Method of 4-hydroxyproline substructure-containing compound synthesis

FIELD: chemistry.

SUBSTANCE: method of obtaining compound of the formula VIII where R12 and R13 each are removable protective group where protective group R12 is more resistant to extraction by hydrolysis or hydration than R13. Method involves reaction of compound of the formula IX with relevant R12 donor compound selected out of anhydrides, halogenides, carbamates and N-hydroxysuccinimides.

EFFECT: improved method.

4 cl, 6 ex

 

The present invention relates to methods of producing peptides and intermediates used to produce these peptides.

One object of the present invention includes:

(A) Method of obtaining compounds of formula I

where R1means reactive Deputy or the place of attachment to the solid phase;

R2means reactive Deputy, and

R3, R4and R5each independently mean hydrogen or one or more substituents that are attached to each benzene ring and which is selected from the group comprising hydroxy, amino, C1-C10alkyl, C1-C10alkoxy, C1-C10alkylamino, di(C1-C10)alkylamino, carbarnoyl, C1-C10allylcarbamate, di(C1-C10)allylcarbamate, halogen(C1-C10)alkyl, halogen and nitro;

in free form or in salt form; and the method includes

(a) interactions of the compounds of formula VI with an electrophilic compound:

where R3, R4and R5defined above;

R9means-OH, -OM or-OMX, where M denotes a metal, and X is a nucleophilic Deputy;

R10means-M or-MX, where M denotes a metal, and X is a nucleophilic Deputy;

in free form or in salt form;

and hydrolysis of the compounds with the formation of the compounds of formula I, where

R2means a hydroxy-group;

(b) optional conversion of the compounds of formula I, where R2means a hydroxy-group in the compound of formula I, where R2means another group, in addition to hydroxy;

(b) optional conversion of R1in the composition of the compounds of formula I in another group R1;

(g) optional removal of the protective group in the compound of the formula I containing a protective group; and

(d) if necessary, the conversion of the compounds of formula I obtained in free form into the desired salt or Vice versa;

(B) a method of obtaining a solid-phase system, including the production of the compounds of formula I according to the method described above, and condensation compounds with modified or contain the appropriate functional group of the solid phase material;

(C) a compound of the formula V in free form or in salt form

where R3, R4, R5and R9defined above, and

R7means nucleophilic Deputy;

(G) compound of formula VI in free form or in salt form

where R3, R4, R5and R9defined above, and

R10means-M or-MX, where M means meta is l, and X is a nucleophilic Deputy.

The present invention offers a simple way to obtain the compounds of formula I, which is used for solid phase chemical synthesis. According to the method of the present invention can directly obtain the compound of formula I, attached to the solid phase, or, if R1means reactive Deputy, the compound of the formula I can be a simple way to attach to the solid phase at a later stage. The presence of a reactive substituent R2allows the use of the compounds of formula I as connecting links in the synthesis of oligomers and polymers, such as glycopeptides, nucleotides and proteins, primarily for solid-phase synthesis of peptides. The compounds of formula I, especially those in which R2means halogen, is used in chemical synthesis as a protective agent for protecting functional groups, such as, for example, amino - and hydroxy-group.

Compounds of formulas V and VI are used as intermediates for producing compounds of formula I.

The compound of formula VI obtained when the interaction of the compounds of formula V with a metal or ORGANOMETALLIC compound:

where R3, R4, R5and R9defined above, and

R7means nuclei the local Deputy.

The compound of formula V receive the following way:

(i) the interaction of the compounds of formula II with a metal or ORGANOMETALLIC compound

where R6and R7every means of nucleophilic Deputy, and R3defined above and, if necessary, protected by removable protective group; and

(ii) the interaction of the compound obtained according to p.(i)with the compound of the formula III

where R4and R3defined above and, if necessary, protected by removable protective group.

The method according to the present invention is carried out in one reaction vessel without isolation of intermediate compounds.

Terms used in this description have the following meanings:

"Alkyl" means a straight or branched radical, preferably1-C4alkyl.

"Alkoxy" means a straight or branched radical, preferably1-C4alkoxy.

"Acylamino" means a group of the formula-NH-C(O)-R, where R is a straight or branched C1-C10alkyl, cycloalkyl or aryl, preferably R is C1-C4alkyl.

"Acyloxy" means a group of the formula-O-C(O)-R, where R is defined above.

"Aryl" preferably means6-C10aryl, for example phenyl.

"Halogen" means fluorine, chlorine, br is m or iodine.

"Halogenated" means a straight or branched C1-C10alkyl, substituted by one or more, e.g. one, two or three halogen atoms, preferably fluorine atoms or chlorine. Preferably halogenated means1-C4alkyl, substituted one, two or three fluorine atoms or chlorine.

"ORGANOMETALLIC compound" means a compound in which a carbon atom of an organic group bound to the metal. ORGANOMETALLIC compound preferably means metallicy, for example alkality, for example, straight or branched C1-C10acility, or in another embodiment, means allmetal, for example ability.

More preferably alkylate means3-C6alkality, such as utility or exility.

In another embodiment, the ORGANOMETALLIC compound means an organic compound of magnesium, for example straight or branched alkilani or arulmani, preferably C1-C6alkilani. Organic compounds of magnesium known as Grignard reagents. Organic compound of magnesium, preferably means an organic halide compounds of magnesium, preferably iodide or bromide.

In other embodiments, embodiments of the present invention, the ORGANOMETALLIC compound may mean with the unity alkyl - or arylzinc, for example, the connection C1-C6alkylzinc or connection C1-C6alkyl - or alloleva.

M means preferably lithium or magnesium.

R1means reactive Deputy suitable for attaching compounds to the solid phase. R1means-C(O)R', -C(O)-OR', -C(O)-NR'r R", -R12-R NR'r", -R12-OR', -NR'r R ' or-C(O)X, where R' and R" each independently mean hydrogen or a straight or branched C1-C10alkyl, for example, With1-C4alkyl, R12means a straight or branched C1-C10alkyl, for example, With1-C4alkyl, and X is a nucleophilic Deputy, preferably halogen, for example chlorine. Deputy R1may be in a para-, ortho - or meta-position, preferably the para-position.

In another embodiment, R1means the group through which the connection is attached to a solid phase material, and solid-phase material, for example, means polystyrene. Preferably the means-C(O)-R, -C(O)ORA, -C(O)-NR'-P, -R12-NR'-P, -R12-OP, -NR'-P-C(O)R12P, -C(O)-OR12P, -C(O)-NR'r R12P, -R12NR'r R12P, -R12OR12P, -NR'r R12-P or-R12-P, where R', R" and R12defined above, and R means of solid-phase material. More preferably R1means-C(O)ORA, -C(O)-OR12-P, -C(O)-NH-P, -C(O)-NH-R12-P, -NH-R12Riley-R 12-P, where R12means methyl, for example-CH2-R.

