Method for preparing n-methyl-n-[(1s)-1-phenyl-2-((3s)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide as pure enantiomer

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of N-methyl-N-{(1S)-1-phenyl-1-[(3S)-3-hydroxypyrrolidin-1-yl]ethyl}-2,2-diphenylacetamide. Method involves the following steps: (a) interaction of N-substituted derivative of phenylglycine of the formula (I): , wherein R means -OR1, -SR1; R1 means A, benzyl, unsubstituted phenyl or phenyl, biphenyl or naphthyl mono- or disubstituted with halogen atom, -OA or (C1-C6)-alkyl; A means linear or branched (C1-C6)-alkyl; M means hydrogen atom (H) or a cation chosen from group comprising alkaline metals, earth-alkaline metals, ammonium or alkylammonium with compound of the formula (II): , wherein R2 means H, A, or with acid-additive salt of compound of the formula (II) of acids HCl, HBr, HJ, H2SO4, H3PO4, or with organic carboxylic acid to obtain compound of the formula (III): , wherein R and R2 have above given values; (b) synthesized compound is converted to compound of the formula (IV): , by reduction reaction that is converted optionally to acid-additive salt of acids HCl, HBr, HJ, H2SO4, H3PO4, or to salt of organic carboxylic acid, and (c) synthesized compound of the formula (IV) is subjected for interaction with activated carboxylic acid of the formula (V): , wherein R4 means F, Cl, Br, J, -OA or -O-CO-A to yield compound of the formula (VI): , that is converted to a corresponding acid-additive salt using inorganic acid chosen from group comprising HCl, HBr, HJ, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, ortho-phosphoric acid or using organic acid.

EFFECT: improved method of synthesis.

7 cl, 8 ex

 

The present invention relates to a new method of obtaining the N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidine-1-yl)ethyl]-2,2-diphenylacetamide or N-methyl-N-[(1R)-1-phenyl-2-((3R)-3-hydroxypyrrolidine-1-yl)ethyl]-2,2-diphenylacetamide, as well as new compounds, N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidine-1-yl) ethane] and N-methyl-N-[(1R)-1-phenyl-2-((3R)-3-hydroxypyrrolidine-1-yl)ethane], formed as intermediate products in the implementation of this method.

As described by Barber and others (B.J.Pharmacol. 113 (1994), str-1327), as the compound N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidine-1-yl)ethyl]-2,2-diphenylacetamide, and its physiologically acceptable salts have valuable pharmacological properties, such as analgesic, anti-inflammatory and water efficiency, thanks to which they are particularly suitable for the manufacture of the drugs.

In the same way as described in the application DE 19523502, respectively EP 752246, it was found that this compound is a particularly effective compound, which can only be successfully used as a drug for the treatment of inflammatory bowel disease. First of all thanks to this indication connection manifests in its application high efficiency, because at the same time it is capable of minisat pain, associated with such diseases, and if due to acute inflammation, respectively triggered by the inflammation of the danger of blockage of the lumen of the intestine it normalizes bowel motility or contributes to resume his normal activities without causing noticeable side effects. In addition, the connection can also be used with non-inflammatory bowel diseases, such as IBS (irritable bowel syndrome).

In the applications DE 4034785 A1 and DE 4215213 A1, EP respectively 0569802 A1 describes the obtaining of N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidine-1-yl)ethyl]-2,2-diphenylacetamide interaction (2S)-2-N-carboxyethyl-2-phenylglycine-N,N-[(3S)-3-hydroxyacetylamino] diphenylacetylene. As described in DE 4215213, the original connection (2S)-2-N-carboxyethyl-2-phenylglycine-N,N-[(3S)-3-hydroxytyramine, its other name (1S)-[1-N-methylamino-1-phenyl-2-((3S)-3-hydroxypyrrolidine)ethane], can be obtained by the interaction of (1S)-1-amino-1-phenyl-2-chlorethane with (3S)-3-hydroxypyrrolidine and subsequent methylation of methyliodide. However, this method of obtaining certain inherent problem lies in the poor solubility of the starting materials, and that upon completion of the synthesis for the separation obtained containing impurities are by-products of racemic mixtures require significant is s costs. For this reason, the currently known way to obtain N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidine-1-yl)ethyl]-2,2-diphenylacetamide uneconomical and does not provide to the same high enough yield depending on the source of the connection.

Based on the foregoing, the present invention was based on the task of developing a simple and economical method to produce N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidine-1-yl)ethyl]-2,2-diphenylacetamide, respectively, when using the enantiomeric doctow N-methyl-N-[(1R)-1-phenyl-2-((3R)-3-hydroxypyrrolidine-1-yl)ethyl]-2,2-diphenylacetamide, based on budget, well soluble source products that would provide the opportunity to obtain the product as the most pure enantiomer and then, also hassle-free allocation and cleanup.

This task is solved by the method according to paragraph 1 of the claims, in which to obtain N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidine-1-yl)ethyl]-2,2-diphenylacetamide as a new intermediate product use unknown at present compound is N - methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidine-1-yl)ethane], and for N N-methyl-N-[(1R)-1-phenyl-2-((3R)-3-hydroxypyrrolidine-1-yl)ethyl]-2,2-diphenylacetamide well as new intermediate products the KTA use N-methyl-N-[(1R)-1-phenyl-2-((3R)-3-hydroxypyrrolidine-1-yl)ethane].

It was found that the compounds of formula III

in which R and R2have the following meanings:

R denotes H, OR1or SR1,

R1means And aryl, heteroaryl, Si(R3)3or COR3,

R2denotes H, A, aryl, heteroaryl, and Si(R3)3or COR3,

R3denotes H, A, aryl or heteroaryl,

And indicates remotemachine or branched alkyl residue with 1-6 C-atoms

can be obtained with high yield and in the form of a pure enantiomer, if, depending on the desired final product, (3S)-3-hydroxypyrrolidine or (3R)-3-hydroxypyrrolidine formula II

in which R2denotes H, A, aryl, heteroaryl, and Si(R3)3or COR3, R3denotes H, A, aryl or heteroaryl or their salts formed with HCl, HBr, HI, H2SO4N3PO4or sootvetstvuyushie organic acids, and are subjected to interaction by the reaction of the amide combination with the corresponding (S)- or (R)-enantiomeric forms of N-substituted phenylglycine formula I

in which R denotes H, OR1or SR1,

R1means And aryl, heteroaryl, Si(R3)3or COR3,

R3denotes H, A, aryl or Goethe is auril,

M denotes H or a cation from the group comprising alkali metals, alkaline earth metals, ammonium and alkylammonium.

The alkyl contains 1 to 6, preferably 1, 2, 3 or 4 C-atoms, and is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, and pentyl, 1-, 2 - or 3-methylbutyl, 1,1-, 1,2 - or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3 - or 4-were, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1 - or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2 - or 1,2,2-trimethylpropyl.

Aryl preferably represents unsubstituted phenyl, or mono - or doubly substituted with halogen, OA or alkyl phenyl, and, for example, biphenyl or naphthyl.

Heteroaryl preferably represents, for example, furanyl, thiophenyl, pyridinyl, pyrrolyl or thiazolyl.

Si(R3)3means is preferably, for example, Si(CH3)3.

COR3means is preferably, for example, acetyl or benzoyl.

R preferably denotes, primarily, for example, methoxy or ethoxy.

R1indicates first of all, for example, methyl, ethyl, propyl, butyl, phenyl, Si(CH3)3or acetyl.

R2indicates first of all, for example, N, tert-butyl, Si(CH3)3, acetyl, benzyl or benzoyl, but most preferably N.

the received amides of formula III by a simple method by restoring, optional when the removal of the protective group of hydroxyl group pyrrolidine can be converted to N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidine-1-yl)ethane] or N-methyl-N-[(1R)-1-phenyl-2-((3R)-3-hydroxypyrrolidine-1-yl)ethane] formula IV.

Interaction with activated carboxylic acids of formula V

in which R4denotes F, Cl, Br, I, OA or O-CO-A,

of the free bases of the compounds of formula IV

any of their salts formed with HCl, HBr, HI, H2SO4N3PO4or with the appropriate organic acids may be obtained enantiomeric compounds of formula VI

in its pure form. It is preferable to obtain these compounds in the form of hydrochloride, under the compound N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidine-1-yl)ethyl]-2,2-diphenylacetamide have in mind the well-known form of EMD 61753; in a similar way can be obtained and the corresponding salts, as with other acids from the number above.

