyl, amino, -NH-R9, -N(R9)-R10, -COOH, -COOR11, -(C=O)-R12and in the alkyl residues of one or more hydrogen atoms may be replaced by fluorine;

R3-R8, independently of one another denote hydrogen, fluorine, chlorine, bromine, hydroxyl, CF3, -NO2CN, (C1-C8-alkoxy, (C1-C8)-alkyl, amino, -NH-R9, -N(R9R10, COOH, -COOR11, -(C=O)-R12and in the alkyl residues of one or more hydrogen atoms may be replaced by fluorine;

R9-R12, independently of one another, mean hydrogen, (C1-C8)belt not mean: R1is phenyl; R2is phenyl; X is CH; Y is CH;

and their physiologically acceptable salts.

Especially preferred compounds of formula (I) in which one or more residues have the following meaning:

R1means pyridyl, pyrimidyl, thienyl, thiazolyl, and the heteroaromatic ring can be from once to three times substituted by fluorine, chlorine, bromine, iodine, hydroxyl, CF3, -NO2CN, (C1-C8-alkoxyl, (C1-C8)-alkyl, amino, -NH-R9, -N(R9R10, CHO, -COOH, -COOR11-(C= O)-R12;

R2means phenyl and an aromatic ring can be from once to three times substituted by fluorine, chlorine, bromine, hydroxyl, CF3, -NO2CN, (C1-C8-alkoxyl, (C1-C8)-alkyl, amino, -NH-R9, -N(R9R10, -COOH, -COOR11, -(C=O)-R12;

R3-R8, independently of one another denote hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, CF3, -NO2CN, (C1-C8-alkoxy, (C1-C8)-alkyl, amino, -NH-R9, -N(R9R10, CHO, -COOH, -COOR11, -(C=O)-R12and in the alkyl residues of one or more hydrogen atoms can be replaced is/BR> X is CH;

Y represents N;

and their physiologically acceptable salts.

Under physiologically acceptable salts accession acids understand easily soluble, soluble or partially soluble in water connection according to the definition given in the book "German Pharmacopoeia" (9th edition, 1986, the official publication of the German Medical Publishing house, Stuttgart) on page 19. Preferred are hydrochloride and sulphate compounds.

The subject of the invention are as a mixture of isomers of formula (I), and pure enantiomers of the formula (I).

The invention relates further to a method for producing derivatives of propanolamine formula (I):

Method AND

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Method B

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Method And obtain the compounds of formula (I), characterized in that a) unknown from the literature, replaced with1and R2imine, and R1and R2are specified for formula (I) is, get known from the literature by means of amines of type II and aldehydes of type III. For this purpose, for example, amine type II enter into interaction with the aldehyde of type III in a suitable solvent or in his absence, such as ethanol, toluene or acetic acid, without EXT is>/P>Substituted residues R3-R8catasetinae formula (VII), and R3-R8are specified for formula (I) is, get known from the literature methods or by following such methods. So, for example, derived picoline formula (V) metallinou using a suitable base, such as n-utility, and in tetrahydrofuran or other suitable solvent is injected into engagement with the corresponding derivatives of carboxylic acids of the formula (VI), for example, as dialkylamide or alkalemia esters of carboxylic acids, at temperatures from -80oWith up to 20oC.

Compounds of type VIII get what imine type IV enter into interaction with the ketones of type VII, which can be substituted residues R3-R8and R3-R8are specified for formula (I) value. This reaction can be performed, for example, by mixing the two compounds in the absence of subsequent heating or in a suitable solvent, such as ethanol, toluene, diglyme or tetradecane, at temperatures from 20 to 150oWith (C).

Catasetinae type VIII in a suitable solvent, such as, for example, methanol, tetrahydrofuran, or a mixture of tetrahydrofuran with water, vosstanavlivaya of hydroxiapatite type I, moreover, the compound of formula (I) may be substituted residues R3-R8and R3-R8are specified for formula (I) is (d).

The compounds of formula (I) after the above-described recovery obtained as a mixture of isomers. Various racemates can be separated from each other by fractional crystallization or by column chromatography. Pure enantiomers can be obtained from the racemates of compounds of formula (I), by chromatography on chiral material or by known literature methods using optically active auxiliary reagents, such as, for example, described in J. Org.Chem., 44, 4891 (1979).

Method B to obtain the compounds of formula (I), characterized in that Imin formula (IV) receive and emit not as in method a, a compound of type VIII, substituted residues R3-R8, synthesize three-component reaction of ketones VII, amines II and aldehydes III. For this purpose, these three components is injected into the interaction in the absence of solvent or in a suitable solvent, like ethanol, tetradecane or toluene, at temperatures from 20 to 150oWith (e). The compounds of formula (VIII) is reduced to compounds of formula (I), (f), as described in the case of method A, the compounds of formula the reaction.

The present invention also relates to pharmaceutical compositions, which along with non-toxic, inert, pharmaceutically suitable carriers include one or more proposed according to the invention biologically active substances or consist of one or more proposed according to the invention are biologically active substances, as well as to a method for producing these compositions.