R2preferably means reactive Deputy suitable for attaching compounds to biological oligomer or polymer or Monomeric unit, for example the amino acid or polypeptide. R2may indicate a hydroxy group, acylamino, acyloxy, amino, halogen, sulfhydryl, C1-C10alkoxy or6-C10aryloxy, preferably halogen.

Each benzene ring represented by formulas I-VII, may contain as substituents one or more groups. For example, R3means from one to four substituents, preferably one or two substituent attached to the benzene ring, as represented by formulas I, II and IV-VII. R4and R5can mean from one to five substituents, preferably from one to three substituents that are attached to each benzene ring, as represented by formulas I, II and IV-VII. Each Deputy can be in any position of the benzene ring to which they are attached. More preferably R4and/or R5indicate substituents in ortho - or para-position of the benzene ring to which they are attached.

Each of the substituents R3, R4and R5if necessary, protected by removable protective GRU is sing, for example, if they contain the group-HE or-NH2that do not participate in the reaction. Protective groups, their introduction and removal are described, for example, in the book "Protective Groups in Organic Synthesis", T.W.Greene and others, John Willey & Sons Inc; Second Edition, 1991. Preferably, each of the substituents R3, R4or R5means a group that does not require protection, for example any of the above groups except the hydroxy, amino or nitro.

If the substituents R3, R4or R5means halogen, it is preferably denotes fluorine or chlorine. If the substituents R3, R4or R5mean halogenated, it means preferably trifluoromethyl. Preferably R3means1-C4alkyl, halogen or hydrogen. Preferably R4and R5each independently mean C1-C4allylcarbamate, di(C1-C4)allylcarbamate, carbarnoyl, trifluoromethyl, fluorine or chlorine. Preferably R4and R5are the same.

Preferably the nucleophilic substituents R6and R7each independently denotes a halogen, preferably bromine or iodine, and most preferably R6and R7every means bromine. R7may be in a para-, ortho - or meta-position, preferably in the para-position.

In one variant embodiment this is about the invention of the compound of formula II is first interacts with the metal or ORGANOMETALLIC compound with the formation of the compounds of formula IV:

where R3and R7defined above, a R8means-M or-MX, where M denotes a metal, and X is a nucleophilic Deputy, preferably halogen.

If the means a lithium metal or ORGANOMETALLIC compound means an organic compound of lithium, R8means-Li. If the metal means magnesium or ORGANOMETALLIC compound means a Grignard reagent, R8means MgX, a X preferably denotes halogen. Then the compound of formula IV interacts with the compound of the formula III to form compounds of formula V.

There is no need for separation and purification of compounds of formulas IV and V, get them in situ.

Suitable electrophilic compounds used in this way include carbon dioxide, isocyanates, NITRILES, acylhomoserine (such as phosgene), leading to the formation of, for example, compounds of formula I, where R1means carboxy group, carbarnoyl, allylcarbamate or acyl. In another embodiment, the electrophilic compound may include modified solid-phase material, for example polymer Merrifield providing direct coupling of compounds of formula VI with the solid phase. In one variant embodiment of the electrophilic compound means a compound of the formula X'-(CH2)n-R, where X' means nucleophilic replace the e l e C for example, a halogen or tosyloxy, n means an integer from 1 to 4, preferably 1, and R means of solid-phase material.

If the electrophilic compound is used carbon dioxide, the method preferably includes the interaction of the compounds of formula V with a metal or ORGANOMETALLIC compound with the formation of the compounds of formula VI, as described above, and the subsequent interaction, preferably in situ, the compounds of formula VI with carbon dioxide.

If the electrophilic compound is used carbon dioxide, preferably formed compound of the formula VII:

where R3, R4, R5and R9defined above, and

R11means-OH, -OM or-OMX, where M denotes a metal, and X nucleophilic Deputy, preferably halogen, in salt form or in free format.

In another embodiment, carboxylation stage involves reacting the compounds of formula V with carbon dioxide in the presence of a metal or ORGANOMETALLIC compound with the formation of the compounds of formula VII.

Stage hydrolysis preferably includes the interaction of the compounds of formula VII, where R11means-OM or-OMH and/or R9means-OM or-OMX, with water or acid to form compounds of formula I, where R1means carboxy is the Rupp, a R2means a hydroxy-group in salt form or free form. Suitable acids include ammonium chloride, acetic acid, sulfuric acid and hydrochloric acid. Use a buffer solution with a specific pH value. Preferably use a weak acid and/or stage is carried out at a pH from 4 to 7. The reaction temperature maintained within the range from -50 to 50°C, preferably in the range from -10 to 10°C.

In another embodiment, the compound of formula VII, where R11means-OM or-OMX, interacts with the nucleophilic agent, such as an amine or halide, with the formation of the compounds of formula I, where R1means-C(O)-NR'r R ' or-C(O)-X, a, R', R" and X are defined above.

The method according to the present invention is carried out in an inert organic solvent, preferably an ether, for example diethyl ether, tetrahydrofuran or tert-butyllithium ether. As the solvent used as the hydrocarbon. The reaction temperature in stage (a) is supported in the range from -30 to +10°C., preferably from -5 to 0°C. the Reaction is carried out, for example, from 0.5 to 2 EQ., preferably from 0.8 to 1.2 equivalents. and most preferably about 1 EQ. metal or ORGANOMETALLIC compound in the presence of 1 EQ. the compounds of formula II. Also use from 0.5 to 2 EQ., preferably from 0.8 to 1.2 aquaeductu formula III in the presence of 1 EQ. the compounds of formula II.

The temperature for the reaction of compounds of formula V with a metal or ORGANOMETALLIC compound is supported in the interval from 0 to +50°C, preferably from +20 to +30°C. the Temperature of the reaction with an electrophilic agent (e.g., CO2support in the interval from 0 to -30°C., preferably from -5 to -10°C. the Stage of hydrolysis, for example in the presence of acid, is carried out at a temperature in the range from -10 to +10°C, preferably from 0 to +5°C. Using 0.5 to 2 EQ., more preferably from 0.8 to 1.2 equivalents. metal or ORGANOMETALLIC compound in the presence of 1 EQ. the compounds of formula V.

