The method of separating a mixture of proline with valine, or proline with leucine, or proline with oxyproline

 

(57) Abstract:

Describes a method of separating a mixture of Proline and valine, leucine or hydroxyproline by passing through the layer of adsorbent and elution, the sorbent used anion exchange resin AV-17-2P in the form, and the mixture is passed at a speed of 2 m/h, which in turn yields a concentrated solution of Proline, and elute residual Proline distilled or deionized water at the same speed, and sorbed anion valine, leucine or hydroxyproline elute 1 M hydrochloric acid at a speed of 2 m/h Technical result is simplification. table 1.

The invention relates to methods for selection of individual amino acids from the mixture and can be used in chemical, medical, food and other industries.

Known methods for isolating amino acids in the conditions of centrifugation with the addition of an organic solvent not miscible with water, for example n-butanol (Japan patent N 63-203652, class C 07 C 99/12, 23.08.88), processing of the water-ethanol solution of L-Proline containing organic and inorganic impurities, activated carbon and the release of Proline acetone with subsequent cooling of the mixture. Also known SPO is Normandie resins (USSR author's certificate, N 960163, class C 07 C 99/12, 23.09.82, N 35).

The closest in technical essence to the described method is a method of allocation of L-Proline from other amino acids by passing the solution through sulfonation KU-2-8 in H+-form (USSR author's certificate N 639862, class C 07 C 99/12, 30.12.78, N 48).

The disadvantage of this method is the complexity of the preliminary preparation of the solutions before passing through suffocation.

A significant simplification of separating a mixture of valine and Proline is achieved by the use as a sorbent of anionite AV-17-2S in IT. The preferred anion exchange resin due to the possibility to use differences in the pK values of the constants protolith functional groups.

These tables show that pK2Proline significantly greater than the corresponding values pK2valine, leucine and hydroxyproline, which allows the latter to more selectively retained by the anion exchange resin in the form of anions. Proline in this example is mainly in zwitterionic form, weakly retained by the anion exchange resin and easily desorbed water.

Example 1. 140 ml of solution with a concentration of Proline 11.4 g/l and valine 7.2 g/l passed with a speed of 2 ml/min through the column diameter is th column of the solution, does not contain amino acids, cast. Subsequent 60 ml, containing Proline at a concentration of 14 g/l, collect. Next pass through the column 55 ml of distilled water at a speed of 2 m/H. the First 15 ml of the resulting solution from the column contain Proline (16 g/l), and valine (3.6 g/l) and sent to the next cycle of separation in a mixture with the initial solution. The next 40 ml of a solution containing Proline at a concentration of 8.5 g/l and valine at a concentration of 0.8 g/l, together with containing Proline solution obtained at the stage of sorption. Then hold desorption valine 60 ml of hydrochloric acid with a speed of 1 m/H. the First 15 ml of the resulting solution from the column drop. Subsequent 60 ml valine content of 16 g/l Proline 3.9 g/l collected. Then miss 60 ml of water with a speed of 2 m/H. Regeneration of the sorbent is a serial transmission 60 ml of 1 M NaOH and 60 ml of distilled water at a speed of 2 m/h

In the result of the division is obtained:

a) 100 ml of a solution containing the product Proline at a concentration of 11.88 g/l and mixture of valine - 0.28 g/l After drying is obtained 1.23 g of product containing 98% Proline.

b) 60 ml of a solution containing the product to valine at a concentration of 16.0 g/l and the em: Proline - 98%, valine - 98%.

The resulting separation of Proline mixed with valine and valine with a mixture of Proline can be used in the food industry without additional purification. Pure preparations of Proline and valine, obtained by the proposed method results in varying amounts of sorbed fractions, can be applied in several areas of medicine and used in fine chemical experiments.

Example 2. 240 ml of solution with a concentration of Proline 12.0 g/l and the concentration of leucine 6 g/l, pH~6.5 passed at the rate of 2 ml/min through a column Packed with 20 ml of macroporous anion exchange resin AV-17-2S in IT. The first 60 ml (V/V0= 3) after passing through the column does not contain amino acids and are discarded. The next 80 ml contain pure Proline, breakthrough leucine is not observed. Upon further deletion of the amino acid mixture until complete saturation of the column (40 ml) at the outlet from the column appears not only Proline, and leucine. Washing of the anion exchange resin with water after sorption allows you to extract, Proline (2 V/V0), then when processing the resin 0.5 M HCl desorbed leucine.