Under non-toxic, inert, pharmaceutically suitable carriers need to understand pharmaceutically acceptable, semi-solid or liquid diluents, fillers or auxiliary for the preparation of dosage forms tools of any kind, which, after mixing with a biologically active substance bring it to a suitable form of application.

As a suitable dosage forms proposed according to the invention compounds are used, for example, tablets, coated tablets, capsules, pills, aqueous solutions, suspensions and emulsions, if necessary, sterile injectable solutions, non-aqueous emulsions, suspensions and solutions, sprays, as well as the preparative form slow release of biologically active substances.

Therapeutically active soede 0,1-a 99.0 wt.%, preferably 0.5 to 70,0 wt.%, calculated on the total mixture.

Applied concentration for solutions and aerosols in spray form are in General 0.1 to 20 wt.%, preferably 0.5 to 5 wt.%.

Also proposed according to the invention the biologically active substances of the above pharmaceutical compositions can also contain other pharmaceutical biologically active substances.

These pharmaceutical compositions have the usual manner by known methods, for example by mixing the biologically active substances or biologically active substances with a carrier or carriers.

Biologically active substance or pharmaceutical composition can be administered orally, parenterally, administered intraperitoneally and/or rectally.

Used, such as lipid compounds of the present invention and their salts can be used to obtain pharmaceutical preparations which contain an effective amount of the active substance together with the media and are suitable for intestinal or parenteral administration. Preferably use a tablet or capsule (gelatin capsules), which contain the biological is Trosa, raw sugar, mannitol, sorbitol, cellulose, various types of starch and/or glycine, and substances which impart lubricity, such as silica, talc, stearic acid or its salts, such as magnesium stearate or calcium stearate and/or polyethylene glycol. The tablets also contain binders, as magnesium carbonate, magnesium aluminosilicate, starch, gelatin, tragant, methylcellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone, and, if necessary, dyes, substances, corrective unpleasant taste of the medicine, and sweetening tools. Injectable solutions are preferably isotonic aqueous solutions or suspensions, which may be sterilized and may contain auxiliary substances, such as preservatives, stabilizers, wetting and/or emulsifying agents, agents, dissolution, salts for regulating osmotic pressure and/or buffer substances. Proposed according to the invention the preparations which, if desired, may contain other pharmacologically active substances, receive, for example, conventional methods of mixing-granulating and drazhirovanija, and they contain from 0.1% to preferably 80%, preferably about 5-65%, biologically active substances.

PE or capsules, who, for example, contain 5-1000 mg per daily dose, preferably 20-200 mg of biologically active substances in a mixture with conventional media and/or component, and you can enter single doses of 5-200 mg, preferably from one to three times a day.

However, it may be necessary deviation from the specified dosage, namely depending on the kind and weight of curable object, type and severity of the disease, the type of composition and the method of administration of the medicinal product, and time period, respectively, of the interval during which the medication. Thus, in some cases, it may be sufficiently smaller than the above, a number of biologically active substances, while in other cases it is necessary to exceed the above number of biologically active substances. Install required in each case, the optimal dosage and route of administration of biologically active substances can easily any person based on their special knowledge.

The compounds of formula (I) and their physiologically acceptable salts are an ideal drug for the treatment of lipid metabolism disorders, especially hyperlipidemia. With treatment arteriosclerotic phenomena. These data confirm the pharmacological activity proposed according to the invention compounds.

Biological test proposed according to the invention compounds is carried out by determining the inhibition of receipt of [3H]-taurocholate in membrane vesicles to the brush border of the ileum of rabbits. Test for inhibition is as follows:

1. Preparation of membrane vesicles to the brush border of the ileum of rabbits.

Preparation of membrane vesicles to the brush border cells of the small intestine is performed using the so-called method of precipitation MD2+. Male new Zealand rabbits (weighing 2-2 .5 kg) killed by intravenous injection of 0.5 ml T61, an aqueous solution of 2.5 mg of tetragidrofolata, 100 ml embutramide and 25 mg mebezonium. The small intestine is recovered and washed with ice physiological solution of sodium chloride. End 7/10 small intestine (measured in oral-rectal direction, i.e., limit the ileum, which contains an active, Na+- dependent transport system bile acids) used to prepare membrane vesicles brush to For preparation of membrane vesicles frozen guts thawed at 30oC in a water bath. The mucous membrane is scraped and suspended in 60 ml ice 12 mmol of Tris/Hcl-buffer (pH= 7,1)/300 mm mannitol/5 mmol of ethylenebis(oxyethylenenitrilo)-tetraoxane acid/10 mg/l phenylmethylsulfonyl /1 mg/l trypsinogen inhibitor from soybeans (32 U/mg) /0.5 mg/l trypsinogen inhibitor from the lungs of cattle (193 U/mg) 5 mg /l bacitracin. Once diluted to 300 ml with ice distilled water, homogenized under ice cooling with the help of the device Ultraturrax (18-rod, IKA Werk Staufen, Germany) for three minutes at 75% of maximum power. After adding 3 ml of 1 M solution of magnesium chloride (final concentration 10 mmol) maintain just one minute at a temperature of 0oC. By addition of Mg2+aggregate cell membrane and precipitated with the exception of the brush border membranes. After centrifugation for 15 minutes at acceleration 3000 g (5000 rpm, SS-34 rotor) precipitate discarded and the supernatant, which contains the brush border membrane, centrifuged for 30 minutes at acceleration 48000 g (20,000 rpm, SS-34 rotor). Supernatant discarded, the residue is again homogenized in 60 ml of 12 mmol of Tris/Hcl buffet is and Potter Elvejhem (brown, Melsungen, 900 rpm, 10 strokes). After adding 0.1 ml of 1 M solution of magnesium chloride and the incubation time of 15 minutes at a temperature of 0oWith again centrifuged for 15 minutes at acceleration 3000 g. The supernatant is then again centrifuged for 30 minutes at acceleration 48000 g (20,000 rpm, SS-34 rotor ). The residue is treated with 30 ml of 10 mmol of Tris/HEPES buffer (pH of 7.4)/300 mm mannitol and again suspended by 20 strokes in a Potter homogenizer-Elvejhem at a speed of 1000 revolutions per minute. After centrifugation for 30 minutes at acceleration 48000 g (20,000 rpm, SS-34 rotor) contribute sediment in 0.5 to 2 ml of Tris/HEPES buffer (pH of 7.4)/280 mm mannitol (final concentration 20 mg/ml) and resuspended using a tuberculin syringe with needle 27-gauge. Vesicles or used directly after preparation for research, transport, or store at a temperature of -196oPortions 4 mg in liquid nitrogen.