Group R1and R2turn in the other groups R1and R2as described above, according to known methods, such as esterification, amidation or nucleophilic substitution. For example, the compound of formula I, where R2means a hydroxy-group, can be converted into a compound of formula I, where R2means halogen, when interacting with acylchlorides, such as acylchlorides.

Preferably the compound of formula I is used in a free form. Compounds in free form or salt form is obtained in the form of hydrate or solvate containing the solvent used for crystallization.

The compounds of formula I can be isolated from the reaction mixture and purify according to known methods./p>

Starting compound to obtain the compounds of formula II or III are known in the art or can be obtained according to methods known to experts in this field of technology. ORGANOMETALLIC compounds get by standard methods, for example by reaction of alkyl - or helgaleena with metal, for example with lithium or magnesium, suspended in diethyl ether or tetrahydrofuran. ORGANOMETALLIC compound preferably is received and used in inert (containing no oxygen) anhydrous atmosphere such as in nitrogen atmosphere.

The method of the present invention may include the stage of joining the compounds of formula I, where R1means reactive Deputy, to the solid-phase material. Suitable solid phase materials are described, for example, in DE 4306839 A1, and include natural or synthetic organic or inorganic polymers in standard form, for example in the form of granules or preferably in the form of a surface layer on a suitable inert substrate. Examples of suitable polymeric materials include cross-linked polystyrene, for example polystyrene granules, Gly-HMD-MA/DMA and DUMB. The compounds of formula I can be attached to solid-phase material in the interaction group contained in the solid phase, with the substituent R1. Thus, solid-phase mA is Arial preferably contains a reactive group, such as amino groups. Preferably the compound of formula I, where R1means carboxypropyl or activated carboxypropyl, for example in the presence of diisopropylcarbodiimide, interacts with the polymer containing free amino groups.

The compound of the formula I can be used as a bridge. Thus, the method according to the present invention includes a step of attaching the compounds of formula I, optionally associated with a solid-phase material with biological oligomer or polymer or Monomeric unit. The connection can be condensing with the biological molecule, for example, amino acid or polypeptide, in the interaction of groups of biological molecules, Deputy R2. For example, if R2means a hydroxy-group, and the biological molecule means a polypeptide or amino acid, the carboxyl end group of biological molecules atrificial when interacting with the hydroxy-group R2not necessarily through the initial interaction of the compounds of formula I with acylchlorides, which leads to the substitution of the hydroxy-group on halogen in situ.

In another embodiment, the present invention features:

(D) the method of obtaining the compounds of formula VIII

where R12and R13every means remove the Yu protective group, group and R12and R13are different;

moreover, the method includes the interaction of the compounds of formula IX

with suitable connection-donor R12;

(E) an intermediate compound used in the above-described method, the General formula XIV

where R16means removable protective group, except group fluorenylmethoxycarbonyl, and differs from R18;

R17means hydrogen or a blocking group is removed by hydrolysis or hydrogenation, and

R18means hydrogen or a removable protective group, with the exception of fluorenylmethoxycarbonyl.

The present invention offers a simple and effective method of obtaining compounds of formula VIII, which is used in the synthesis of peptides, for example, as described in the application WO 02/10192. The compounds of formula XIV are used as intermediates in obtaining the compounds of formula VIII.

The compound of formula IX is obtained from the compounds of formula X

where R13defined above,

R14means remove the protective group and R14differs from R12and R13and

R15means blocking group is removed under conditions of hydrolysis or hydrogenation.

Protective groups, their introduction and removal of the written, for example, in the book "Protective Groups in Organic Synthesis", T.W.Greene and others, John Willey & Sons Inc; Second Edition, 1991. Suitable donor compounds for the introduction of protective groups, for example aminosidine agents, known to experts in the art, for example anhydrides, halides, carbamates or N-hydroxysuccinimide that used for the introduction of protective groups described below.

The protective group R12preferably means fluorenylmethoxycarbonyl. R13or R16preferably means a protective group different from fluorenylmethoxycarbonyl group, and preferably is more stable in terms of hydrolysis (e.g., hydrolysis, catalyzed by bases) and/or in the conditions of hydrogenation compared to R12and/or R14for example, is more stable than fluorenylmethoxycarbonyl and/or benzyloxycarbonylamino groups. More preferably R13or R16means tert-butoxycarbonyl.

The protective group R14or R18preferable are more stable in terms of hydrolysis compared with group R12for example, more stable compared to fluorenylmethoxycarbonyl group. Group R14and R18preferably removed in the conditions of hydrogenation.

Suitable substituents R14or R18including the with benzyloxycarbonyl, 1,1-dimethylphenylcarbinol, vinyloxycarbonyl, N-hydroxyprednisolone, 9-antimetastasis and phenylenecarbonyl, allyl, nitrobenzyl, triphenylmethyl, (para-methoxyphenyl)diphenylmethyl, diphenyl-4-pyridylmethyl or benzylmethyl. Preferred R14or R18means a protective group containing oxycarbonyl, such as benzyloxycarbonyl (carbobenzoxy).

R15or R17mean:

(i) C1-C10alkyl, for example With1-C4alkyl, preferably methyl, ethyl, propyl or butyl, different from tert-butilkoi group, more preferably methyl;

(ii)3-C8cycloalkyl, optionally substituted by one or more substituents With1-C4alkyl, for example methyl. Preferred cycloalkyl means3-C6cycloalkyl;

(iii)6-C10aryl, optionally substituted by one or more stabilizing substituents, such as halogen groups, or nitro;

preferred aryl means phenyl, optionally substituted with one, two or three halogen, preferably chlorine;

(iv) (C6-C10aryl)1-3(C1-C10)alkyl, optionally substituted in the aryl group (i) one or more stabilizing substituents, such as halogen or nitro, or (ii) two substituents that VM is the extent to carbon atoms in the cycle, to which they are attached, form a 5 - or 6-membered cycle, optionally containing one or two nitrogen atom, or oxygen. (C1-C10aryl)1-3(C1-C10)alkyl preferably denotes (i) (phenyl)1-3-C1-C4alkyl, more preferably benzyl, diphenylmethyl or triphenylmethyl, optionally substituted in each benzene ring by one, two or three halogen atoms, for example chlorine, (ii) antimetal, for example, 9-antimetal, or (iii) piperonyl;

(v)6-C10aryl(C1-C4)alkoxy(C1-C4)alkyl, preferably benzyloxyethyl;

(vi)6-C10arylcarbamoyl(C1-C4)alkyl, preferably pencil.