Example 3. 120 ml of solution with a concentration of Proline 10 g/l and the concentration of hydroxyproline 4 g/l and the neutral value of the Les of the sorption process occurs both amino acids by ion exchange and the first 3 volumes (60 ml) do not contain the target product and discarded. Upon further transmission 60 ml of the mixture at the outlet from the column contains pure Proline, still hydroxyproline is retained by the resin. To extract the Proline with a column in the quality of the eluate is water (40 ml). Hydroxyproline decarbonate 0.5 M HCl (40 ml).

The method of separating a mixture of Proline roller, or Proline with leucine, or Proline with oxyproline by passing through the layer of adsorbent and elution, characterized in that the sorbent using an anion exchange resin AV-17-2P in the form, and the mixture is passed at a speed of 2 m/h, which in turn yields a concentrated solution of Proline, and elute residual Proline distilled or deionized water at the same speed, and sorbed anion valine, leucine or hydroxyproline elute 1 M hydrochloric acid with the speed of 2 m/H.

 

Same patents:

The invention relates to 1,4-disubstituted the piperazines of General formula (I), which means the group-CO - or-CH2-OCO; D - heteroaryl selected from a range including 1, 3, 5-triazinyl, pyrimidinyl and pyridinyl, possibly substituted by one or two substituents selected from a range, including mono-(C1-C6)-alkylamino, mono-(C3-C7)- alkynylamino-, di-(C1-C6)-alkylamino-,

(C1-C6)-alkyl-(C3-C7)-alkylamino and pyrrolidin-I-yl group; Raand Rbis a hydrogen atom or (C1-C3)-alkyl; n is an integer from 1 to 4; their enantiomers, racemic mixtures and their salts with pharmaceutically acceptable acids and bases

The invention relates to the derivatives of pyrrolidine formula (I) in which either R is methylene, ethyleneglycol, >SO, >SO2group or a sulfur atom; R1means pyridinyl, furyl, thienyl, optionally substituted by one or more alkyl groups, naphthyl, indolyl or phenyl, optionally substituted by one or more substituents selected from halogen atoms, alkyl-, alkoxy-, hydroxy - and dialkylamino; R5means a hydrogen atom; or R is methylene, R1is a hydrogen atom and R5means phenyl; or R is a group > CHR6, R1and R5mean a hydrogen atom; R2means alkoxycarbonyl, cycloalkyl-alkyloxy-carbonyl -, etc., R3means indolyl - or phenylaminopropyl, the phenyl nucleus of which is substituted by one or more substituents selected from a range that contains the halogen atom, the alkyl-, alkoxy-, alkylthio group and others; R4means a hydrogen atom and alkylaryl; R6means phenyl radical in the form of iamiceli mixture or enantiomers and their salts

The invention relates to heterocyclic amines of formula I:

,

in which

X represents-CH2-group or-S-group;

B denotes a group selected from a number containing-CO -, - CH2OCO-, -CH2OCS-, -CH2NHCO - CH2NHCS-group;

D represents benzhydryl or phenyl group, optionally substituted by halogen atoms, and heterocyclic group, selected from a number containing 1,3,5-triazine-2-yl, pyridin-2-yl and pyrimidine-4-yl, and optionally substituted by one or two substituents selected from the group comprising amino, mono - or di-(C1C6) alkylamino, mono- (C3-C7)-alkynylamino, mono-(C3-C7)-quinil-amino group and pyrrolidin-1-yl group;

The is a simple carbon-carbon bond or a group of the formula: -CH2CH2or CRaRb-, where Raand Rbis a hydrogen atom, (C1-C3)alkyl, or taken together with the carbon atom to which they are attached, form a (C3-C6) cycloalkyl;

A is selected from the group comprising (a) carboxyl group optionally esterified (C1-C4) Ukrspirt the crystals: -C–ěNHRgOH, where Rcand Rdidentical or different, represent a hydrogen atom, (C1-C6) alkyl, benzyl, pyridin-2-yl, or taken together with the nitrogen atom to which they are bound, form piperidino, morpholino-, 4-thiomorpholine-, 4,5-diazepino, 4-(C1-C4)alkylpiperazine; Rfis a tolyl; Rgis a (C1-C4) alkyl;

(b) (C1-C3) alkyl;