2. Inhibition of PA+-dependent arrivals [3H]taurocholate in membrane vesicles to the brush border of the ileum.

The flow of substrates in the above-described membrane of the brush border vesicles is determined using the so-called way is tubazioni tubes made of polystyrene (1170 mm), which contains the incubation medium with the appropriate ligands (90 μl). The incubation medium contains 0.75 ál = 0,75 µci of [3H(G)]-taurocholate (specific activity of 2.1 CI/mmol)/0,5 ál of 10 mm taurocholate/8,75 ál retrytransaction buffer (10 mmol Tris/HEPES (pH=7,4)/100 mm mannitol/100 mmol sodium chloride) (Na-T-B), respectively, of 8.75 μl of potassium transport buffer (10 mmol Tris/HEPES (pH=7,4)/100 mm mannitol/100 mm KCl) (K-T-B) and 80 μl of each solution of the inhibitor, dissolved depending on the experiment in Na-T-buffer or K-T-buffer. The incubation medium was filtered through a membrane filter made of polyvinylidene difluoride (SYHVLO 4NS, 0.45 μm, 4 mm in diameter, firm Millipore, Eschborn, Germany). By mixing vesicles with incubation medium start measuring transportation. Concentration taurocholate in the incubation mixture is 50 µm. After the desired time of incubation (usually 1 minute) transportation stoppering by adding 1 ml ice solution of the stopper (10 mmol Tris/HEPES (pH of 7.4) /150 mm KCl). The resulting mixture was immediately filtered under vacuum 25-35 mbar through a membrane filter of cellulose nitrate (mass unit 25, 0.45 μm, 25 mm diameter, Schleicher and Schuell, Acceltable radioactively labeled taurocholate membrane filter is dissolved in 4 ml of scintillator Quickszint 361 (Zinsser Analytik GmbH, Frankfurt, Germany) and measure the radioactivity by measuring the scintillation fluid in the measuring device TriCarb 2500 (Canberra Packard GmbH, Frankfurt, Germany). The measured values obtained after calibration with standard samples and after correction possible available chemiluminescence as the number of disintegrations per minute.

In each case, determine the control values in Na-T-B and T-B. the Difference between arrival in Na-T-B and K-T-B gives PA+-dependent transport share. As IR50Na+denote this concentration of inhibitor at which the Na+-dependent transport share is inhibited by 50%, based on the control.

Pharmacological data includes a series of tests, which investigated the interaction proposed according to the invention compounds with intestinal transport of bile acids in the terminal small intestine. The results are presented in table A.

In table a provides data measuring the inhibition of receipt of [3N] -taurocholate in membrane vesicles to the brush border of the ileum of rabbits. It shows the relationship between values IR50Nastandard substances in the form of taurochenodeoxycholate (DDH) according to the invention, without limiting the invention described in the examples of products and forms of implementation.

EXAMPLE 1.

A.

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To a solution of 25 g (266 mmol) of 2-aminopyridine and 40 g (265 mmol) of 3-nitro-benzaldehyde in 300 ml of toluene added 0.7 g of p-toluenesulfonic acid and the mixture is refluxed for 6 hours. After cooling, half of the solvent is removed in vacuum and the mixture was incubated over night. The precipitation is sucked off, washed with cold toluene and dried in vacuum. By subsequent recrystallization from a mixture of n-heptane to ethyl acetate in the ratio of 2:1 to receive and 48.8 g (81%) of the imine. WITH12H9N3ABOUT2(227,2); mass spectrum (fast atom bombardment): to 228.2 M+N+< / BR>
b.