Preferred R15or R17mean group which is removed under the conditions of hydrogenation, such as benzyl, benzoyloxymethyl, pencil, triphenylmethyl, piperonyl or 9-antimetal, preferably benzyl.

The compound of formula IX receive (i) by hydrolysis of ester compounds of the formula X with the formation of the corresponding carboxylic acid and (ii) upon removal of the protective group R14. Preferably stage hydrolysis is carried out before the removal of the protective group R14. The protective group R14remove recovery hydrogenation. This method includes the stage of hydrolysis is suitable, if the group R 15not removed in the conditions of hydrogenation. Stage hydrolysis is preferably carried out in the presence of a base as catalyst, for example in the presence of sodium hydroxide and in the presence of a polar solvent, such as methanol.

In another embodiment, the compound of formula IX is obtained by hydrogenation of compounds of formula X, where R15means the group to be deleted in the hydrogenation conditions, for example benzyl. Stage hydrogenation is carried out with the use of a suitable catalyst, for example palladium on coal.

The compound of the formula X obtained when the interaction with the compound of the formula XI

where x is the nucleophilic Deputy, a R14and R15defined above, with a compound of formula XII

where R13defined above. This stage is carried out in any suitable organic solvent, preferably in a hydrocarbon solvent, more preferably in toluene.

The compound of formula XII is a protected Ethylenediamine, in which one amino group is protected removable protective group. Nucleophilic Deputy X in the compound of formula XI means preferably halogen, such as fluorine, chlorine, bromine or iodine, more preferably chlorine. The compound of formula XI, where X means halogen, get in the interaction is soedineniya formula XIII

with acylchlorides, such as phosgene, triphosgene, phenylcarbamates or 4-nitrophenylphosphate, preferably 4-nitrophenylphosphate. This stage is carried out in the presence of organic bases, such as dimethylaminopyridine, in a nonpolar solvent such as toluene.

The compound of formula XIII is a commercial product, for example, if R15means methyl, or it is produced by esterification of 4-hydroxyproline according to methods known in the art, for example when interacting with benzyl alcohol or methanol. The obtained ester is then protect when interacting with suitable connection R14for the introduction of a protective group, for example with benzyloxycarbonyl-N-hydroxysuccinimide.

There is no need for separation and purification of the compounds of formula XI, as the compound of formula XIII interacts with acylchlorides and the reaction product then reacts with the compound of the formula XII in the same vessel.

The introduction of the protective group R12in the compound of formula IX is carried out in the presence of sodium carbonate/acetonitrile.

The compound of formula VIII is recovered from the reaction mixture and purified according to standard methods.

In the compounds of formulas VIII-XI and XIII, as described above, oxygraph in Proline may be in CIS - or the Rance-position, preferably in the TRANS-position. CIS - and TRANS-isomers receive in the form of individual compounds using as starting material the corresponding CIS - or TRANS-hydroxyproline.

Although in the literature there is no such description of the methods of obtaining raw materials, these compounds are known or can be obtained according to methods known in the art or described below in the present description.

The following object of the present invention relates to the production of the compounds of formula VIII, where R12means fluorenylmethoxycarbonyl, and R13means removable protective group, in contrast to fluorenylmethoxycarbonyl group, and the method includes the interaction of the compounds of formula VIII with a compound for introducing fluorenylmethoxycarbonyloxy groups, such as fluorenylmethoxycarbonyl-N-hydroxysuccinimide.

The present invention is described with reference to the following appropriate ways of its embodiment, in which the following abbreviations are used:

Fmoc means fluorenylmethoxycarbonyl;

BOC means tert-butoxycarbonyl;

Cbo means carbobenzoxy (benzyloxycarbonyl);

OSu means N-hydroxysuccinimide;

HPTF means the fraction of heptane;

GHUR means liquid chromatography high resolution;

p> THF means tetrahydrofuran;

TBME means tert-butyl methyl ether;

DMF means dimethylformamide.

Example 1

Getting 4-(diphenylhydrazone)benzoic acid

1,4-Dibromobenzyl (47,2 g, 0.2 M) was added to THF (240 ml). The clear solution was cooled to -65°C. for 30 min was added to the solution of utility (0.22 M, 94 ml of 20% solution in cyclohexane).

The mixture was stirred for 5 min and then for 30 min was added a solution of benzophenone (36,4 g, 0.2 M) in 180 ml of THF, the process is exothermic). The mixture was stirred for 30 min at -65°C. Then after 30 min the temperature was raised to -10°C and the solution was stirred at this temperature for 1 hour

The reaction mixture was cooled to -65°C., then for 30 min was added to the solution of utility (0.22 M, 94 ml of 20% solution in cyclohexane).

The resulting suspension was diluted with 200 ml of THF. Then through the solution for 90 min at -65°C. was passed a gaseous carbon dioxide. The temperature was raised to 20°C and the mixture was stirred over night. The mixture was cooled to 0°C and for 30 min was added an aqueous solution of ammonium chloride (120 ml 10% solution). At this stage received 4-(diphenylhydrazone)benzoic acid.

The mixture was evaporated in vacuum at 45°C. the pH Value of the residue is brought to 4 with acetic acid and the solution was mixed with 400 ml of N2O. the Extraction was performed with use is using ethyl acetate (2×150 ml). The organic phase was extracted with 100 ml of water, the combined phase was shaken with 10% aqueous potassium hydroxide solution (2×120 ml). The combined aqueous phase was brought to pH 1-2 with hydrochloric acid at 20°C and then were extracted with TBME (2×150 ml). Combined phase in TBME was mixed with 50 ml water and 50 ml of a saturated solution of Na2SO4, dried over magnesium sulfate and evaporated at 45°C in vacuum, it was obtained the crude product.

to 38.3 g of the Crude product was dissolved in TBME (300 ml) at 40°C. the Clear yellow solution was concentrated to a volume of 60 ml (240 ml TBME drove). The mixture was stirred for 1 h at 40°C (crystallization). Added 50 ml HPTF, the mixture was cooled to 0°C and stirred at 0°C for 1 h After evaporation, washing (2×15 ml) HPTF and drying overnight at 45°C in vacuum was obtained crystals white.

Attach 4-(diphenylhydrazone)benzoic acid to a solid phase

15 g of 4-(Diphenylhydrazone)benzoic acid and rate of 7.54 g of hydroxybenzotriazole were dissolved in 140 ml of DMF under stirring for 15 minutes Then added and 15.3 ml of diisopropylcarbodiimide and the solution kept at room temperature for 30 minutes the Solution was stirred over night at room temperature in the presence of aminomethylpropanol polystyrene. After washing DMF, methanol and THF is the l, containing the link, was dried in vacuum.