First of all similarly specified as the last interaction with the acid chloride diphenyloxazole acid can be obtained N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidine-1-yl)ethyl]-2,2-diphenylacetamide.

Synthesized as an intermediate product of the compounds of formula IV can be obtained by the interaction of the compounds of formula I with compounds of the formula II. Preferably used in this reaction such compounds of the formula I in which the R value is OR1where R1means And aryl, heteroaryl, Si(R3)3or COR2and R2denotes H, alkyl, aryl or heteroaryl, with the above preferred values. Unexpected was the possibility to obtain, in contrast to applications of the corresponding formyl compound of formula III in the form of pure enantiomers. This does away with the need for separation of the racemate, which should be attributed to the undoubted advantages of the invention.

The interaction of compounds of formulas I and II can be implemented in any aprotic solvent. Especially suitable for these purposes, polar aprotic solvents selected from the group comprising diethyl ether, petroleum ether, acetone, nitrobenzene, dimethylformamide, dimethyl sulfoxide or other appropriate solvents. Thus educti dissolved in such a solvent, to obtain the result 10-30%solution. It is preferable to choose for the reaction in the solvent tetrahydrofuran.

The reaction between the compounds of formulas I and II is carried out in appropriate conditions at temperatures in the range from 0 to 50°C. Especially good results are achieved, however, when anatoy temperature in the range from 20 to 30° With and under normal pressure.

To activate doctow requires auxiliary reagent, a function which can perform such auxiliary substances, which are also used in the reactions of peptide combinations. Suitable for this purpose such compounds as, for example, oxytrichloride phosphorus, the phosphorus halides with valence III and V, phosgene, dicyclohexylcarbodiimide, tributylammonium salt of pyridine, phenyldichlorophosphine, 2-chloro-1,2,3-trinitrobenzene, esters of phosphoric acid, chlorosulfonylisocyanate, CH3SO2Cl-(C2H5)3N, (C6H5)3R-CCl4-(C2H5)3N, N,N'-carbonyldiimidazole, N-(alkylsulphonyl)imidazoles, acid anhydrides or acid chlorides of the acids and primarily alkylaromatic, such as ethyl ether of Harborview acid. Other relevant ancillary reagents described in various handbooks, such as .Ferri "Reaktionen der organischen Synthese"; R.C.Larock "Comprehensive Organic Transformations, A Guide to Functional Group Preparations", published by Verlag Chemie, 1989.

In addition to the presence of an auxiliary reagent from among the above, it is necessary the presence of a base. When selecting the appropriate base can also be guided by these publications. As an example we may refer to such reasons as tertiary amines, in particular triethylamine. At the same time, m is tenderly add and inorganic bases. As inorganic bases are suitable primarily carbonates. When using hydroxides of alkali metals, such as NaOH or KOH, to be especially careful to follow the exact dosage, because otherwise there may be undesirable side effects. To simplify processing, you can also use hydroxypyrrolidine in abundance, thanks to which he himself performs the function of reason.

Processing of the obtained reaction product of formula III can be performed after filtering off precipitated sludge using conventional laboratory methods, working with the filtrate. For example, traditionally used method is that the solvent is distilled off, the crude product is re-dissolved in an organic solvent, the resulting solution was extracted several times with water, the solvent is again distilled off and the obtained product is recrystallized from an appropriate solvent, such as methanol. In principle, there are other options known to a person skilled in the technical field, in particular such which require chromatographic purification.

Depending on the conditions in which carry out the reaction, the product of formula III obtained as free base or as an acid additive salts of the acids HCl, HBr, HI, H2SO4or any of the content of inorganic fillers carboxylic acids from water-containing solvent mixtures. In the latter cases, the selection of the product can be carried out after separation of the phases using conventional laboratory methods.

As acceptable organic carboxylic acids can be used primarily aliphatic, alicyclic, analiticheskie, aromatic or heterocyclic one - or polybasic carboxylic, sulfonic or sulfuric acids, such as formic acid, acetic acid, propionic acid, pavlikova acid, diethyloxalate acid, malonic acid, succinic acid, Emelyanova acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinamide acid, methane - or econsultation, ethicalfashion, 2-hydroxyethanesulfonic, benzosulfimide p-toluensulfonate, naphthalenamine and dissolvability and louisanna acid.

The recovery of the compounds of the formula III is carried out in a protective gas atmosphere, for example under nitrogen atmosphere, in the presence of hydride transfer reagent. Suitable for this purpose by hydride transfer reagents are those of the group including alumoweld metals, preferably of alumoweld lithium, alkoxylated metals, as, for example, triaxiality lithium, orovided metals, preferably NaBH4or boron, and in addition they require the presence of a Lewis acid such as boron TRIFLUORIDE. The restoration carried out preferably in a polar aprotic inert with respect to the hydride solvent. Suitable for this purpose, the same solvents as mentioned above. Especially it is advisable to use additional area diethyl ether or tetrahydrofuran.

To effect the hydrogenation of the compound of formula III is dissolved in an appropriate solvent and added dropwise while heating the solution containing the reagent hydride transfer in equimolar amounts, respectively, in a small excess. Alternatively, according to which first loaded into the reactor gidriruemyi original connection, and then accordingly add hydrogenating reagent in accordance with the number getting in the reaction mixture in which the concentration of the educt is from 10 to 25 wt.% in terms of the solvent. To complete the reaction the mixture is stirred for several hours using a reflux apparatus. Then the reaction solution by methods known to the person skilled in the technical field, is subjected to further processing in which, in particular, by adding a solvent mixture consisting of a solvent, giving the protons, the aprotic solvent, decompose the excess hydride transfer reagent and produce the reaction product. As the giver protons solvents are suitable, for example, water or alcohols, such as ethanol or methanol. As aprotic solvents acceptable all polar aprotic solvents mentioned above, and especially tetrahydrofuran. The last is most preferred for use because technologically it can be obtained in the form of anhydrous product.

Processing product may be carried out after separation of the phases using conventional laboratory methods. Thus, in particular, the resulting crude product can be processed according to the methods of crystallization, or it can be dissolved, for example, in organic, not miscible with water, the solvent and to admix in excess of any inorganic acid, preferably hydrochloric acid. Thus formed salt may then be separated by crystallization.

The subsequent interaction of N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidine-1-yl)ethane] or its dihydrochloride with the corresponding derived diphenyloxazole acid, preferably the acid chloride acid, to obtain the desired final product, which is N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidine-1-yl)ethyl]-2,2-diphenylacetamide (formula VI, EMD 61753), carry out using methods opisannyh application DE-A1 4034785 and DE-A1 4215213, accordingly EP 0569802 A1.

Below the present invention is illustrated in more detail by examples of its implementation, which in no way limit its scope, because there are other options, also leading to the desired intermediate product is N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidine-1-yl)ethane] [formula IV], used as such to obtain N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidine-1-yl)ethyl]-2,2-diphenylacetamide.

Examples

N-substituted (2S)-2-phenylglycine-N,N-[(3S)-3-hydroxyethylamide] formula III from (2S)-2-phenylglycinol formula I

Example 1

(2S)-N-Formyl-2-phenylglycine-N,N-[(3S)-3-hydroxytyramine]

This compound is obtained from (2S)-N-formyl-2-phenylglycine (derived from (S)-(+)-α-aminophenylarsonic acid and acetanhydride/formic acid, for example, according to Peter Huszthy, Masatoshi Oue, Jerald S.Bradshaw, Cheng Y.Zhu, Tingmin Wang and others, J.Org. Chem., EN, 57 (20) [1992], str-5394) and (3S)-3-hydroxypyrrolidine (obtained from commercially available (S)-1-benzyl-3-pyrrolidinone, for example, according to Kristina L.Bhat, Denise M.Flanagan, Madeleine M.Joullie, Synth. Commun., EN, 15 (7) [1985], str-598, or Alan Naylor, Duncan .Judd, David I.C.Scopes, Ann G.Hayes, Philip J.Birch, J.Med. Chem., EN 37 (14) [1994], str-2144) in the following way.