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To a solution of 50 g (0.54 mol) of 2-picoline in 770 ml of tetrahydrofuran at a temperature of -55oWith added dropwise to 250 ml of n-utility (15% in hexane) and stirred for 10 minutes. Then heated to 0oFrom and after the next 30 minutes, cooled to -55oC. then slowly added dropwise a solution of 77 g (0.52 mol) of N,N-dimethylbenzamide in 570 ml of tetrahydrofuran. After adding warmed to room temperature and stirred for 1 hour. After adding 500 ml of water and 35 Etat. After drying over magnesium sulfate the organic phase was concentrated in vacuo and the residue is distilled in high vacuum. Boiling point 134-136oWith/0.3 mbar. Output: 47,5 g (47%)of the ketone. WITH13H11NO (197,2); mass spectrum (fast atom bombardment): 198,1 M+N+.

C.

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5.8 g (25.5 mmol) of imine of example 1A and 5.0 g (25,4 mmol) of ketone from example 1b mixed well and heated on the steam bath. After about 20 minutes, the mixture begins to melt and with further heating crystallizes. After cooling, the residue in 200 ml of ethyl acetate is heated to boiling, cooled, the precipitate is sucked off and dried in vacuum. Yield: 6.7 g (62%). C25H20N4O3(424,2); mass spectrum (fast atom bombardment): 425,2 M+H+.

d.

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3.0 g (7.1 mmol) of catasetinae from example 1C was dissolved in 50 ml of a mixture of tetrahydrofuran with water at a ratio of 10:1, mixed with 1.35 g (35,7 mmol) of sodium borohydride and stirred for 1 hour at room temperature. Using a 2H. hydrochloric acid adjusted to pH 1 and stirred for 30 minutes at a temperature of 50oC. After cooling, the reaction mixture was alkalinized using 2n. solution of sodium hydroxide and extrage farout on silica gel using a mixture of heptane to ethyl acetate in the ratio of 6:4. Thanks to this product get 2 of racemic compounds.

1st Fraction: 1.26 g (42%) nonpolar racemate; C25H22N4O3(to 426.2); mass spectrum (fast atom bombardment): 427,2 M+N+.

2nd Fraction: 1,15 g (38%) of the polar racemate; C25H22N4O3(to 426.2); mass spectrum (fast atom bombardment): 427,2 M+N+.

E.

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50 mg nonpolar racemate from example Id by preparative high performance liquid chromatography (HPLC) liquor enantiomers. The splitting is carried out on a column with a chiral phase CSP Chiralpak (company Daicel, düsseldorf) using a mixture of n-hexane with propane-2-I in the ratio of 50: 10 + 0.1% diethylamine as solvent. As of the 1st faction will receive 20 mg of (-)-enantiomer and as a 2nd faction will receive 20 mg of (+)-enantiomer.

f.

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1.0 g (2.34 mmol) of nonpolar racemate from example Id is dissolved in 200 ml of methanol and in the presence of about 20 mg of 10% palladium-on-coal hydronaut in hydrogen atmosphere for three hours at room temperature. Filtered from the catalyst and the solution is evaporated. The remainder chromatographic on silica gel using a mixture of ethyl acetate fast atom): 397,3 M+N+.

g.

From 2.0 g (4,69 mmol) polar racemate from example Id as described in example 1f to the way we obtain 1.2 g (65%) of the corresponding amine. WITH25H24N4O (396,2); mass spectrum (fast atom bombardment): 397,2 M+N+.

EXAMPLE 2.

A.

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of 78.8 g (0.4 mol) of the ketone from example 1b, to 37.6 g (0.4 mol) of 2-aminopyridine and 21.2 g (0.4 mol) of benzaldehyde are dissolved in 1 l of ethanol with vigorous stirring and refluxed for one and a half hours. Then additionally stirred for 4 hours and incubated overnight. The precipitate is sucked off, washed with a small amount of ethanol and dried in vacuum. Output: 134 g (88%). WITH25H21N3About (to 379.2); mass spectrum (fast atom bombardment): 380,1 M+N+.

b.

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56,9 g (0.15 mol) of the ketone from example 2A are suspended in 1 l of methanol and slowly added in several portions to 60 g of NaBH4in 100 ml of water; the temperature rises from 22oWith up to 34oC. the Alcohol is removed in vacuo, the residue is mixed with about 200 ml of water and extracted three times with ethyl acetate. The organic phase is dried and evaporated. The remainder chromatographic on silica gel using a mixture of n-heptane with ethyl is Amata; C25H23N3O (381); mass spectrum (fast atom bombardment): 382 M+N+.

2nd Fraction: 14 g (24%) of the polar racemate; C25H23N3(381); mass spectrum (fast atom bombardment): 382 M+N+.

C.

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100 mg nonpolar racemate from example 2b were cleaved as described in example 1E. Using a mixture of n-hexane with propane-2-I in the ratio of 25: 10+0.1% diethylamine as solvent is obtained as the 1st fraction 40 mg (-)-enantiomer, as well as the 2nd fraction 30 mg (+)-enantiomer.

EXAMPLE 3.