Example 2

Getting 4-(diphenylhydrazone)benzoic acid (alternative method)

To a 12 l TBMA carefully dried in the Hastelloy reactor with a volume of 100 l for 20 min was added 3.0 kg n-utility (20% in cyclohexane; 9,37 mole) at a temperature of -5°C. (clear solution). For 30 min at a temperature in the range from -5 to 0°C was added 2.00 kg 1,4-dibromobenzene with (8,48 mole)dissolved in 16 l TBMA. The container, which was added to the reagent, washed with 3 l TBMA.

The mixture was stirred at -5°C for 30 min, and then for 20 min at a temperature in the range from -5 to 0°C was added 1,55 kg benzophenone (8,50 mole) in 8 l TBMA. The container, which was added to the reagent, washed with 3 l TBMA. Thus was formed a small amount of solid white. After stirring for 15 min at -5°C, a sample was taken for analysis GHUR (sample 1). The reaction mixture was stirred for 25 min at -5°C and was heated to 25°C.

To the mixture for 25 minutes at a temperature in the range from +25 to +27°C was added 3.2 kg n-utility (20% in cyclohexane, 10,00 mol). Adding observed slightly exothermic reaction, the color of the mixture changed to green and formed a certain amount of sludge and foam. After stirring for 20 min, a sample was taken for analysis GHUR (sample 2). In the depending on the analysis result of the sample 2 by the method of GHWA was added 0.3 kg n-utility after stirring for 35 min at 25°C. Then after stirring for 15 min, a sample was taken for analysis GHUR (sample 3). Hoses, through which was added n-utility, washed with 1.5 l TBME and the reaction mixture was cooled to -10°C. To the mixture for 20 minutes at a temperature in the range from -10 to -5°C. portions were added 1,99 kg of dry ice (solid CO2). It was observed exothermic reaction and the formed precipitate a light yellow color. After stirring for 15 min at -10°C was added 11 l TBME and the reaction mixture was heated to 0°C. over 15 min at a temperature in the range from 0 to +5°C was added 5 l of 18% aqueous hydrochloric acid. It was observed exothermic reaction and dissolution of the precipitate (pH≤1).

A transparent solution was transferred into a separator and the reactor was washed with 5 l TBMA. After separation of the aqueous phase the organic phase is washed with 20 l of water. After separating the two layers, the organic phase was extracted with 13 l of 5% aqueous solution of KOH. The alkaline aqueous phase was separated and the organic layer was again extracted with 13 l of 5% aqueous solution of KOH. The combined alkaline aqueous layers was transferred into a Hastelloy reactor with a volume of 100 L. for 20 min at a temperature in the range from 0 to 5°C was added 22 l TBMA and 6 l 18% aqueous hydrochloric acid. It was observed exothermic reaction and the formation of a white precipitate, which races varelse at low pH (pH≤1 after addition of HCl). The mixture was stirred for 10 min and transferred into the separator. The layers were separated and the aqueous phase was extracted with 16 l TBMA. After separation of layers, the combined organic phases were concentrated at a pressure of 500 mbar, the temperature in the bath 45°C to a volume of 4.5 liters (32 l TBMA drove) and added crystals for starters. The temperature was raised to 50°C. and under vigorous stirring was slowly added to 20 l HPTF. The precipitated white was stirred for 2 hours at a temperature in the bath of 50°C. the Temperature in the bath was lowered to 0°C and stirring was continued overnight (16 h), the temperature of the suspension was maintained at 0°C. the white Suspension was filtered and the reactor was washed 5 times with 5 l of stock solution. The precipitate was dried at a temperature in the bath 45°C in vacuum (≥10 mbar) until a constant weight (during the night).

Example 3

Obtaining Fmoc-(2S,4R)-Pro(4-OCO-NH-CH2-CH2-NH-Boc)-OH from Cbo-(2S,4R)-Pro(4-OH)-OMe

1. Dimethylaminopyridine (30.5 g, 250 mmol) and Cbo-(2S,4R)-Pro(4-OH)-OMe (34,9 g, 125 mmol) was dissolved in toluene (870 ml). To the resulting solution at a temperature of from 0 to 5°C for 20 min was added dropwise a solution of 4-nitrophenylphosphate (31,5 g, 157 mmol) in toluene (206 ml) and was stirred for 2 h Then the solution was added BOC-Ethylenediamine (80,1 g, 500 mmol) in toluene (205 ml) and stirred at ambient temperature for 12 hours To the mixture at a temperature of 20 is about 25°C. the solution was added concentrated sulfuric acid (43,7 g, 450 mmol) in water (873 ml). The white suspension was filtered under vacuum and washed with toluene (30 ml). Phase in toluene was washed with water (450 ml), sodium carbonate (10 wt./wt.%, 450 ml) and three times with water (450 ml). Phase in toluene were dried at distillation of the azeotropic mixture (300 ml), which was replaced with dry toluene (2×300 ml). To a solution of dry toluene at 50°C was added heptane (130 ml) and cooled to 0°C for 2 hours the precipitate was filtered, washed twice with toluene/heptane (1:2 V/V, 70 ml) and dried at 50°C in vacuum, given Cbo-(2S,4R)-Pro(4-OCO-NH-CH2-CH2-NH-Boc)-OMe in the form of a solid white color.

2. Cbo-(2S,4R)-Pro(4-OCO-NH-CH2-CH2-NH-Boc)-OMe (20,0 g, 43,0 mmole) was dissolved in a mixture of tetrahydrofuran and methanol (1:1, 380 ml). To the solution was added 1M sodium hydroxide solution (51,6 ml) and the resulting mixture was stirred for 4 h at ambient temperature. The pH value of the mixture was brought to 3 by the addition of sulfuric acid (50 ml, 1M). Tetrahydrofuran and methanol kept at 50°C and 50 mbar until the termination of the distillation of solvents. The resulting milky white solution was diluted with isopropylacetate (113 ml) and water (57 ml), the phases were separated and the phase in isopropylacetate washed with sodium chloride solution (10%, 113 ml). The solvent drove (50°C, 50 mbar), received Cbo-(2S,4R)-Pro(4-OCO-NH-CH2-CH2-NH-Boc)-OH (19,8 g) in the form of foam, which used the Ali in the next stage without additional purification.