In nitrogen atmosphere to 9 g of (2S)-N-formyl-2-phenylglycine and 5.5 ml of N-methylmorpholine in 250 ml of THF at -15°With add when mixing 4.8 ml of ethylchloride is in 10 ml of tetrahydrofuran and after 10 min exposure add a solution of 6.2 g of the hydrochloride of (3S)-3-hydroxypyrrolidine and 7 ml of triethylamine in 50 ml of dimethylformamide. After stirring for 18 h the precipitated precipitate was separated from the filtrate using a conventional laboratory methods by concentration and subsequent chromatographic purification allocate the resulting (2S)-N-formyl-2-phenylglycine-N,N-[(3S)-3-hydroxytyramine.

1H-NMR (D6-DMSO): 3,0-3,8 (m), 4,25 (d)5,0 (s, W), 5,7 (dd), 7,4 (ArH), 8.0 A (ArH), 8,8 (SNO).

MC-FAB: (M+1)+221, 205.

Crystals with tPL97-101°C.

[α]D20=+208, C=1 in methanol.

Example 2

(2S)-N-Carboxymethyl-2-phenylglycine-N,N-[(3S)-3-hydroxytyramine]

This compound is obtained from (2S)-N-carboxymethyl-2-phenylglycine (derived from (S)-(+)-α-aminophenylarsonic acid benzyl ester harpalinae acid according to, for example, Raymond C.F.Jones, lan Turner, Kevin J.Howard, Tetrahedron Lett., 34 (39) [1993], str-6332) and (3S)-3-hydroxypyrrolidine (obtained from commercially available (S)-1-benzyl-3-pyrrolidinone, for example, according to Kristina L.Bhat, Denise M.Flanagan, Madeleine M.Joullie, Synth. Commun., EN, 15 (7) [1985], str-598, or Alan Naylor, Duncan C. Judd, David I.C. Scopes, Ann G.Hayes, Philip J.Birch, J.Med. Chem., EN 37 (14) [1994], str-2144) in the following way.

In nitrogen atmosphere to 14.3 g (2S)-N-carboxymethyl-2-phenylglycine in 100 ml of tetrahydrofuran stirred into cold 5.5 ml 4-methylmorpholine and a solution of 4.8 ml of ethylchloride and 10 ml of tetrahydrofuran, and then stirred for 30 minutes Then add a solution of 4,36 g of (3S)-3-guide is oxopyrrolidin and 10 ml of tetrahydrofuran. After stirring for 18 h, the precipitation is separated and the resulting (2S)-N-carboxymethyl-2-phenylglycine-N,N-[(3S)-3-hydroxytyramine separated from the filtrate using a conventional laboratory methods by concentration, dissolution in an organic solvent, washing the aqueous phase, re-concentration and crystallization.

1H-NMR (D6-DMSO+TFUC): 5,1 (s), PhCH2R.

FAB-MS: 355 (M+1)+, 311, 196, 176.

Texture: butter.

[α]D20=+108, C=1 in methanol.

Example 3

(2S)-N-Carboxyethyl-2-phenylglycine-N,N-[(3S)-3-hydroxytyramine]

3A)

In this embodiment, the specified connection is obtained from (2S)-N-carboxyethyl-2-phenylglycine (derived from (S)-(+)-α-aminophenylarsonic acid and ethyl ester harpalinae acid according to, for example, ..Bodurow, B.D.Boyer, J.Brennan, C.A.Bunnell, J.E.Burks and others, Tetrahedron Lett., EN, 30 (18) [1989], str-2324) and (3S)-3-hydroxypyrrolidine (obtained from commercially available (S)-1-benzyl-3-pyrrolidinone, for example, according to Kristina L.Bhat, Denise M.Flanagan, Madeleine M.Joullie, Synth. Commun., EN, 15 (7) [1985], str-598 or Alan Naylor, Duncan .Judd, David I.C.Scopes, Ann G.Hayes, Philip J.Birch, J.Med. Chem., EN 37 (14) [1994], str-2144) in the following way.

In nitrogen atmosphere to 16.7 g (2S)-N-carboxyethyl-2-phenylglycine in 100 ml of tetrahydrofuran stirred into cold of 8.3 ml of 4-methylmorpholine and solution of 7.1 ml of ethylchloride and 20 ml tetrahydrofur the Ana, then stirred for 60 minutes Then add a solution of 6.5 g of (3S)-3-hydroxypyrrolidine and 30 ml of tetrahydrofuran. After stirring for 18 h, the precipitation is separated and the resulting (2S)-N-carboxyethyl-2-phenylglycine-N,N-[(3S)-3-hydroxytyramine separated from the filtrate using a conventional laboratory methods by concentration, dissolution in an organic solvent, washing the aqueous phase, re-concentration and crystallization.

3b) In this embodiment, the specified connection is obtained from (2S)-N-carboxyethyl-2-phenylglycine (receipt see above) and hydrochloride (3S)-3-hydroxypyrrolidine (commercially available) in the following way.

To 11 g of ethylchloride in 100 ml THF at a temperature of approximately -10°add a mixture of 24 g of (2S)-N-carboxyethyl-2-phenylglycine and 10 g of methylmorpholine in 100 ml of THF. Next, after stirring, add a mixture of 12 g of the hydrochloride of (3S)-3-hydroxypyrrolidine in 10 ml of completely demineralized water and the other a mixture of 10 g of methylmorpholine in 20 ml of THF. After further stirring for several hours, and phase separation using conventional laboratory methods by concentration, dissolution in an organic solvent, washing the aqueous phase, re-concentration and crystallization produce (2S)-N-carboxyethyl-2-phenylglycine-N,N-[(3S)-3-gidroksimetil filename.

Below analysis data obtained in the variants 3A) and 3b)are the same.

1H-NMR (D6-DMSO): 1,2 (t), 3-3,8 (m, W), of 4.05 (q), 4,25 (s, W), 7,25 was 7.45 (m).

MS: 293 (M+1)+, 247, 178, 106.

Crystals with tPL124-126°C.

[α]D20=+137, C=1 in methanol.

N-Methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidine-1-yl)atany] formula IV

Example 4

N-Methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidine-1-yl)ethane]=1-[(3S)-3-hydroxypyrrolidine-1-yl]-(2S)-2-methylamino-2-Penilaian

In nitrogen atmosphere slightly heated 2200 ml 1,08-molar solution of lithium aluminum hydride in tetrahydrofuran, and with stirring, a solution of 264 g of (2S)-N-carboxyethyl-2-phenylglycine-N,N-[(3S)-3-hydroxyacetylamino] and 1400 ml of tetrahydrofuran. Upon completion of the process of adding heated for 3 hours under reflux and cooled hydrolyzing solution using a mixture of water and tetrahydrofuran.

After treatment with sodium carbonate and removal of inorganic components of the product by conventional laboratory methods are separated from the filtrate. From a crude oily product after purification by crystallization or by chromatography, a solid substance.

1H-NMR (D6-DMSO): 2,1-3,1 (m), 3,6 (dd), 4,3 (m), 7,15-7,35 (m).

MC: 220 (M)+, 205, 120, 100, 91.

Appearance: yellowish oil, which depending on the received portions of the cu is stillsuits.

[α]D20=+66,8; C=0,0938 g in 10 ml of methanol.

Example 5

The dihydrochloride of N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidine-1-yl)ethane] or the dihydrochloride of 1-[(3S)-3-hydroxypyrrolidine-1-yl]-(2S)-2-methylamino-2-phenylethane

In nitrogen atmosphere slightly heated 2200 ml 1,08-molar solution of lithium aluminum hydride in tetrahydrofuran, and with stirring, a solution of 264 g of (2S)-N-carboxyethyl-2-phenylglycine-N,N-[(3S)-3-hydroxyacetylamino] and 1400 ml of tetrahydrofuran. Upon completion of the process of adding heated for 3 h under reflux, then cooled and hydrolyzing the reaction solution using a mixture of 80 ml of water and 400 ml of tetrahydrofuran. After treatment with sodium carbonate and removal of inorganic components of the product by conventional laboratory methods are separated from the filtrate. The crude oily product is dissolved in an organic, not miscible with water, solvent and mixed with a certain excess of hydrochloric acid. The resulting crystalline product is isolated and dried.

1H-NMR (D6-DMSO): 3,4 (m)to 3.8 (m)4,2 (m), 4,4 (m), 4,9 (m)of 7.5 and 7.8 (ArH).

The melting point of 240-242°C.

[α]D20=-22,4, C=1 in water.