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Nonpolar racemate from example 47 in table 2, we can get similarly to the method of example 2; 160 mg (0.36 mmol) of this complex methyl ester was dissolved in 20 ml of ethanol, mixed with 1.6 ml of 2n. an aqueous solution of sodium hydroxide and stirred for 40 hours at room temperature. The solvent is then completely removed, the residue is dissolved in water and using a 2H. hydrochloric acid set in a solution of pH=6.5. Extracted twice with 50 ml ethyl acetate, the organic phase is dried and concentrated. Chromatography of the residue on silica gel using a mixture of n-heptane to ethyl acetate in the ratio of 1:1 gives 110 mg (71%) of product. WITH27H24

EXAMPLE 95

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300 mg (from 0.76 mmol) of the amine from example 62 was dissolved in 10 ml of pyridine, mixed with 75 μl (0.80 mmol) of acetic anhydride and 5 mg dimethylaminopyridine and stirred for two hours at room temperature. Then add 30 ml of water and extracted three times with ethyl acetate. The organic phase is dried and concentrated. Chromatography on silica gel using a mixture of n-heptane to ethyl acetate in the ratio of 4: 1 yield 200 mg (60%) of product. C27H25N4O2(438,2); mass spectrum (fast atom bombardment ): 439,2 M+N+.

EXAMPLE 96

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Similarly to the method of example 94, using the acid chloride pavlinovoi acid get the above connection. WITH30H32N4ABOUT2(480,3); mass spectrum (fast atom bombardment): 481,3 M+N+.

EXAMPLE 97

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1,99 g (0,005 mol) of the compound from example 66 and 1 g of powdered potassium carbonate bring in 50 ml of dimethyl-formamide. To the solution was added 0.7 ml (0,006 mol) of ethyl ether bromoxynil acid and refluxed for 6 hours. Then concentrated in vacuo and the residue is (80%). WITH29H29N3O4(483); mass spectrum (fast atom bombardment): 484 M+N+.

EXAMPLE 98

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The target compound of example 98 is produced from compound of example 97 as described in example 3 method. WITH27H25N3ABOUT4(455); mass spectrum (fast atom bombardment): 456 M+N+.

EXAMPLE 99.

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1,99 (0,005 mol) of the compound from example 66 and 8.8 g (0.1 mol) of ethylene carbonate resulting heated on an oil bath up to 90-95o(The melt). At this temperature, add 0.14 g (0.001 mol) of potassium carbonate and stirred for 5 hours. After cooling the resulting solution was filtered and concentrated in vacuo. Chromatography on silica gel using a mixture of n-heptane to ethyl acetate in the ratio of 1:1 gives 1.5 g (68%) of product. WITH27H27N3ABOUT3(441); mass spectrum (fast atom bombardment): 442 M+N+.

EXAMPLE 100

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The target compound of example 100 is obtained from the compound of example 70 as described in example 99. method. WITH27H27N3ABOUT3(441); mass spectrum (fast atom bombardment): 442 M+N+.

EXAMPLE 101

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To a solution of 1.83 g (12 mmol) of benzyloxyethanol and 3.67 g (14 mmol) of triveneto elata and then of 3.97 g (10 mmol) of the compound of example 70. After stirring overnight the solvent is removed and dissolved again in ethyl acetate. This solution is shaken out twice with sodium carbonate solution, then dried and concentrated. Chromatography on silica gel gives of 3.85 g (72%) of product. WITH34H33N3ABOUT3(531,3); mass spectrum (fast atom bombardment): 532 M+N+.

1. Derivatives propanolamine formula (I)

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where R1and R2, independently of one another denote phenyl, naphthyl, pyridyl, thienyl, pyrimidyl, thiazolyl, hinely, piperazinil, oxazolyl, and aromatic or heteroaromatic ring can be from once to three times substituted by fluorine, chlorine, bromine, iodine, hydroxyl, NO2, (C1-C8-alkoxyl, NH2-THE OTHER9, -N(R9R10, -COOH, -COOR11, (C1-C6)-alkyl, (C1-C6)-alkyl-(OH)-phenyl, (C1-C6)-alkyl-COOH, (C1-C6)-alkyl-R11,

-O-(C1-C6)-alkyl-OH, -N-SO3H, -SO2-CH3, -O-(C1-C6)-alkyl-O-(C1-C6-alkylphenyl,

R3-R8independently from each other denote hydrogen, hydroxyl, (C1-C8-alkoxy, NH2-THE OTHER9, -N(R9Rthe mean CH or N;

Y represents CH or N;

provided that the residues R1, R2X and Y are not simultaneously mean R1- phenyl, R2is phenyl, X is CH, Y is CH,

or their physiologically acceptable salts accession acids.

2. The compounds of formula (I) under item 1, in which R1and R2, independently of one another denote phenyl, naphthyl, thienyl, pyrimidyl, thiazolyl, hinely, piperazinil, oxazolyl, and aromatic or heteroaromatic ring can be from once to three times substituted by fluorine, chlorine, bromine, hydroxyl, NO2, (C1-C8-alkoxyl, NH2-THE OTHER9, -N(R9R10, -COOH, -COOR11; R3-R8independently from each other denote hydrogen, hydroxyl, (C1-C8-alkoxy, NH2-THE OTHER9, -N(R9R10; R9-R11, independently of one another, mean hydrogen or a (C1-C8)-alkyl; X represents CH or N; Y represents CH or N; provided that the residues R1, R2X and Y are not simultaneously mean R1- phenyl, R2is phenyl, X is CH, Y is CH, or their physiologically acceptable salts accession acids.