3. Palladium on coal (10%, 1,94 g 0,042 mmole) was added to a solution of Cbo-(2S,4R)-Pro(4-OCO-NH-CH2-CH2-NH-Boc)-OH (19,4 g, 43,0 mmole) in isopropanol (350 ml) and water (37 ml). After the resulting mixture was passed hydrogen gas for 4 h, the catalyst was filtered and the residue was washed with a mixture of isopropanol (50 ml) and water (50 ml). Phase in a mixture of isopropanol and water was dried distillation azeotrope mixture to reduce by 2/3, which is continuously replaced with a mixture of toluene and isopropanol (1:1 V/V). The obtained anhydrous solution was concentrated in vacuum to dryness (50°C., 200 mbar), was obtained (2S,4R)-Pro(4-OCO-NH-CH2-CH2-NH-Boc)-IT is in the form of a solid substance of a brownish color, which is used in the next stage without additional purification.

4. (2S,4R)-Pro(4-OCO-NH-CH2-CH2-NH-Boc)-OH (5.0 g, 15 mmol) was dissolved in a mixture of water (25 ml) and triethylamine (1.5 g, 15 mmol) at 40°C. To the clear solution was added a solution of Fmoc-OSu (4,65 g, 14 mmol) in acetonitrile (25 ml) for 30 min and was stirred for 2 hours and Then the pH of the mixture was brought to 3 using hydrochloric acid (1 M, 13 ml) and was stirred for 1 h Acetonitrile drove (40°C, 80 mbar) and replaced isopropylacetate, received a two-phase mixture. The lower aqueous phase was separated and the organic phase is washed with water, twice distilled and replaced with isopropylate the t and concentrated until foamy brownish color. The resulting foam was dissolved in izopropilazette (25 ml) and was added dropwise to heptane (200 ml), it was obtained a residue. The solid was filtered, washed with isopropylacetate/heptane and dried in vacuum at 40°C, were obtained Fmoc-(2S,4R)-Pro(4-OCO-NH-CH2-CH2-NH-Boc)-OH.

Example 4

Obtaining Fmoc-(2S,4R)-Pro(4-OCO-NH-CH2-CH2-NH-Boc)-OH from Cbo-(2S,4R)-Pro(4-OH)-OBzl

Synthesis of Cbo-(2S,4R)-Pro(4-OH)-OBzl described in T.Makoto, H.Guoxia, V.J.Hruby, J.Org.Chem., 66, 1038-1042 (2001). Used the method of synthesis described in example 3, but instead of Cbo-(2S,4R)-Pro(4-OH)-OMe was used Cbo-(2S,4R)-Pro(4-OH)-OBzl and performed only stages 1, 3 and 4 (excluding stage 2).

Example 5

Obtaining Fmoc-(2R,R)-Pro(4-OCO-NH-CH2-CH2-NH-Boc)-OH

Used the method of synthesis described in example 3 or 4, but instead of Cbo-(2S,4R)-Pro(4-OH)-OMe or Cbo-(2S,4R)-Pro(4-OH)-OBzl used Cbo-(2R,4R)-Pro(4-OH)-OMe or Cbo-(2R,4R)-Pro(4-OH)-OBzl.

Example 6

Obtaining Fmoc-(2S,4S)-Pro(4-OCO-NH-CH2-CH2-NH-Boc)-OH

Used the method of synthesis described in example 3 or 4, but instead of Cbo-(2S,4R)-Pro(4-OH)-OMe or Cbo-(2S,4R)-Pro(4-OH)-OBzl used Cbo-(2S,4S)-Pro(4-OH)-OMe or Cbo-(2S,4S)-Pro(4-OH)-OBzl.

1. The method of obtaining the compounds of formula VIII

where R12and R13every means removable protective group, the protective group R12is more resistant to removal by hydrolysis or hydrogenation than R13;
including wsimages is of the compounds of formula IX

with suitable connection - donor R12selected from anhydrides, halides, carbamates and N-hydroxysuccinimide.

2. The method according to claim 1, where the compound of formula IX is obtained by:
(i) hydrolysis of compounds of formula X

where R13defined in claim 1,
R14means removable protective group selected from the group comprising benzyloxycarbonyl, 1,1-dimethylphenylcarbinol, vinyloxycarbonyl, N-hydroxyprednisolone, 9-antimetastasis, phenylenecarbonyl, allyl, nitrobenzyl, triphenylmethyl, para-methoxyphenyl, diphenylmethyl, diphenyl-4-pyridylmethyl and benzylmethyl, and
R15means blocking group is removed under conditions of hydrolysis or hydrogenation, selected from C1-C10of alkyl; C3-C8cycloalkyl, optionally substituted by one or more1-C4by alkyl; C6-C10aryl, optionally substituted by one or more halogen or nitro; and (C6-C10aryl)1-3(C1-C10)alkyl, optionally substituted in the aryl group (i) one or more halogen or nitro, or (ii) two substituents that, together with the carbon atoms in the cycle to which they are attached, form a 5 - or 6-membered cycle, optionally containing one or two nitrogen atom or CI is the oxygen; With6-C10aryl(C1-C4)alkoxy(C1-C4)alkyl and C6-C10arylcarbamoyl(C1-C4)alkyl;
where the hydrolysis or hydrogenation are hydrolysis, catalyzed by bases, which can be carried out in a polar solvent, to obtain the corresponding carboxylic acid, and
(ii) removing the protective group R14by reductive hydrogenation in the resulting carboxylic acid.

3. The method of obtaining the compounds of formula VIII according to claim 1, where R12means fluorenylmethoxycarbonyl, a R13means removable protective group, other than fluorenylmethoxycarbonyl, including interaction of the compounds of formula IX with a compound-donor group fluorenylmethoxycarbonyl.

4. The compound of formula XIV

where R16means tert-butoxycarbonyl;
R17means hydrogen or a blocking group is removed by hydrolysis or hydrogenation, selected from C1-C10of alkyl; C3-C8cycloalkyl, optionally substituted by one or more1-C4by alkyl; C6-C10aryl; and (C6-C10aryl)1-3(C1-C10)alkyl;
R18means hydrogen or a removable protective group, representing benzyloxycarbonyl.



 

Same patents:

FIELD: chemistry; medicine.

SUBSTANCE: invention relates to derivatives of 2-hydroxytetrahydrofurane , of general formula (I) , which possess ability to inhibit calpaines and/or ability to catch active oxygen forms and can be used to obtain medication, intended for inhibiting calpaines and/or lipid peroxidation.

EFFECT: medications possess higher efficiency.