Additional examples

Description of the experiment

Alumoweld lithium (270 g) in 180 g of tetrahydrofuran is heated in a nitrogen atmosphere. To the reaction mixture at paramesh the processes debiteur a solution of 60 g of (2S)-N-carboxyethyl-2-phenylglycine-N,N-[(3S)-hydroxyacetylamino] 600 g of tetrahydrofuran and the mixture is refluxed with stirring for 3 hours The mixture is then cooled and cooling hydrolyzing a mixture of 160 ml of water and 30 g of tetrahydrofuran. The organic phase is separated, the aqueous phase is washed with THF, the combined organic extracts evaporated to remove solvent. After the usual processing gain of 39 g (yield 87%) of N-methyl-N-[(1S)-1-FINEP-2-((3S)-hydroxypyrrolidine-1-yl)ethanamine].

N-Matip-N-[(1S)-1-phenyl-2-((3S)-hydroxypyrrolidine-1-yl)ethanamine] (22 g) was dissolved in 180 ml of THF under nitrogen atmosphere and cooled to -5°C. and Then at a temperature of from -5 to 0°C for 120 min added dropwise a solution of 27 g of the acid chloride definepackage acid in 35 ml tetrahydrofuran. The resulting suspension is stirred for a further 90 minutes and finally filtered at 0°With vacuum. After processing receive 43 g (yield 95%) of the hydrochloride of N-methyl-N-[(1S)-1-phenyl-2-((3S)-hydroxypyrrolidine-1-yl)ethyl]-2,2-diphenylacetamide in the form of a colorless solid.

Recovery vicedom

14,73 g of (2S)-N-carboxyethyl-2-phenylglycine-N,N-[(3S)-hydroxyacetylamino] dissolved in 250 ml of tetrahydrofuran in a nitrogen atmosphere. Then, with stirring, to the mixture is added dropwise a solution of 79.5 g Vitrea in toluene (70% solution). After adding the reducing agent reational the mixture is heated under stirring for 3 hours Then the reaction mixture is cooled and cooling hydrolyzing a solution of 10 g of the carbonate is of the atrium in 40 ml of water. The formed precipitate was separated by filtration and the filtrate is separated organic phase. The residue (aqueous phase) is extracted with 100 ml THF. The combined organic phases are dried to remove solvent. After the usual processing gain of 9.9 g (yield 89%) of N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxyprop-lidin-1-yl)ethanamine. tpl.246-248° (dihydrochloride) (gas formation/decomposition).

Description additional experiment

S-Ethyl ester of [2-((3S)-3-hydroxypyrrolidine-1-yl)-2-oxo-(1S)-1-phenylethyl]methylthiocarbamate acid (compound IIIα, tpl.144° (C) received in the interaction of ethylsulfanyl-(2S)-aminophenylarsonic acid (compound Iα, tpl.123-125° (C) hydrochloride (3S)-3-hydroxypyrrolidine same way as described in examples 2 and 3 of the present invention.

0.9 g of sociallyengaged in nitrogen atmosphere suspended in 20 ml of dry tetrahydrofuran and within 10 min is added dropwise to a stirred solution of 2.6 g of compound (IIIα) in 20 ml of tetrahydrofuran. After addition of the reagent, the reaction mixture is refluxed under stirring for 3 h, then cooled to room temperature and slowly add a mixture of 1 ml of water and 5 ml of tetrahydrofuran. The formed precipitate was separated by filtration, the filter residue washed with 50 ml of THF and discarded. About yedinenye organic solutions are evaporated in vacuum, the remainder in the form of oil crystallizes during storage, thus obtain 2.17 g (84%) of 1-[(3S)-3-hydroxypyrrolidine-1-yl]-2-(2S)-methylamino-2-phenylethane (compound IVα).

For optional receipt dihydrochloride crystalline substance is transferred into 40 ml of acetate, filtered, the filtrate is cooled to 10°and mixed with a solution of hydrochloric acid in ethanol. Mix mix for 30 min at 10°that fell to precipitate the hydrochloride is separated by filtration and dried in vacuum, thus receive the dihydrochloride of compound IVα. tpl.247-248°With (gas formation/decomposition).

Physical data (NMR) of compounds (Iα), (IIα), (IIIαand (IVα)

Application

Clinical trials are given to demonstrate the effect obtained according to claim 7 connections ("asimadoline") as a new agonist of peripheral Kappa-opioid receptors on pain induced by rectal distension in patients with irritable bowel syndrome (IBS).

Asimadoline is a novel agonist of peripheral Kappa-opioid receptors, which participate in signal transduction in visceral afferents.

The aim of the study was to assess the impact asimadoline on the nature of the perception of the large intestine by measuring the swelling of the left part of the colon to the loud and patients suffering from TFR, using barostat (barometric contact sensor).

Patients and method

The experiment was carried out with the participation of twenty patients suffering from IBS (40+/-a criterion Roma). Barometric bag (10 cm, 700 ml) was injected in the left colon during the colonoscopy under anesthesia (Protocol IV). On the following day (day 1) patients on an empty stomach in 9 h caused a series of swellings, increasing the pressure in the bag (at intervals of 5 mm RT. Art., duration 5 min) until pain (background bloating). Then patients with pain threshold, equal to or less than 32 mm RT. Art., randomized, double-controlled trial: 15 hours, patients were administered a single oral dose asimadoline 0.5 mg or placebo, and 16 h caused a series of swellings on the specified schema. On the second day with patients conducted similar tests, but in reverse order. The response to the swelling characterized by the pressure inside the bag, causing pain at the level of 4 points or more, which was assessed by six-point verbal scale. In addition, compared AUC (srednekamennogo value) responses, fixed in the pressure range from 5 to 40 mm RT. Art. At each stage of swelling were recorded volume of the bag, and to determine the elasticity of the colon build individual curves pressure on JEM.

Results

Response of patients compared with the background swellings were all parameters are identical in the first and second day. Pain threshold pressure (mean SD) was higher with the introduction of 0.5 mg asimadoline (29,8 7.2 mm RT. Art.)than the introduction of placebo (26,3 7.8 mm RT. Art.) (NS). However, the AUC of pain intensity indicated by the patients at each stage of growth pressure, calculated with the LOCF analysis in the pressure range from 5 to 40 mm RT. century, was significantly lower with the introduction of 0.5 mg asimadoline (89,3 33,9 mm RT. Art.)than the introduction of placebo (101,1 29,7 mm RT. Art.) (P=0,0411). In addition, the mean score of pain was significantly lower with the introduction of 0.5 mg asimadoline swelling at the level of 20 mm RT. Art. (P=0,0243) and tended to decrease at 25 and 30 mm Hg (P=0,0576) compared with placebo. Conversely, animadores did not influence the perception of pain when no painless swellings or when assessing the elasticity of the colon, calculated as the slope of a curve pressure-volume.

Conclusions

Asimadoline when a single oral dose of 0.5 mg reduces the feeling of painful swellings of the colon in patients (women)suffering from IBS, with no impact on the elasticity of the colon.

Thus, these data indicate a very promising potential new treatment for IBS.

1. The way recip is of N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidine-1-yl)ethyl]-2,2-diphenylacetamide, characterized in that

a) N-substituted phenylglycine derived formula I

in which

R denotes a OR1or SR1,

R1denotes a benzyl, unsubstituted phenyl, one - or disubstituted by halogen, OA or C1-C6the alkyl phenyl, biphenyl or naphthyl;

And indicates remotemachine or branched alkyl residue with 1-6 C-atoms

M denotes H or a cation from the group comprising alkali metals, alkaline earth metals, ammonium or alkylammonium, is subjected to the interaction with the compound of the formula II

in which R2denotes H, or an acid additive salt of the compounds of formula II acids HCl, HBr, HI, H2SO4N3PO4or organic carboxylic acid to obtain the compounds of formula III

in which R and R2have the above values;

b) then by restoring transformed into a compound of formula IV

which does not necessarily translate into an acid additive salt of the acids HCl, HBr, HI, H2SO4N3PO4or salt of organic carboxylic acid, and

C) thus obtained compound forms the crystals IV is subjected to interaction with an activated carboxylic acid of formula V

in which R4denotes F, Cl, Br, I, OA or O-CO-A, with obtaining the compounds of formula VI

which is not necessarily by using an inorganic acid selected from the group comprising HCl, HBr, HI, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, phosphoric acid, or with organic acids transferred to the corresponding acid additive salt.