(c) the group-NRcRdwhere Rcand Rddefined above,

(d) a cyano, if "y" does not mean a simple carbon-carbon bond

in the form of S-enantiomers, diastereomers, in the form of various racemic mixtures and their salts with pharmaceutically acceptable acids and bases

The invention relates to new derivatives of dipeptides with pharmacological activity, and the way they are received, and may find application in medicine

-aminobutyric acid, method for their preparation and method of treatment and pharmaceutical composition" target="_blank">

The invention relates to new compounds which are analogs-aminobutyric acid (DAWA), which can be used as a means protivogrippoznoj therapy of disorders of the Central nervous system

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cycloalkyl C3-C6, R2- H or CH3, R3- H, CH3or carboxyl, provided that when each of R2and R3- H, R1distinguished from CH3interoperability connectionswhere R is benzyl or 1,1-dimethylethyl, which is then hydrolized and restore

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel 1,2,3-tris-[(ammonio)methylcarbonyloxypoly(alkyleneoxy)]-propane trichlorides of the general formula:

wherein at -X+ as -N+R1RR, R1 = R2 mean hydrogen atom (H), R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms, a + c + e (the general degree of oxypropylation) = 49,b + d + f (the general degree of oxyethylation) = 0; at -X+ as -N+R1R2R3, R1 = R2 mean H, R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms, a + c + e = 55, b + d + f = 0; at -X+ as -N+R1R2R3, R1 = R2 mean H, R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms, a + c + e = 80, b + d + f = 24; at -X+ as -N+R1R2R3, R1 = R2 mean H, R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms, a + c + e = 90, b + d + f = 27; at -X+ as -N+R1R2R3, R1 = R2 means H, R3 means phenyl, a + c + e = 80, b + d + f = 24; at -X+ as -N+R1R2R3, R1 = R2 mean H, R3 means phenyl, a + c + e = 90, b + d + f = 27; at -X+ as , a + c + e = 80, b + d + f = 24; at -X+ as , a + c + e = 90, b + d + f =27. Also, invention relates to a method for synthesis of these compounds. Method involves interaction of 1,2,3-tris-[hydroxypoly(alkyleneoxy)]-propane of the formula:

wherein a + c + e = 49-90, b + d + f = 0-27 with monochloroacetic acid in the presence of acidic catalyst, in boiling organic solvent medium with azeotropic removal of water formed and the following treatment of synthesized reaction product in polar solvent medium at heating with amino-compounds of the formula: NR1R2R3 wherein R1 = R2 mean H, R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms, phenyl, or morpholine of the formula:

in the following mole ratios of reagents - propane hydroxyl derivative : monochloroacetic acid : amino-compound or morpholine = 1:(3.0-3.2):(3.0-3.2), respectively. New compounds show the bactericidal and fungicide activity and properties of demulsifying agents for petroleum emulsions.

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

7 cl, 3 tbl, 8 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel 1,2,3-tris-[(ammonio)methylcarbonyloxypoly(alkyleneoxy)]propane trichlorides of the formula: wherein: if R1 = R2 = R3 mean -CH2CH2OH then a + c + e (the total degree of oxypropylation) = 49, b + d + f (the total degree of oxyethylation) = 9; if R1 = R2 = R3 mean -CH2CH2OH then a + c + e = 55, b + d + f = 10; if R1 = R2 = R3 mean -CH2CH2OH then a + c + e = 66, b + d + f = 15; if R1 = R = R3 -CH2CH2OH then a + c + e = 76, b + d + f = 18; if R1 = R2 mean hydrogen atom (H); R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms then a + c + e = 76, b + d + f =18; if R1 = R2 mean H; R3 means aliphatic hydrocarbon radical comprising 17-20 carbon atoms then a + c + e = 49, b + d + f = 0; if R1 = R2 mean H; R3 means aliphatic hydrocarbon radical comprising 17-20 carbon atoms then a + c + e = 55, b + d + f = 0; if R = R means H; R3 means then a + c + e = 49, b + d + f = 9; if R1 = R2 mean H; R3 means then a + c + e = 55, b + d + f =10, and to a method for their synthesis. Method involves interaction 1,2,3-tris-[hydroxypoly(alkyleneoxy)propanes of the formula: wherein a + c + e = 49-76, b + d + f = 0-18 with monochloroacetic acid in the presence of acidic catalyst, in boiling organic solvent medium and azeotropic removal of formed water and the following treatment of the synthesized reaction product at heating with amino-compounds of the formula: R1R2N wherein R1 = R2 mean -H, -CH2CH2OH; R3 means -CH2CH2OH, aliphatic radical comprising 10-16 or 17-20 carbon atoms, and in the molar ratio of reagents - propane hydroxyl derivatives : monochloroacetic acid : amino-compounds = 1:(3.0-3.2):(3.0-3.2), respectively. Novel compounds possess properties of emulsifiers of aqueous-mazut emulsions.