9 cl, 64 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: present invention refers to bioactive compounds of formula (Ic) , pharmaceutical compositions and application at cancer treatment, where R2-R7, X2, R, Q, G, J, L and M represent values estimated in invention formula and description.

EFFECT: production of compounds which can be used for anticancer medical product.

55 cl, 19 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to compounds of general formula: , wherein R1 represents phenyl-С16-alkyl group or 1-naphthyl-С16-alkyl group; R2 biologically labile ether forming group in the form of pharmaceutically acceptable metal salt, which is selected from lithium, calcium, magnesium, and zinc slats; and also to a method for preparing above-defined compounds and to pharmaceutical composition containing salts according to this invention. These compounds are used in treatment cardiac diseases or hypertension, in improvement of gastrointestinal blood circulation, and in treatment and prevention of cardiac disturbances induced by adriamicyn and analogous antitumor agents.

EFFECT: increased assortment of pharmaceutically active compounds of benzazepin series.

15 cl, 2 tbl, 5 ex

Peptide compounds // 2281955

FIELD: chemistry of peptides, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I): wherein R1 represents benzofuranyl substituted with halogen atom or styryl substituted with halogen atom; R2 represents substituted hydroxyl substituted with mercapto-group or substituted sulfonyl, or its pharmaceutically acceptable salts. Compound of the formula (I) and its pharmaceutically acceptable salts possess the strong inhibitory effect on production of nitrogen oxide (NO) and can be useful in prophylaxis and/or treatment of NO-mediated diseases in humans and animals.

EFFECT: valuable medicinal and biochemical properties of compounds.

The invention relates to a group of compounds of General formula (I) high degree of purification

The invention relates to a derivative of D-Proline General formula

< / BR>
or

< / BR>
where R is SH, benzyl or phenyl, optionally substituted by a hydroxy-group or a lower alkoxygroup, or a group of the formula

< / BR>
R1is hydrogen or halogen; X represents -(CH2)n-; -CH(R2)(CH2)n-; -CH2O(CH2)n-; CH2NH-; benzyl, -C(R2)=CH-; CH2CH (OH)- or thiazol-2,5-diyl; Y represents-S -; (CH2)n; -O-; -NH-; -N (R2)-; -CH=CH-; -NHC(O)NH-; -N(R2)C(O)N(R2)-; -N[CH2WITH6H3(OCH3)2]-; -N(CH2WITH6H5)-; -N(CH2WITH6H5)C(O)N(CH2WITH6H5)-; -N(alkoxyalkyl)-; -N(cyclooctylmethyl)-; 2,6-pyridyl; 2,5-furanyl; 2,5-thienyl; 1,2-cyclohexyl; 1,3-cyclohexyl; 1,4-cyclohexyl; 1,2-naphthyl; 1,4-naphthyl; 1,5-naphthyl; 1,6-naphthyl or diphenylene; 1,2-phenylene; 1,3-phenylene or 1,4-phenylene, where phenylenebis group optionally substituted by 1-4 substituents selected from the group comprising halogen, lower alkyl, lower alkoxygroup, the hydroxy-group, carboxypropyl, -COO-lower thiazolyl, 2-oxo[1,2,3,5] oxadiazolyl, 5-thioxo[1,2,4]oxadiazolyl and 5-tert-butylsulfonyl[1,2,4] oxadiazolyl; X' represents -(CH2)n-; (CH2)nCH(R2)-; -(CH2)nOCH2-; -NHCH2-; benzyl, -CH= C(R2)-; -CH(OH)CH2or thiazol-2,5-diyl; R2denotes lower alkyl, lower alkoxygroup or benzyl and n = 0-3, their pharmaceutically acceptable salts, mono - and diesters, except (R)-1-[(R)- and (R)-1-[(S)-3-mercapto-2-methylpropionyl] pyrrolidin-2-carboxylic acid; medicinal product with amyloidoses activity, and the method of obtaining these derivatives

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

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I: where A,Y,R and R2 assume values given in the description. The invention also relates to methods of producing compounds of formula I and their intermediate compounds, pharmaceutical compositions and methods of using the compounds and their pharmaceutical compositions for inhibiting caspase.

EFFECT: novel compounds have useful biological properties.

44 cl, 5 tbl, 66 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolidine-3,4-dicarboxamide derivatives of formula (I): , where: X is N or C-R6; R1 is C1-7alkyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-7alkyl, fluoro-C1-7alkyl, hydroxy-C1-7alkyl, CN-C1-7alkyl, R10C(O), R10OC(O)-, N(R11,R12)C(O)-; R10OC(O)C1-7alkyl, N(R11,R12)C(O)-C1-7alkyl, R10SO2, R10-SO2-C1-7alkyl, N(R11, R12)-SO2, N(R11,R12)-SO2-C1-7alkyl, aryl-C1-7alkyl, 5-member monocyclic heteroaryl containing a nitrogen atom, where the ring carbon atom can be substituted with a carbonyl group, heteroaryl-C1-7alkyl, where the term "heteroaryl" represents an aromatic -member monocyclic ring with 1 S atom or a 6-member monocyclic ring with 1 N atom, C1-7alkoxy-C1-7alkyl, C1-7alkoxycarbonyl-C3-10cycloalkyl-C1-7alkyl or halogen substituted 4-member heterocyclyl-C1-7alkyl with one O atom; R2 is H, C1-7alkyl; R3 is aryl, aryl-C1-7alkyl, heteroaryl, heteroaryl-C1-7alkyl, where the term "heteroaryl" represents a 5-member monocyclic ring with 1 S atom, a 6-member monocyclic ring with 1 or 2 N atoms, 9-, 10-member bicyclic system with 1 or 2 N atoms in one ring; R4 is H, C1-7alkyl, OH; R5, R6, R7, R8 are independently selected from a group consisting of H, halogen, C1-7alkyl, C1-7alkoxy, flouro-C1-7alkyl, fluoro-C1-7alkyloxy; R9 is aryl, heterocyclyl, heteroaryl, heterocyclyl-C(O)-; R10 is H, C1-7alkyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-7alkyl, fluro-C1-7alkyl, heteroaryl, heteroaryl-C1-7alkyl, where the term "heteroaryl" represents a 5-member monocyclic ring with 4 N atoms, a 5-member heterocyclyl with 1 N atom; R11, R12 are independently selected from a group consisting of H, C1-7alkyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-7 alkyl; and pharmaceutically acceptable salts thereof; where the term "aryl" represents a phenyl group which can be optionally substituted with 1 to 5 substitutes which are independently selected from a group consisting of the following: halogen, CF3, NH2, C1-7alkylsulphonyl, C1-7alkoxy, fluoro-C1-7alkyl, fluoro-C1-7 alkoxy; the term "heterocyclyl" represents a nonaromatic monocyclic 5-, 6-member heterocyclic group with 1, 2 N atoms, or with 1 N atom and 1 O atom, where the heterocyclyl group can be substituted as indicated with respect to the term "aryl", and one carbon atom of the ring system of the heterocyclyl group can be substituted with a carbonyl group; the term "heteraryl" represents an aromatic 5- or 6-member monocyclic ring system which can have 1, 2, 3 N atoms, or 1 N atom and 1 S atom, where the heteroaryl group can be substituted as indicated with respect to the term "aryl", and one carbon atom of the ring system of the heteroaryl group can be substituted with a carbonyl group. Formula I compounds have inhibitory activity towards coagulation factor Xa.