2. The method according to claim 1, characterized in that the reaction using compounds of the formula I in which the R value is OR1where R1means And unsubstituted phenyl, one - or disubstituted by halogen, OA or C1-C6the alkyl phenyl, biphenyl or naphthyl.

3. The method according to claim 1, characterized in that the interaction of the compounds of formulas I and II is carried out in aprotic, preferably polar aprotic solvent such as tetrahydrofuran, at a temperature in the range from 0 to 50°C, preferably in the range from 20 to 30°C.

4. The method according to any one of claims 1 and 3, characterized in that the interaction of the compounds of formulas I and II is carried out in the presence of an auxiliary reagent from the group of C1-C6alkylphosphonate, such as ethylchloride, as well as organic or inorganic bases.

5. The method according to any of the or more of claims 1, 2-4, characterized in that the interaction of the compounds of formulas I and II is carried out in the presence of organic base such as triethylamine or 4-methylmorpholine.

6. The method according to any one of claims 1, 3-6, characterized in that the recovery of the compounds of the formula III is carried out in the presence of hydride transfer reagent selected from the group comprising alumoweld metals, preferably of alumoweld lithium, alkoxylated metals, preferably triaxiality lithium, borohydride metals, preferably NaBH4and boron, and preferably in the presence of a Lewis acid such as boron TRIFLUORIDE, in a polar aprotic solvent selected from the group comprising diethyl ether, petroleum ether, acetone, nitrobenzene, dimethylformamide and tetrahydrofuran.

7. The method of obtaining N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidine-1-yl)ethyl]-2,2-diphenylacetamide as a drug for the treatment of non-inflammatory bowel disease nature, characterized in that the carry out stage a), b) and C)defined in claim 1.



 

Same patents:

FIELD: organic chemistry, chemical technology, biochemistry, medicine.

SUBSTANCE: invention relates to novel isoquinoline compounds of the general formula (I): wherein R1 represents hydrogen atom, halogen atom or alkyl; Y is absent or represents alkylene chain comprising from 1 to 8 carbon atoms wherein arbitrary carbon atom can comprise hydroxyl group as a substitute; R represents the following formula (II): wherein X represents -CH or nitrogen atom under condition that if Y absent in the formula (I) then X must represent -CH; W represents -CH or nitrogen atom under condition that if X represents -CH then W must represents nitrogen atom; s represents a whole number from 1 to 3; t represents a whole number from 1 to 3; if R3 represents hydrogen atom or alkyl then R2 represents hydrogen atom, alkyl, hydroxyl group or hydroxyalkyl, and R2' represents hydroxyl group or hydroxyalkyl, and if R3 represents hydroxyalkyl then R2 and R2' represent hydrogen atom. Also, invention relates to their optically active forms, pharmaceutically acceptable salts, aqueous adducts, hydrates and solvates. Compounds of the formula (I) elicit inhibitory effect on activity of poly-(ADP-ribose)-polymerase and can be used in prophylaxis of diseases associated with cerebral infarction.

EFFECT: valuable medicinal properties of compounds, improved method of synthesis.

40 cl, 4 tbl, 55 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds including all its enantiomeric and diastereomeric forms, and to their pharmaceutically acceptable salts wherein indicated compound corresponds to the formula: wherein A represents a conformationally limited ring system chosen from the group comprising the following formulae: (a) (d) and (e) wherein carbon atoms labeled by asterisks can be in any stereochemical configuration or their mixtures wherein Y has a formula: -(CH2)b-R15 wherein index b = 1-4, and R15 represents -OH, -NH2, guanidine-group, and Z has a formula: wherein R represents hydrogen atom; R9 represents naphthylmethyl; R10 represents -C(X)N(R16)2 wherein each R16 represents independently hydrogen atom or (C1-C10)-alkyl; X represents oxygen atom; or Z represents naphthylmethyl wherein W has a formula: wherein R represents phenyl substituted optionally with halogen atom of OH-group wherein fragment L is chosen from the group comprising: -NH- or -NHC(O)-; B represents hydrogen atom of fragment of the formula: wherein fragments R2, R3 and R4 are chosen independently among the group comprising hydrogen atom, -NHC(O)CH3, benzyl substituted optionally with hydroxy-group or halogen atom, imidazolylmethyl; or fragments R2, R3 and R represent in common naphthalinyl or isoquinolinyl; or one radical among R2, R3 and R4 represents hydrogen atom and two radical among R, R3 or R4 chosen in common form piperidine ring or tetrahydroisoquinoline ring substituted optionally with the group -C(O)CH3. Also, invention relates to a pharmaceutical composition possessing the agonistic activity with respect to MC-3/MC-4 receptors based on these compounds. Invention provides preparing new compounds and pharmaceutical compositions based on thereof for aims in treatment of disorders mediated by function of MC-3/MC-4 receptors.

EFFECT: valuable medicinal properties of compounds and compositions.

17 cl, 14 tbl, 12 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to compounds that inhibit binding ligands with α4β1-integrin (VLA-4) selectively. Compounds have the formula (I):

wherein W means unsubstituted phenyl or phenyl substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom, (C1-C4)-alkoxy-group and halogen alkyl; W1 means unsubstituted phenylene or phenylene substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom and (C1-C4)-alkoxy-group, pyridylene, pyridylene substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom and (C1-C4)-alkoxy-group, 2-oxopyrrolylene or thiazolylene; A means oxygen atom (O); R means -(CH2)n- wherein n = 1 or 2; X means -C(O)-; M is taken among the following groups: a)

wherein means divalent 5- or 6-membered heterocyclic radical wherein nitrogen atom is located in the joining point to X wherein Q represents -CH2-, -O- or -S-; R1, R2 and R3 are taken independently among the group involving: hydrogen atom (-H), hydroxyl group (-OH), quinolinyloxy-group, -NH2, mono- or dialkylamino-group, (C1-C6)-alkylsulfonylamino-, arylsulfonylamino-, naphthyloxy-, phenyloxy-group substituted optionally with di-(C1-C6)-alkylamine, (C1-C6)-alkyl, benzyloxymethyl, halogen atom, phenyl, (C1-C4)-alkoxy-group; or two adjacent R1, R2 and R3 taken in common can form alkylene- or alkylenenedioxy-group substituted optionally with 1-3 alkyl groups; R4 means hydrogen atom (H), lower alkyl; Y is taken among a bond, (C2-C8)-alkenylene group, (C2-C8)-alkynylene group, -C(O)-, -C(O)NH- and -(CH2)kY2 wherein k is taken among 1, 2 and 3; Y2 means a direct bond or divalent radical taken among -O-, -S-, -S(O)-, -S(O)2- and -NY3- wherein Y3 is taken among hydrogen atom (H), lower alkyl; Z means (C3-C8)-cycloalkylene, optionally substituted phenylene, pyridylene, piperidylene, piperazinylene; A1 means a direct bond, -(CH2)t-alkynyl wherein t is taken among 1, 2 and 3; R5 means -OH, lower alkoxy-group, , ; b) means wherein R11 is taken among , -NR12- wherein R12 is taken among hydrogen atom (-H), optionally substituted lower alkyl, lower alkenyl, lower alkynyl, phenyl; Z3 is taken among a direct bond, (C1-C12)-alkyl wherein one or some carbon atoms can be replaced with -O- or -NR13- wherein R13 means hydrogen atom (-H), lower alkyl, wherein x = 0 or 1; y = 1, 2 or 3; R14 means hydrogen atom (-H), ; and when R11 means NR12 then Z3 is taken among: wherein 14Ra means hydrogen (H), halogen atom; , and ; Q2 means wherein R17 and R18 mean hydrogen atom (H), lower alkyl; or phenylene that can be substituted; L1 means -COOH or -COOR19 wherein R19 means lower alkyl. Compounds of the formula (I) inhibit activity of VLA-4-mediated adhesion of cells that allows their using in pharmaceutical compositions.

EFFECT: valuable medicinal properties of compounds and compositions.