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

6 cl, 1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to methods for synthesis of compounds of formula (A), where R1 denotes halogen, C1-C6halogenalkyl, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl; R2 denotes halogen, C1-C4alkyl or C1-C4alkoxy; R3 and R4 independently denote a branched C3-C6alkyl; and R5 denotes C3-C12cycloalkyl, C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6alkoxy(C1-C6)alkyl, C1-C6alkanoyloxy(C1-C6)alkyl, C1-C6aminoalkyl, C1-C6alkylamino(C1-C6)alkyl, C1-C6dialkylamino(C1-C6)alkyl, C1-C6alkanoylamino(C1-C6)alkyl, HO(O)C-(C1-C6)alkyl, C1-C6alkyl-O-(O)C-(C1-C6)alkyl, H2N-C(O)-(C1-C6)alkyl, C1-C6alkyl-HNC(O)-(C1-C6)alkyl or (C1-C6alkyl)2N-C(O)-(C1-C6)alkyl, or their pharmaceutically acceptable salts which have renin inhibiting activity, as well as to basic intermediate compounds obtained during steps for synthesis of the desired compounds and to methods for synthesis of said intermediate compounds.

EFFECT: alternative synthesis method.

43 cl, 8 dwg, 11 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to new (N-substitutes glycyl)-2-cyanopyrrolidines of formula I , wherein R is adamantly, substituted in 3- and/or 5-site with one or more substituents, selected from group including C1-C10-alkyl, OR1 (R1 is C1-C10-alkyl, C1-C8-alkanoyl, -CO-NR4R5, wherein R4 and R5 are independently from one another hydrogen, cyclohexyl, C1-C10-alkyl, phenyl optionally substituted with C1-C10-alkyl or C1-C10-alkoxy), in free form or in form of acid additive salt. Claimed compounds inhibit dipeptidyl-peptidase IV (DPP-IV) activity and useful in pharmaceutical composition for treatment of conditions mediated by DPP-IV, such as insulin-independent diabetes mellitus and obesity.

EFFECT: new pharmaceutical compounds inhibiting dipeptidyl-peptidase IV.

5 cl, 1 dwg, 4 tbl, 12 ex

FIELD: organic chemistry, medicine, endocrinology, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (1) or its pharmaceutical salts wherein A means

R1 means hydrogen atom (H), (C1-C6)-alkyl (including branched alkyl and cycloalkyl), -(CH2)aNHW1, -(CH2)bCOW2, -(CH2)cOW3, -CH(Me)OW4, -(CH2)d-C6H4-W5, -(CH2)eSW6 wherein a = 2-5; b = 1-4; c = 1-2; d = 1-2; e = 1-3; W1 means -COW6, -CO2W6, -SO2W6; W2 means -OH, -NH2, -OW6, -NHW6; W3 means hydrogen atom (H), W6; W4 means H, W6; W5 means H, -OH, -OMe; W6 means (C1-C6)-alkyl, benzyl, optionally substituted phenyl wherein optional substitutes (up to two groups) are taken among (C1-C3)-alkyl, (C1-C3)-alkoxy-group, fluorine (F) and/or chloride (Cl) atoms; R2 means H, -(CH2)nNH-C5H3N-Y wherein n = 2-4; Y means H, F, Cl atoms, -NO2 and -CN; or R1 and R2 represent in common -(CH2)p- wherein p = 3 or 4; X is taken among: (i) one L-alpha-aminoacyl group taken among Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val, or two such groups that represent Arg and Ile; (ii) groups -R3CO wherein R3 represents H, (C1-C6)-alkyl (including branched alkyl and cycloalkyl) or phenyl; (iii) groups -R4COOC, -(R5)(R6)OCO wherein R4 means H, (C1-C6)-alkyl (including branched alkyl and cycloalkyl), benzyl or optionally substituted phenyl wherein substituted (up to two groups) are taken among (C1-C3)-alkyl, (C1-C3)-alkoxy-group, F and Cl atoms; each R5 and R6 means independently H or (C1-C6)-alkyl; or R5 and R6 mean in common -(CH2)m- wherein m means a whole number 4-6; and (iv) methoxycarbonyl, ethoxycarbonyl and benzyloxycarbonyl groups; R7 is taken among pyridyl and optionally substituted phenyl wherein substitutes (up to two groups) are taken among (C1-C3)-alkyl, (C1-C3)-alkoxy-group, F, Cl atoms, -NO2, -CN and -CO2H; R8 means H or (C1-C3)-alkyl; R9 means H, (C1-C6)-alkyl, phenyl or (C1-C6)-alkoxy-group and under condition that indicated compound doesn't represent N(Z-Val)-2-cyanopyrrolidine. Compounds of the formula (1) are inhibitors of DP-IV and can be used in pharmaceutical compositions in treatment of the tolerance disturbances to glucose and diabetes mellitus of type 2.