EFFECT: possibility of using said compounds in a pharmaceutical composition and for preparing a medicinal agent.

27 cl, 90 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a method of producing compounds of formula (I) , with ACE inhibitory activity, and to pharmaceutically acceptable salts thereof, in which the carboxyl group of an amino acid of formula (II) is activated with a uronium salt of formula (III) in the presence of an aprotonic solvent, and the activated amino acid is reacted with a corresponding amine from the HR3 family. Substitutes R1-R3, R6-R9, B are given in the formula of invention.

EFFECT: end product with high output and high purity.

17 cl, 1 ex, 1 dwg

FIELD: medicine.

SUBSTANCE: there are described 2-(R)-phenylpropionic acid derivatives of formula (1) and their pharmaceutically acceptable salts where R' is chosen from H, OH and provided R' represents H, R is chosen from H, C1-C5-alkyl, C3-C6-cycloalkyl, C1-C3-alkoxy, thiazolyl, substituted CF3, the remained formula -CH2-CH2-Z-(CH2- CH2O)nR', where n is equal to 2, and Z represents oxygen, the remained formula - (CH2)n-NRaRb, the remained formula SO2Rd, provided R' represents OH, R is chosen from C1-C5alkyl. The compounds are applied to inhibit chemotactic activation of neutrophils (PMN leukocytes) induced by interaction of interleukine-8 (IL-8) and membrane receptors CXCR1 and CXCR2. The compounds are applied to prevent and treat the pathologies generated by specified activation. There are also described application of the compounds for manufacturing of medicinal agents for treating psoriasis, nonspecific ulcerative colitis, melanoma, angiogenesis, chronic obstructive pulmonary disease (COPD), bullous pemphigoid, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and to prevent and treat the damages caused by ischemia and reperfusion, the pharmaceutical composition and method for making the compounds of formula (1) where R' represents H and R - group SO2Rd.

EFFECT: higher clinical effectiveness.

8 cl, 3 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I), their R and S isomers; or a mixture of R and S isomers; or pharmaceutically acceptable salts. Disclosed compounds can be used as a medicinal agent with agonist properties towards PPAR. In formula (I) and L represents (II) or (III); R1, R2, R3, Ya, R4a, R", Yb, R4b are hydrogen; R and R' are independently hydrogen, C1-C4alkoxy; n equals 0, 1 or 2; m equals 0, 1 or 2; X1 is a -Z-(CH2)P-Q-W group; X2 is -CH2-, -C(CH3)2-, -O- or -S-.

EFFECT: invention relates to a pharmaceutical composition, which contains the disclosed compound, to use of the pharmaceutical composition as a medicinal agent, to use of the disclosed compound in making the pharmaceutical composition.

13 cl, 35 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to method of producing compounds of formula VII: and intermediate compounds for producing said compounds. Values of Y, R1, R2, R3, R4, R5, X, n are given in paragraph 1 of the formula.

EFFECT: increased efficiency of the method of producing said compounds.

24 cl, 2 dwg, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of obtaining N-(N'-substituted glycyl)-2-cyanopyrrolidine with formulae IA and IB; (IA) or (IG), where R' is hydroxyl, C1-7alkoxy group, C1-8alkanoyloxy group or R"'R""N-C(O)O-, where R"' and R"" are independently C1-7alkyl or phenyl, which is not substituted or substituted with a substitute, chosen from C1-7alkyl, C1-7alkoxy group, halogen and trifluoromethyl, and where R'" additionally represents hydrogen; or R' and R" are independently C1-7-alkyl; in form of a free base or acid addition salt, involving (a) reaction of formula (V) compound, where X1 and X3 independently represent a halogen; X2 is a halogen, OH, O-C(=O)-CH2X3, -O-SO2-(C1-8)alkyl or -O-SO2-(aryl), with L- prolineamide in the presence of dimethylformamide, subsequent reaction (b) of the obtained compound with halogen (halogenalkylene)dialkylammonium as a dehydrating agent, without extraction of the obtained compound, subsequent reaction (c) of the obtained compound with the corresponding amine with formula (VI), without extraction of the obtained compound, in the presence of a base H2NR (VI), where R is substituted adamantyl, described above, and (d) extraction of the obtained compound in form of a free base or acid addition salt.

EFFECT: method allows for obtaining desired product without extraction of toxic intermediate compounds.

3 cl, 2 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

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: 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: 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: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel 1,2,3-tris-{[aminopoly(ethyleneamino)ethylammonio]-methylcarbonyloxypoly(alkyleneoxy)]}propane trichlorides of the formula:

wherein at a + c + e (the general degree of oxypropylation) = 49; b + d + f (the general degree of ethylation) = 0, n = 1-6; at a + c + e = 55, b + d + f = 0, n = 1-6; at a + c + e = 49, b + d + f = 9, n = 1-6; at a + c + e = 10, b + d + f = 10, n = 1-6; at a + c + e = 66, b + d + f = 15, n = 1-6; at a + c + e = 76, b + d + f = 18, n = 1-6, and to a method for their synthesis. Method involves interaction of 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 catalysts, in boiling organic solvent medium, azeotropic removing water formed and the following treatment at heating the synthesized reaction product with polyethylenepolyamines of the formula: H2N(CH2CH2NH)nCH2CH2NH2 wherein n = 1-6, and in the following mole ratios of reagents - hydroxyl derivatives of propane : monochloroacetic acid : polyethylenepolyamines = 1:(3.0-3.2):(3.0-3.2), respectively. New compounds possess the fungicide activity, properties of emulsifiers of cationic bitumen emulsions, capacity to enhance adhesion of bitumen to mineral materials.

EFFECT: improved preparing method, valuable properties of compounds.

6 cl, 3 tbl, 6 ex

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