21 cl, 11 tbl, 283 ex

New compounds // 2261245

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (I): wherein m = 0, 1, 2 or 3; each R1 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C6)-halogenalkoxy-group, -NR9R10, (C3-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group or (C1-C6)-alkyl; X represents -O- or CH2-, OCH2-, CH2O-, CH2NH-, NH-; Y represents nitrogen atom (N) or group CH under condition that when X represents -O- or CH2O-, CH2NH- or NH-group then Y represents group CH; Z1 represents a bond or group (CH2)q wherein q = 1 or 2; Z2 represents a bond or group CH2 under condition that both Z1 and Z2 can't represent a bond simultaneously; Q represents -O- or sulfur atom (S) or group CH2 or NH; R2 represents group of the formula: n = 0; each R4, R5, R6 and R7 represents independently hydrogen atom (H), (C1-C6)-alkyl either R4, R5, R6 and R7 represent in common (C1-C4)-alkylene chain joining two carbon atoms to which they are bound to form 4-7-membered saturated carbon ring, either each R5, R6 and R7 represents hydrogen atom, and R4 and R8 in common with carbon atoms to which they are bound form 5-6-membered saturated carbon ring; R8 represents hydrogen atom (H), (C1-C6)-alkyl or it is bound with R4 as determined above; each R9 and R10 represents independently hydrogen atom (H), (C1-C6)-alkyl; R15 represents (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, (C5-C6)-cycloalkenyl, adamantyl, phenyl or saturated or unsaturated 5-10-membered heterocyclic ring system comprising at least one heteroatom taken among nitrogen, oxygen and sulfur atoms wherein each group can be substituted with one or more substitute taken independently among nitro-group, hydroxyl, oxo-group, halogen atom, carboxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, phenyl and -NHC(O)-R17 under condition that R15 doesn't represent unsubstituted 1-pyrrolidinyl, unsubstituted 1-piperidinyl or unsubstituted 1-hexamethyleneiminyl group; t = 0, 1, 2 or 3; each R16 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C)-halogenalkoxy-group, -NR18R19, (C1-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group, (C1-C6)-alkyl; R17 means (C1-C6)-alkykl, amino-group, phenyl; each R18 and R19 means independently hydrogen atom (H), (C1-C6)-alkyl, or its pharmaceutically acceptable salt or solvate. Compounds of the formula (I) elicit activity of a modulating agent with respect to activity of chemokine MIP-1α receptors that allows their using in pharmaceutical composition in treatment of inflammatory diseases.

EFFECT: valuable medicinal properties of new compounds.

14 cl, 98 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new inhibitors of farnesyltransferase of the formula (I):

wherein R1 means hydrogen atom (H), group of the formula R5C(O)- wherein R5 means phenyl, pyridyl or N-methylpiperidine; R2 means hydrogen atom (H), isopropyl, cyclopentyl or N-methyltetrahydropyridyl; R3 means hydrogen atom (H), halogen atom; R4 means hydrogen atom (H), halogen atom; L means -CH2-Z- wherein Z means NH; Y means sulfur atom (S), S(O) or S(O)2; or its salt. Compounds of the formula (I) inhibit activity of enzyme, farnesyl(protein)transferase, that allows their using in pharmaceutical composition in cancer treatment.

EFFECT: valuable medicinal properties of inhibitors.

18 cl, 3 tbl, 3 sch, 6 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to substituted derivatives of N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide of the formula (I): wherein n = 1 or 2; R1 represents chlorine, fluorine, bromine atom, methyl or methoxy-group; R2 is taken among of one the following groups: (i) halogen atom, nitro-, hydroxy- amino- or cyano-group; (ii) -X1-R5 wherein X1 represents -O-, -S-, -SO-, -SO2-, NR6-, -CO-, -CONR6-, -NR6CO- wherein R6 represents hydrogen atom and R5 is taken among (C1-C6)-alkyl optionally substituted with one or some A, and so on; (iii) 4-8-membered heterocyclic group joined by nitrogen atom that represents saturated monocyclic ring comprising 4-8 carbon atoms among that at least one is nitrogen atom and so on; R3 represents (C1-C6)-alkyl optionally substituted with one or some A and so on; A is taken among hydroxy-, amino-group, halogen atom, carboxy-, N-(C1-C4-alkyl)-amino-, N,N-di-(C1-C4-alkyl)-amino-group, carbamoyl and (C1-C6)-alkoxy-group; D is taken among: (i) -Xa-Rc wherein Xa represents -SO2, -CO-, -NRdCO-, -NRd- or -CONRd-; (iv) cyano-group or halogen atom; (v) -XcRf wherein Xc represents -C(O)- and Rf represents 4-8-membered heterocyclic group joined by nitrogen atom that represents saturated monocyclic ring comprising 4-8 carbon atoms among that at least one is nitrogen atom with optionally additional heteroatom taken independently among oxygen atom (O), optionally substituted at ring carbon atom by the hydroxy-group, halogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl or cyano-group; G represents (C1-C6)-alkanoyl; R4 represents hydrogen or fluorine atom; or to its pharmaceutically acceptable salt or its ester hydrolyzed in vivo. Also, invention proposes a method for preparing compound of the formula (I). Also, invention proposes pharmaceutical composition enhancing activity of pyruvate dehydrogenase comprising substituted derivatives of N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide of the formula (I) or its pharmaceutically acceptable salt or ester hydrolyzed in vivo in combination with pharmaceutically acceptable vehicle or carrier. Invention provides preparing derivatives of N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide enhancing activity of pyruvate dehydrogenase.

EFFECT: valuable medicinal and biochemical properties of compounds.

14 cl, 1 tbl, 85 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to new compounds of formula I ,

solvates or pharmaceutically acceptable salts having antiarrhythmic activity, including ventrical fibrillation, as well as pharmaceutical compositions containing the same. Compounds of present invention are useful in treatment or prevention of arrhythmia, modulation of ion channel activity, for topic or local anesthesia, etc. In formula I X is direct bond, -C(R6,R14)-Y- and C(R13)=CH-; Y is direct bond, O, S, and C1-C4-alkylene; R13 is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, unsubstituted aryl or benzyl; R1 and R2 are independently C3-C8-alkoxyalkyl, C1-C8-hydroxyalkyl and C7-C12-aralkyl; or R1 and R2 together with nitrogen atom directly attached thereto form ring of formula II ,

wherein said ring is formed by nitrogen and 3-9 ring atoms selected independently from carbon, sulfur, nitrogen and oxygen, etc; R3 and R4 are independently attached to cyclohexane ring in 3-, 4-, 5-, or 6-position and represent independently hydrogen, hydroxyl, C1-C6-alkyl and C1-C6-alkoxy; and when R3 and R4 are bound with the same atom of cyclohexane ring they may form together 5- or 6-membered spiroheterocycle ring containing one or two heteroatoms selected from oxygen and sulfur; A is C5-C12-alkyl, C3-C13-carbocyclic ring, or ring structure as defined herein.

EFFECT: new antiarrhythmic drugs.

30 cl, 12 dwg, 34 ex

The invention relates to stereochemical controlled way to obtain usacycling compounds of formula (Ia,), where R1R2CH-group in the 5-position of cyclic fragment and the hydroxy-group at the 3-position of cyclic element are in TRANS-position is obtained with respect to each other and where the substituent R44-polozheniii and the hydroxy-group at the 3-position of cyclic fragment are zespolony relative to each other and where n is 0 or 1, R1-R3is hydrogen, R4is hydrogen or lower alkyl, or R3andR4together mean WITH2-C6-alkylenes chain, R5-R7is hydrogen,R8is hydrogen, lower alkyl, (lower alkoxy)lower alkyl, phenyl or phenyl-lower alkyl, R6andR7together can also form a bond, and R5andR8together with the carbon atoms to which they are linked, can form an aromatic6ring system, R9is hydrogen or a protective amino group, or R8and R9together can form WITH3-C4-alkylenes chain or their salts

The invention relates to a new group of individual chemical compounds - cyclic amino compounds represented by the following formula:

< / BR>
where R1represents a phenyl group which may be optionally substituted by at least one Deputy, which represents a halogen atom; R2represents a C1-C8aliphatic acyl group or (C1-C4alkoxy) carbonyl group; and R3represents a saturated cyclic amino group which has from 2 to 8 carbon atoms in one or more cycles, with the highest nitrogen cycle has from 3 to 7 atoms in the cycle, and the specified saturated cyclic amino group substituted by a group having the formula-S-S-R4where R4and X have the meanings as defined below, and the said saturated cyclic amino group attached via its cyclic nitrogen atom adjacent to the carbon atom that is attached to the substituents R2and R1; R4represents a phenyl group which may be optionally substituted by at least one Deputy, selected IGP and nitro groups; WITH1-C6alkyl group which may be optionally substituted by at least one Deputy, selected from the group consisting of amino groups, carboxyl groups, (C1-C4alkoxy)carbonyl groups, substituents having the formula-NH-A1(where a1represents an-amino acid residue), and substituents having the formula-CO-AND2(where a2represents an-amino acid residue); or (C3-C8cycloalkyl group, and X represents a sulfur atom, sulfinol group or sulfonyloxy group, and the above-mentioned cyclic aminecontaining group may be optionally additionally substituted by a group having the formula = CR5R6where R5and R6are the same or different, and each independently represents a hydrogen atom, a carboxyl group, (C1-C4alkoxy)carbonyl group, karbamoilnuyu group, (C1-C4alkyl) karbamoilnuyu group or di-(C1-C4alkyl)karbamoilnuyu group; or their pharmacologically acceptable salts, pharmaceutical composition having inhibitory action in Rel is the prevention of disease, selected from the group consisting of embolism and thrombosis in a warm-blooded animal