EFFECT: valuable medicinal properties of compounds and compositions.

26 cl, 2 tbl, 19 ex

FIELD: biochemistry.

SUBSTANCE: invention relates to new compounds of formula wherein R1 represents linear or branched C1-C9-alkyl optionally substituted with C3-C8-cycloalkyl, C6-cycloalkyl, 2-furil; 3-furil, 2-thiazolyl, 2-thenyl, 3-thienyl, phenyl; X represents oxygen, NR4, wherein R4 is H, C1-C4-alkyl; Z represents H with the proviso, that when X and Y are oxygen, R1 is not methyl, ethyl, isopropyl, isobutyl or phenyl; and when X is oxygen, and Y is NR2, wherein R2 is hydrogen, methyl, isopropyl or tert-butyl R1 is not methyl. Compounds of present invention are useful as synthetic intermediates for bioactive substances.

EFFECT: new synthetic intermediates for bioactive substances.

8 cl, 28 dwg, 3 tbl, 38 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compounds of the general formula (1): wherein X is chosen from sulfur atom and methylene group; X1 is chosen from sulfur atom and methylene group; X2 is chosen from oxygen (O), sulfur (S) atoms and methylene group; X3 means -NR5 or carbonyl group; R1 means hydrogen atom or nitrile group; R and R3 are chosen independently from hydrogen atom (H) and (C1-C6)-alkyl; R4 means R4A when X3 means -NR5 and R4B when X3 means carbonyl group; R4A is chosen from -R6R7NC(=O), -R6R7NC(=S), -R8(CH2)qC(=O), -R8(CH2)qC(=S), -R8(CH2)qSO2 and -R8(CH2)qOC(=O); R4B means -R6R7N; R5 means hydrogen atom (H); R6 and R7 are chosen independently from -R8(CH2)q, or they form in common -(CH2)2-Z1-(CH2)2- or -CHR9-X2-CH2-CHR10-; R8 is chosen from hydrogen atom (H), (C1-C4)-alkyl, cycloalkyl group condensed with benzene ring, acyl, dialkylcarbamoyl, dialkylamino-group, N-alkylpiperidyl, optionally substituted aryl, optionally substituted α-alkylbenzyl, optionally substituted aroyl, optionally substituted arylsulfonyl and optionally substituted heteroaryl representing monocyclic 5- and 6-membered ring aromatic group with one or two heteroatoms chosen from nitrogen, oxygen and sulfur atoms, and derivatives of abovementioned rings condensed with benzene; R9 and R10 are chosen independently from hydrogen atom (H), hydroxymethyl and cyanomethyl groups; Z1 is chosen from -(CH2)r-, -O-, and -N((CH2)q)R8)-; Z2 means optionally the substituted ortho-phenylene group; m = 1-3; n = 0-4; p = 2-5; q = 0-3, and r = 1 or 3. Proposed compounds are inhibitors of dipeptidyl-peptidase IV and can be used in preparing pharmaceutical compositions designated for treatment of different diseases, among them, diabetes mellitus of type 2.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