3. The compounds of formula (I) under item 1 or 2, in which R1means pyridyl, pyrimidyl, thienyl, thiazolyl, and g is the oxyl, NO2, (C1-C8-alkoxyl, NH2-THE OTHER9, -N(R9R10, -COOH, -COOR11; R2means phenyl and an aromatic ring can be from once to three times substituted by fluorine, chlorine, bromine, hydroxyl, NO2, (C1-C8-alkoxyl, NH2-THE OTHER9, -N(R9R10, -COOH, -COOR11; R3-R8independently from each other denote hydrogen, hydroxyl, (C1-C8-alkoxy, NH2-THE OTHER9, -N(R9R10; R9-R11, independently of one another, mean hydrogen or a (C1-C8)-alkyl; X is CH; Y represents N, or their physiologically acceptable salts accession acids.

4. The method of obtaining compounds of formula (I) according to any one of paragraphs.1-3, includes the following stages:

(a) amine of the formula (II)

R1-NH2(II)

subjected to interaction with the aldehyde of formula (III)

R2-CHO, (III)

obtaining imine of formula (IV)

< / BR>
where R1and R2have the above for compounds of formula (I) values,

C) the compound of formula (V)

< / BR>
subjected to interaction with the carboxylic acid derivative of the formula (VI)

< / BR>
where Z denotes the group that you want,

obtaining ketose is R>
(C) a compound of the formula (IV) obtained in stage (a), is subjected to the interaction with the compound of the formula (VII), with compounds of the formula (VIII)

< / BR>
where X, Y, R1-R8have the above for compounds of formula (I) values,

d) compound of formula (VIII) is reduced to the compounds of formula (I) in a suitable solvent at a temperature of from -30 to 40oC.

5. The method of obtaining compounds of formula (I) according to any one of paragraphs.1-3, includes the following stages: (e) compounds of formula (II), (III) and (VII) is subjected to interaction in a suitable solvent at a temperature of from 20 to 150oWith obtaining the compounds of formula (VIII), (f) compound of formula (VIII) is reduced to the compounds of formula (I) in a suitable solvent at a temperature of from -30 to 40oC.

6. The agent with inhibitory receipt of [3N] taurocholate activity and containing one or more compounds according to any one of paragraphs.1-3.

Priority points and features:

04.04.1997 on PP.1-6;

26.01.1998 on PP.1-6, specification features.

 

Same patents:

The invention relates to the derivatives of pyrrolidine formula I

< / BR>
where R1- H, C1-C6alkyl; phenyl, possibly substituted; biphenyl, possibly substituted; 1H, 5H - pyrido [3,2,1-ij] chinolin; phenyl WITH1-C6alkyl, optionally substituted; biphenyl WITH1-C6alkyl, optionally substituted; biphenylcarboxylic; terphenyl; naphthyl, optionally substituted; Z denotes-S-, -O-, -och2-, -N(R16), where R16- H, C1-C6alkyl, C3-C8cycloalkyl1-C6alkyl, panels1-C6alkyl, a chemical bond; X1means-CO-, -(CH2)r-CO-N(R17), where R17means H, C1-C6alkyl (where r = 0 or 1), -CH2NHSO2-, -(CH2)s-N (R18)-CO- (where R18- N, s=1-3), - CH2NHCОСН2O-, -CH2N (R19Of PINES = CH- (where R19- H, -CH2OCH2-, -CH2-N (R20)-CH2- (where R20- H, C1-C6alkyl, C1-C6alkylsulphonyl, phenylcarbinol)1-C5alkylen,2-C4albaniles, a chemical bond; X2- phenylene, optionally substituted hydroxy, theoffender, purandar, piperidinyl,< / BR>
< / BR>
< / BR>
R2and R3each - H; and R4- phenyl, possibly substituted with halogen; R5- phenyl, possibly substituted; a cycle of G is phenyl,3-C7cycloalkyl, pyridyl, thienyl; loop J is phenyl; L is phenyl; p=0-2;----- means the presence or absence of chemical bonding;displays a CIS - or TRANS-configuration D relative to E; provided that X1means-CH2NHCО-, X2means 1,4-phenylene and X3means a chemical bond or a C1-C5alkylen, when the carbon atom bound CD and adjacent carbon atom in the cycle are connected by a simple relation and V1does not mean a chemical bond, when X1means-CH2O-; and pharmaceutically acceptable salt or hydrate of the compound

The invention relates to new heterocyclic compounds of the formula (I), where R1represents a group of formula (II), R is 2,4-dioxothiazolidine-5-ylmethylene group and others, And represents C1-6alkylenes group, A represents an oxygen atom, R4represents a substituted phenyl or pyridyl which may have a Deputy, R6represents a hydrogen atom or a C1-6alkyl group, D represents an oxygen atom or sulfur, E is a CH group or a nitrogen atom, or their pharmacologically acceptable salts