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to new compounds of formula I ,

solvates or pharmaceutically acceptable salts having antiarrhythmic activity, including ventrical fibrillation, as well as pharmaceutical compositions containing the same. Compounds of present invention are useful in treatment or prevention of arrhythmia, modulation of ion channel activity, for topic or local anesthesia, etc. In formula I X is direct bond, -C(R6,R14)-Y- and C(R13)=CH-; Y is direct bond, O, S, and C1-C4-alkylene; R13 is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, unsubstituted aryl or benzyl; R1 and R2 are independently C3-C8-alkoxyalkyl, C1-C8-hydroxyalkyl and C7-C12-aralkyl; or R1 and R2 together with nitrogen atom directly attached thereto form ring of formula II ,

wherein said ring is formed by nitrogen and 3-9 ring atoms selected independently from carbon, sulfur, nitrogen and oxygen, etc; R3 and R4 are independently attached to cyclohexane ring in 3-, 4-, 5-, or 6-position and represent independently hydrogen, hydroxyl, C1-C6-alkyl and C1-C6-alkoxy; and when R3 and R4 are bound with the same atom of cyclohexane ring they may form together 5- or 6-membered spiroheterocycle ring containing one or two heteroatoms selected from oxygen and sulfur; A is C5-C12-alkyl, C3-C13-carbocyclic ring, or ring structure as defined herein.

EFFECT: new antiarrhythmic drugs.

30 cl, 12 dwg, 34 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to substituted derivatives of N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide of the formula (I): wherein n = 1 or 2; R1 represents chlorine, fluorine, bromine atom, methyl or methoxy-group; R2 is taken among of one the following groups: (i) halogen atom, nitro-, hydroxy- amino- or cyano-group; (ii) -X1-R5 wherein X1 represents -O-, -S-, -SO-, -SO2-, NR6-, -CO-, -CONR6-, -NR6CO- wherein R6 represents hydrogen atom and R5 is taken among (C1-C6)-alkyl optionally substituted with one or some A, and so on; (iii) 4-8-membered heterocyclic group joined by nitrogen atom that represents saturated monocyclic ring comprising 4-8 carbon atoms among that at least one is nitrogen atom and so on; R3 represents (C1-C6)-alkyl optionally substituted with one or some A and so on; A is taken among hydroxy-, amino-group, halogen atom, carboxy-, N-(C1-C4-alkyl)-amino-, N,N-di-(C1-C4-alkyl)-amino-group, carbamoyl and (C1-C6)-alkoxy-group; D is taken among: (i) -Xa-Rc wherein Xa represents -SO2, -CO-, -NRdCO-, -NRd- or -CONRd-; (iv) cyano-group or halogen atom; (v) -XcRf wherein Xc represents -C(O)- and Rf represents 4-8-membered heterocyclic group joined by nitrogen atom that represents saturated monocyclic ring comprising 4-8 carbon atoms among that at least one is nitrogen atom with optionally additional heteroatom taken independently among oxygen atom (O), optionally substituted at ring carbon atom by the hydroxy-group, halogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl or cyano-group; G represents (C1-C6)-alkanoyl; R4 represents hydrogen or fluorine atom; or to its pharmaceutically acceptable salt or its ester hydrolyzed in vivo. Also, invention proposes a method for preparing compound of the formula (I). Also, invention proposes pharmaceutical composition enhancing activity of pyruvate dehydrogenase comprising substituted derivatives of N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide of the formula (I) or its pharmaceutically acceptable salt or ester hydrolyzed in vivo in combination with pharmaceutically acceptable vehicle or carrier. Invention provides preparing derivatives of N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide enhancing activity of pyruvate dehydrogenase.

EFFECT: valuable medicinal and biochemical properties of compounds.

14 cl, 1 tbl, 85 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new inhibitors of farnesyltransferase of the formula (I):

wherein R1 means hydrogen atom (H), group of the formula R5C(O)- wherein R5 means phenyl, pyridyl or N-methylpiperidine; R2 means hydrogen atom (H), isopropyl, cyclopentyl or N-methyltetrahydropyridyl; R3 means hydrogen atom (H), halogen atom; R4 means hydrogen atom (H), halogen atom; L means -CH2-Z- wherein Z means NH; Y means sulfur atom (S), S(O) or S(O)2; or its salt. Compounds of the formula (I) inhibit activity of enzyme, farnesyl(protein)transferase, that allows their using in pharmaceutical composition in cancer treatment.

EFFECT: valuable medicinal properties of inhibitors.

18 cl, 3 tbl, 3 sch, 6 ex

New compounds // 2261245

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (I): wherein m = 0, 1, 2 or 3; each R1 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C6)-halogenalkoxy-group, -NR9R10, (C3-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group or (C1-C6)-alkyl; X represents -O- or CH2-, OCH2-, CH2O-, CH2NH-, NH-; Y represents nitrogen atom (N) or group CH under condition that when X represents -O- or CH2O-, CH2NH- or NH-group then Y represents group CH; Z1 represents a bond or group (CH2)q wherein q = 1 or 2; Z2 represents a bond or group CH2 under condition that both Z1 and Z2 can't represent a bond simultaneously; Q represents -O- or sulfur atom (S) or group CH2 or NH; R2 represents group of the formula: n = 0; each R4, R5, R6 and R7 represents independently hydrogen atom (H), (C1-C6)-alkyl either R4, R5, R6 and R7 represent in common (C1-C4)-alkylene chain joining two carbon atoms to which they are bound to form 4-7-membered saturated carbon ring, either each R5, R6 and R7 represents hydrogen atom, and R4 and R8 in common with carbon atoms to which they are bound form 5-6-membered saturated carbon ring; R8 represents hydrogen atom (H), (C1-C6)-alkyl or it is bound with R4 as determined above; each R9 and R10 represents independently hydrogen atom (H), (C1-C6)-alkyl; R15 represents (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, (C5-C6)-cycloalkenyl, adamantyl, phenyl or saturated or unsaturated 5-10-membered heterocyclic ring system comprising at least one heteroatom taken among nitrogen, oxygen and sulfur atoms wherein each group can be substituted with one or more substitute taken independently among nitro-group, hydroxyl, oxo-group, halogen atom, carboxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, phenyl and -NHC(O)-R17 under condition that R15 doesn't represent unsubstituted 1-pyrrolidinyl, unsubstituted 1-piperidinyl or unsubstituted 1-hexamethyleneiminyl group; t = 0, 1, 2 or 3; each R16 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C)-halogenalkoxy-group, -NR18R19, (C1-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group, (C1-C6)-alkyl; R17 means (C1-C6)-alkykl, amino-group, phenyl; each R18 and R19 means independently hydrogen atom (H), (C1-C6)-alkyl, or its pharmaceutically acceptable salt or solvate. Compounds of the formula (I) elicit activity of a modulating agent with respect to activity of chemokine MIP-1α receptors that allows their using in pharmaceutical composition in treatment of inflammatory diseases.

EFFECT: valuable medicinal properties of new compounds.