22 cl, 8 tbl, 453 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-cyano-4-fluoropyrrolidine of the formula (I): or its pharmaceutically acceptable salt wherein A represents group of the general formula (II): wherein B represents carbonyl or sulfonyl group; R1 represents (C1-C6)-alkyl that can be optionally substituted with group chosen from the group comprising -OH or atoms of fluorine, chlorine, bromine or iodine, phenyl optionally substituted with -CN or morpholinyl group, or if B represents carbonyl then R1 can mean hydrogen atom; R2 represents (C1-C6)-alkyl optionally substituted with hydroxyl group or hydrogen atom. Compounds of the formula (I) are inhibitors of enzyme dipeptidyl peptidase IV that allows its using in pharmaceutical composition that is designated for treatment of insulin-dependent diabetes mellitus (diabetes of type 1), non-insulin-dependent diabetes mellitus (diabetes of type 2), diseases associated with resistance to insulin or obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 8 tbl, 11 ex

FIELD: medicine, hematology, organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel peptidylarginals of the formula (I): Xaa-Xbb-Arg-H wherein Xaa means residue of alpha-substituted carbonic acid of the formula (II): Q-CH(R)-CO wherein Q means (C1-C3)-alkyloxycarbonylamino-group, methylamino-group or hydroxyl group; R means (C7-C9)-cycloalkylmethyl group or (C5-C7)-cycloalkyl group; Xbb means residue of L-proline or L- azethidine-2-carboxylic acid, and its additive acid salts formed by organic or inorganic acid. Intermediate compounds are described also. Compounds of the formula (I) possess the inhibitory effect on free thrombin, thrombin bound with a clot, Xa factor, plasmin and plasminogen activators that allows their using in pharmaceutical composition in treatment of a patient suffering from disseminated intravascular coagulation syndrome.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 4 tbl, 10 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula 1 and their pharmaceutically acceptable salts as inhibitors of post-proline aminopepdidases, as well as to pharmaceutical composition based on them and application for manufacturing such composition, and to method of inhibition with their application. Compounds can be applied for treatment of diseases mediated by activity of post-proline aminopeptidases, such as type II diabetes and disturbed tolerance to glucose. In general formula 1 ,

either G1 represents -CH2-X2-(CH2)a-G3, and G2 represents H, or G2 represents -CH2-(CH2)a-G3, and G1 represents H; G3 is selected from group according to general formula 2 ,

group according to general formula 3

and group according to general formula 4 ;

a is 0, 1 or 2; b is 1 or 2; X1 is selected from CH2, S, CF2, CHF and O; X2 is selected from CH2; X3, X4 and X5 are selected from N; X6 is selected from NH; X7 is selected from NH; R1 is selected from H and CN; R2 represents H; R3 is selected from H, Cl, OH, NH2, NH-C1-C10alkyl and N(C1-C10alkyl)2; R4, R5, R6, R7 and R8 are independently selected from H, Br, Cl, F, OH, NO2; R9 represents H; R10, R11, R12, R13 and R14 are independently selected from H, Cl and CF3; R15 and R16 are independently selected from H, C1-C10alkyl, C1-C10alkenyl, C3-C10cycloalkyl, C3-C10cycloalkenyl, quinoline, naphtyl and -CH2-L-R17; R17 is selected from C1-C10alkyl, phenyl, naphtyl, quinolinyl and indolyl; L is selected from covalent bond, CH=CH and -C6H4-; on condition that when R15 and R16 both represent H, and b is 1, then X1 does not represent S or CH2.

EFFECT: obtaining compounds that can be applied for treatment of diseases mediated by activity of post-proline aminopeptidases, such as type II diabetes and disturbed tolerance to glucose.

58 cl, 10 tbl, 1705 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the new naphtylene derivative having general formula (I-A) and to their pharmaceutically acceptable salts having the property of inhibition of the cytochrome ferment P450RAI (Cyp26) activity, to the pharmaceutic composition thereof and to the method of inhibition of cytochrome ferment P450RAI (Cyp26). , wherein X is selected from imidasolyl or triasolyl; R2 and R3, independently represent H, C1-10-alkyl; G1 is -NR72R82 or G1 and R3 taken together with attached carbon atom form 3-10-membered saturated ring or heterocyclic saturated ring containing N as heteroatom which is optionally substituted with substituting group R72, Z, R4b, R5b, Q1, R72, n2, n3 and n4 values are indicated in the formula of the invention.

EFFECT: present invention refers to the intermediates for compounds with general formula (I-A) and to their pharmaceutic salts thereof.

37 cl, 30 dwg, 7 tbl

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