The invention relates to the derivatives of hintline formula I in which Z denotes-O-, -NH - or-S-; m = 1-5, integer, provided that when Z represents-NH-, m = 3 - 5; R1is hydrogen, C1-3alkoxy; R2is hydrogen; R3hydroxy, halogen, C1-3alkyl, C1-3-alkoxy, C1-3alkanoyloxy, trifluoromethyl or cyano; X1denotes-O-, -NR7, -NR8CO-, where R7and R8each is hydrogen, C1-3alkyl; R4choose one of the listed in paragraph 1 of the claims of the seven groups, except 4-(3,4,5-trimethoxyphenyl)-6,7-dimethoxyquinazoline, 4-(3-methoxybenzylthio)-6,7-dimethoxyquinazoline, 4-(3-chlorophenylthio)-6,7-dimethoxyquinazoline, 4-(3-chlorophenoxy)-6,7-dimethoxyquinazolin and 4-(3,4,5-trimethoxyaniline)-6,7-dimethoxyquinazolin, or their salts

The invention relates to the derivatives of hintline formula (I), where Y1represents-O-, -S-, -NR5CO-, where R5is hydrogen; R1represents hydrogen or C1-3alkoxy; R2represents hydrogen; m is an integer from 1 to 5; R3represents hydroxy, halogen, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl or cyano; R4is one of five groups, which is optionally substituted by Spiridonova, phenyl or aromatic heterocyclic group with 1-3 heteroatoms selected from O, N and S, or contains such a group; and their salts, to processes for their preparation and to pharmaceutical compositions containing a compound of the formula (I) or its pharmaceutically acceptable salt as an active ingredient

The invention relates to a method for producing derivatives of 2-aminothiazoline formula I, in which R1represents C1-5alkyl straight or branched chain, R2is1-3alkyl, by reacting the compounds of formula II in which R3represents phenyl which may be optionally mono-pentamidine independently chlorine, methoxy, ethoxy, phenoxy or nitro, with the compound of the formula III in which Y represents a leaving group, in a solvent and in the presence of a base

The invention relates to amide derivative of the General formula I, the symbols in the formula have the following meanings: D is pyrazolidine group which may have 1-3 halogenated derivatives or unsubstituted lower alkyl group as the Deputy(I)her is fenelonov or topendialog group, X represents a group of formula-NH-CO - or-CO-NH -, and a represents a phenyl group which may be substituted by one or more halogen atoms, or a five - or six-membered monocyclic heteroaryl group which may be substituted by one or more of lower alkyl groups

The invention relates to compounds of formula (I) R4-A-CH(R3)N(R2)B-R1where a is optionally substituted phenyl group, provided that the group-CH(R3)N(R2)B-R1and-OR4are in the 1,2-position relative to each other on the carbon atoms of the ring, and provided that the atom of the ring, in anthopology towards OR4- joined the group (and therefore in the 3-position relative to the-CHR3NR2-linking group) is unsubstituted; In - pyridyl or pyridazinyl; R1located on the ring In the 1,3 - or 1,4-position relative to the-CH(R3)N(R2)-linking group and represents carboxy, carbarnoyl or tetrazolyl, or R1represents a group of formula СОNRaRa1where Rais hydrogen or C1-6alkyl, and Ra1- C1-6alkyl, or R1represents a group of formula CONHSO2Rbwhere Rb- C1-6alkyl, trifluoromethyl, or a 5-membered heteroaryl selected from isooxazolyl and thiadiazolyl, optionally substituted C1-6the alkyl or C1-4alkanolamines; R2- C1-6alkyl; R3is hydrogen; R4- C1-4alkyl, C3-7cycloalkyl,1-3alkyl or their pharmaceutically acceptable salt or in vivo hydrolyzable esters

The invention relates to a method for the preparations of thiazolidinediones of the formula III, where a denotes CH=CH or S, W is O; X Is S, O or NR2where the remainder R2is hydrogen or C1-C6by alkyl; Y is CH or N; R is naphthyl, thienyl or phenyl, which optionally one - or twofold substituted C1-C3the alkyl, CF3C1-C3alkoxygroup, F, Cl or bromine; R1is hydrogen, C1-C6alkyl and n = 1-3, by restoring the compounds of formula IV metal aluminum in proton solvent

The invention relates to new isoxazol derivative of formula 1, where D represents hydrogen; one of a and b is a group (1) -E-N= C(NR25R26)NR27R28; E represents a direct link or alkilinity group; R25and R26each represents, independently, hydrogen; C1-4-alkyl; -(CH2)n-CO2R32, n is an integer of 1-3, and R32represents hydrogen, C1-4-alkyl; -(CH2)m-CO2R35m is 2 or 3 and R35represents hydrogen, C1-4-alkyl; -(CH2)mHE, m defined above, or -(CH2)n-C(O)R36n is defined above and R3represents hydrogen, C1-4-alkyl; and t