14 cl, 98 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to compounds that inhibit binding ligands with α4β1-integrin (VLA-4) selectively. Compounds have the formula (I):

wherein W means unsubstituted phenyl or phenyl substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom, (C1-C4)-alkoxy-group and halogen alkyl; W1 means unsubstituted phenylene or phenylene substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom and (C1-C4)-alkoxy-group, pyridylene, pyridylene substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom and (C1-C4)-alkoxy-group, 2-oxopyrrolylene or thiazolylene; A means oxygen atom (O); R means -(CH2)n- wherein n = 1 or 2; X means -C(O)-; M is taken among the following groups: a)

wherein means divalent 5- or 6-membered heterocyclic radical wherein nitrogen atom is located in the joining point to X wherein Q represents -CH2-, -O- or -S-; R1, R2 and R3 are taken independently among the group involving: hydrogen atom (-H), hydroxyl group (-OH), quinolinyloxy-group, -NH2, mono- or dialkylamino-group, (C1-C6)-alkylsulfonylamino-, arylsulfonylamino-, naphthyloxy-, phenyloxy-group substituted optionally with di-(C1-C6)-alkylamine, (C1-C6)-alkyl, benzyloxymethyl, halogen atom, phenyl, (C1-C4)-alkoxy-group; or two adjacent R1, R2 and R3 taken in common can form alkylene- or alkylenenedioxy-group substituted optionally with 1-3 alkyl groups; R4 means hydrogen atom (H), lower alkyl; Y is taken among a bond, (C2-C8)-alkenylene group, (C2-C8)-alkynylene group, -C(O)-, -C(O)NH- and -(CH2)kY2 wherein k is taken among 1, 2 and 3; Y2 means a direct bond or divalent radical taken among -O-, -S-, -S(O)-, -S(O)2- and -NY3- wherein Y3 is taken among hydrogen atom (H), lower alkyl; Z means (C3-C8)-cycloalkylene, optionally substituted phenylene, pyridylene, piperidylene, piperazinylene; A1 means a direct bond, -(CH2)t-alkynyl wherein t is taken among 1, 2 and 3; R5 means -OH, lower alkoxy-group, , ; b) means wherein R11 is taken among , -NR12- wherein R12 is taken among hydrogen atom (-H), optionally substituted lower alkyl, lower alkenyl, lower alkynyl, phenyl; Z3 is taken among a direct bond, (C1-C12)-alkyl wherein one or some carbon atoms can be replaced with -O- or -NR13- wherein R13 means hydrogen atom (-H), lower alkyl, wherein x = 0 or 1; y = 1, 2 or 3; R14 means hydrogen atom (-H), ; and when R11 means NR12 then Z3 is taken among: wherein 14Ra means hydrogen (H), halogen atom; , and ; Q2 means wherein R17 and R18 mean hydrogen atom (H), lower alkyl; or phenylene that can be substituted; L1 means -COOH or -COOR19 wherein R19 means lower alkyl. Compounds of the formula (I) inhibit activity of VLA-4-mediated adhesion of cells that allows their using in pharmaceutical compositions.

EFFECT: valuable medicinal properties of compounds and compositions.

21 cl, 11 tbl, 283 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds including all its enantiomeric and diastereomeric forms, and to their pharmaceutically acceptable salts wherein indicated compound corresponds to the formula: wherein A represents a conformationally limited ring system chosen from the group comprising the following formulae: (a) (d) and (e) wherein carbon atoms labeled by asterisks can be in any stereochemical configuration or their mixtures wherein Y has a formula: -(CH2)b-R15 wherein index b = 1-4, and R15 represents -OH, -NH2, guanidine-group, and Z has a formula: wherein R represents hydrogen atom; R9 represents naphthylmethyl; R10 represents -C(X)N(R16)2 wherein each R16 represents independently hydrogen atom or (C1-C10)-alkyl; X represents oxygen atom; or Z represents naphthylmethyl wherein W has a formula: wherein R represents phenyl substituted optionally with halogen atom of OH-group wherein fragment L is chosen from the group comprising: -NH- or -NHC(O)-; B represents hydrogen atom of fragment of the formula: wherein fragments R2, R3 and R4 are chosen independently among the group comprising hydrogen atom, -NHC(O)CH3, benzyl substituted optionally with hydroxy-group or halogen atom, imidazolylmethyl; or fragments R2, R3 and R represent in common naphthalinyl or isoquinolinyl; or one radical among R2, R3 and R4 represents hydrogen atom and two radical among R, R3 or R4 chosen in common form piperidine ring or tetrahydroisoquinoline ring substituted optionally with the group -C(O)CH3. Also, invention relates to a pharmaceutical composition possessing the agonistic activity with respect to MC-3/MC-4 receptors based on these compounds. Invention provides preparing new compounds and pharmaceutical compositions based on thereof for aims in treatment of disorders mediated by function of MC-3/MC-4 receptors.

EFFECT: valuable medicinal properties of compounds and compositions.

17 cl, 14 tbl, 12 ex

FIELD: organic chemistry, chemical technology, biochemistry, medicine.

SUBSTANCE: invention relates to novel isoquinoline compounds of the general formula (I): wherein R1 represents hydrogen atom, halogen atom or alkyl; Y is absent or represents alkylene chain comprising from 1 to 8 carbon atoms wherein arbitrary carbon atom can comprise hydroxyl group as a substitute; R represents the following formula (II): wherein X represents -CH or nitrogen atom under condition that if Y absent in the formula (I) then X must represent -CH; W represents -CH or nitrogen atom under condition that if X represents -CH then W must represents nitrogen atom; s represents a whole number from 1 to 3; t represents a whole number from 1 to 3; if R3 represents hydrogen atom or alkyl then R2 represents hydrogen atom, alkyl, hydroxyl group or hydroxyalkyl, and R2' represents hydroxyl group or hydroxyalkyl, and if R3 represents hydroxyalkyl then R2 and R2' represent hydrogen atom. Also, invention relates to their optically active forms, pharmaceutically acceptable salts, aqueous adducts, hydrates and solvates. Compounds of the formula (I) elicit inhibitory effect on activity of poly-(ADP-ribose)-polymerase and can be used in prophylaxis of diseases associated with cerebral infarction.

EFFECT: valuable medicinal properties of compounds, improved method of synthesis.

40 cl, 4 tbl, 55 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of N-methyl-N-{(1S)-1-phenyl-1-[(3S)-3-hydroxypyrrolidin-1-yl]ethyl}-2,2-diphenylacetamide. Method involves the following steps: (a) interaction of N-substituted derivative of phenylglycine of the formula (I): , wherein R means -OR1, -SR1; R1 means A, benzyl, unsubstituted phenyl or phenyl, biphenyl or naphthyl mono- or disubstituted with halogen atom, -OA or (C1-C6)-alkyl; A means linear or branched (C1-C6)-alkyl; M means hydrogen atom (H) or a cation chosen from group comprising alkaline metals, earth-alkaline metals, ammonium or alkylammonium with compound of the formula (II): , wherein R2 means H, A, or with acid-additive salt of compound of the formula (II) of acids HCl, HBr, HJ, H2SO4, H3PO4, or with organic carboxylic acid to obtain compound of the formula (III): , wherein R and R2 have above given values; (b) synthesized compound is converted to compound of the formula (IV): , by reduction reaction that is converted optionally to acid-additive salt of acids HCl, HBr, HJ, H2SO4, H3PO4, or to salt of organic carboxylic acid, and (c) synthesized compound of the formula (IV) is subjected for interaction with activated carboxylic acid of the formula (V): , wherein R4 means F, Cl, Br, J, -OA or -O-CO-A to yield compound of the formula (VI): , that is converted to a corresponding acid-additive salt using inorganic acid chosen from group comprising HCl, HBr, HJ, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, ortho-phosphoric acid or using organic acid.

EFFECT: improved method of synthesis.

7 cl, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrrolidinium of the general formula (I): possessing antagonistic effect with respect to muscarinic receptors M3 wherein B means phenyl or thienyl group; each radical among R1, R2 and R means independently hydrogen, fluorine, chlorine atom or hydroxyl; n means a whole number from 0 to 1; A means group chosen from groups -CH2 and -O-; m means a whole number from 0 to 6; R means (C1-C8)-alkyl; X- represents a pharmaceutically acceptable anion of mono- or multibasic acid, and involving all separate stereoisomers and their mixtures. Also, invention relates to methods for synthesis of such compounds, pharmaceutical compositions containing such compounds and to their using in therapy as antagonists of muscarinic receptors M3.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

17 cl, 51 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of the formula (IE) or of its pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, geometric isomer, including its chosen enantiomeric, diastereomeric and geometric isomers and their mixtures, where R4 and R5 are independently selected from C1-C6 alkoxy.

EFFECT: it makes it possible to use them in the pharmaceutical compositions and the methods of blocking Na channels in warm-blooded animals.

18 cl, 5 tbl, 18 ex

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