The invention relates to substituted 1-phenylpyrazol-3-carboxamide formula (Ia) in which R1xis in position 4 or 5 and denotes the group-T-CONRaRbin which T represents a direct bond or (C1-C7-alkylen; NRaRbdenotes a group selected from (a), (b), (C); R5and R6denote, independently of one another, hydrogen, (C1-C6)-alkyl, (C3-C8)-alkenyl or R5and R6together with the nitrogen atom to which they are linked, represent a heterocycle selected from pyrrolidine, piperidine, research, piperazine, substituted in position 4 by Deputy R9; R7denotes hydrogen, (C1-C4)-alkyl or benzyl; R8denotes hydrogen, (C1-C4)-alkyl, or R7and R8together with the carbon atom to which they are attached, form a (C3-C5-cycloalkyl; R9denotes hydrogen, (C1-C4)-alkyl, benzyl or a group-X-NR'5R'6in which R'5and R'6represent, independently from each other, (C1-C6)-alkyl; R10denotes hydrogen, (C1-C4)-alkyl; s= 0-3; t=0-3, provided that (s+t) in the same group greater than or equal to 1; the divalent radicals a and E together with the atom is which in addition, may be substituted by one or more (C1-C4-alkilani; R2xand R3xdenote, independently of one another, hydrogen, (C1-C6)-alkyl, (C3-C8-cycloalkyl, (C3-C8-cyclooctylmethyl provided that R2xand R3xdo not simultaneously denote hydrogen or R2xand R3xtogether form tetramethylene group; and their pharmaceutically acceptable salts

The invention relates to compounds of the formula I

< / BR>
in which R1denotes-C(=NH)-NH2which may be substituted once by a group-COA, -CO-[C(R6)2]n-Ar, -COOA, -HE or normal aminosidine group

< / BR>
R2denotes H, A, OR6N(R6)2, NO2CN, Hal, NHCOA, NHCOAr, NHSO2A, NHSО2Ar, COOR6, SOPS(R6)2, CONHAr, COR6, COAr, S(O)nA or S(O)nAr,

R3means And, cycloalkyl, - [C(R6)2]nAr, - [C(R6)2]n-O-Ar, -[C(R6)2]nHet or-C(R6)2=C(R6)2-Ar,

R6denotes H, a or benzyl,

X is absent or represents-CO-, -C(R6)2-, -C(R6)2-C(R6)2-, -C(R6)2-CO-, -C(R6)2-C(R6)2-CO-, -C(R6)= C(R6)-CO-, NR6CO-, -N{[CR6)2]n-COOR6} -CO - or-C(COOR6R6-C(R6)2-CO-,

Y represents-C(R6)2-, -SO2-, -CO-, -COO - or-CONR6-,

And denotes alkyl with 1-20 C-atoms, where one or two CH2-groups can be replaced by O - or S-atom or single, two - or three-fold substituted by the group And, Ah', OR6N(R6)2, NO2CN, Hal, NHCOA, NHCOAr', NHSO2A, NHSО2Ar', COOR6, CON(R6)2, CONHAr', COR6, COAr', S(O)nA or S(O)nAr is phenyl or naphthyl,

AG' refers to unsubstituted or one-, two - or three-fold substituted by a group A, OR6N(R6)2, NO2CN, Hal, NHCOA, COOR6, SOPS(R6)2, COR6or S(0)nA phenyl or naphthyl,

Het denotes a single or dual core unsubstituted or one - or multi-substituted by a group of Hal, A, Ar', COOR6, CN, N(R6)2, NO2, Ar-CONH-CH2and/or carbonyl oxygen saturated or unsaturated heterocyclic ring system containing one, two, three or four identical or different heteroatoms, such as nitrogen, oxygen or sulphur,

Hal denotes F, C1, Br or J,

n denotes 0, 1 or 2,

and their salts

The invention relates to new derivatives of kalaidjieva, fungicides, method of combating fungal diseases of crops and intermediate compounds for obtaining

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 invention relates to new derivatives of benzoxazinone General formula (I), where R1means N or carboxyethyl, R2represents hydrogen or alkyl, and R3is a different derivatively of amino acids, dipeptides and hydrazones acid groups, respectively, their conjugates with active substances, such as residues from a number of penicillin

The invention relates to compounds: N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino] sulfonyl] -4-(2-oxazolyl)[1,1'-biphenyl] -2-yl] methyl]-N,3,3-trimethylbutyramide and N-(4,5-dimethyl-3-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl] -4'-(2-oxazolyl)[1,1'-biphenyl] -2-sulfonamide and their pharmaceutically acceptable salts, such as lithium, sodium or potassium salt or a salt with a base, which is an organic amine

The invention relates to new derivatives of oxadiazole General formula I, in which X and Y denote oxygen or nitrogen, and X and Y cannot both be oxygen or nitrogen; Z denotes a radical of the formula II, R1means phenyl radical, which is optionally substituted directly or through alkylene bridges with the number of carbon atoms from 1 to 4 once, twice or three times by one or more substituents from the series halogen, C1-C4-alkyl, CF3, -NR5R6, NO2, -OR7

The invention relates to new derivatives of azetidine and pyrrolidine General formula

< / BR>
where a represents an optionally unsaturated 5 - or 6-membered ring which may contain heteroatom selected from N and S, and which may be substituted by oxo or (1-6C) alkyl; R1, R2and R3independently of one another represent H, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkoxy-(1-6C)alkyl, and halogen atom; X is an atom of O or S and n = 1 or 2, or its pharmaceutically acceptable salt, except 3-(naphthas-1-yl-oxy)-pyrrolidine and 3-(5,6,7,8-tetrahydro-naphthas-1-yl-oxy)-pyrrolidin
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