Inhibitors of dipeptidyl-peptidase iv

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

 

The present invention relates to a series of new compounds, which are inhibitors of the enzyme dipeptidylpeptidase IV, to pharmaceutical compositions comprising these inhibitors and to the use of such compositions in the treatment of human diseases.

Background of invention

The enzyme dipeptidyl peptidase IV, commonly referred to in the present description as DP-IV (and the DAP-IV or DPP-IV), also known by the nomenclature of enzymes as AS, is a serine protease that it N-terminal dipeptide from peptides that begin a sequence of N-XAA-Pro (where XAA represents any amino acid, although preferably lipophilic, and Pro denotes Proline). He also uses as a substrate peptides that begin with the sequence H-Xaa-Ala (where Ala denotes alanine). DP-IV was first identified as associated with a membrane enzyme. Was later identified a soluble form.

First, the interest of researchers to DP-IV was associated with the elucidation of its role in the activation of T lymphocytes. DP-IV is identical to the T cell protein CD26. It has been suggested that inhibitors of DP-IV is able to modulate T-cell immune response and thus they can develop new immunomodulators. It was also assumed that CD26 is necessary to further the th receptor for HIV, and in this regard, inhibitors of DP-IV can be useful in the treatment of AIDS.

Also emphasis was placed on examining the role of DP-IV outside the immune system. It is known that DP-IV plays a key role in the degradation of several peptide hormones, including the hormone-releasing factor, growth hormone (RFRG) (GHRH) and glucagon-like peptide-1 and peptide-2 (GLP-1 and GLP-2). Since it is known that GLP-1 exerts potentiate the effect on the action of insulin in regulating glucose levels in the blood after a meal, it is clear that the inhibitors of DP-IV can also be used in the treatment of type II diabetes and impaired glucose tolerance. Currently, at least two inhibitor of DP-IV clinical trials conducted with the purpose of study of this possibility.

Several groups of researchers have been disclosed inhibitors of DP-IV. However, at that time, as some of them were discovered by random screening programs, most of the work in this area was focused on the study of substrate analogues. Inhibitors of DP-IV, which are substrate analogs, are disclosed, for example, in documents US 5462928, US 5543396, WO 95/15309 (equivalent to US 5939560 and EP 0731789), WO 98/19998 (equivalent to US 6011155), WO 99/46272 and WO 99/61431. The most powerful inhibitors belong to AMINOETHYLPIPERAZINE acids, but they are unstable and prone to cyclization, whereas the more stable p is religioue and thiazolidinone derivatives are less affinity to the enzyme, and therefore, their clinical use will require large doses. It seems that pyrrolidinyl represent a good compromise, because they have high affinity to the enzyme, and a moderately long half-period of existence of the solution in the form of free base. However, there remains a need for good inhibitors of DP-IV with improved properties.

Brief description of the invention

The present invention relates to a series of inhibitors of DP-IV with improved affinity to the enzyme. Connections may be used in the treatment of many human diseases, including impaired glucose tolerance and type II diabetes. Accordingly, the invention also relates to the use of these compounds in obtaining pharmaceutical compositions, to the compositions and to the use of such compositions in the treatment of people. Compounds according to the present invention described General formula 1.

In General formula 1, X1selected from-S-, -O-, -SO-, -SO2- and-CH2-; X2selected from-Oh, -S-, -NH - and-CH2-; X3denotes the or-NR5-or >C=O or >C=S group; R1denotes either N or CN; R2and R3chosen independently from H and lower alkyl, or together they may represent -(CH2)p-; R4oznachaet R 4Awhen X3refers to-NR5-, and R4Bwhen X3represents >C=O or >C=S; R4Aselected from R6R7NC(=O)R6R7NC(=S), R8(CH2)qC(=O)R8(CH2)qC(=S), R8(CH2)qSO2, R8(CH2)qOC(=S) and R8(CH2)qOC(=O); R4Bmeans R6R7N; R5denotes H or lower alkyl; R6and R7denote each, independently of R8(CH2)qor together form -(CH2)2-Z-(CH2)2-; R8selected from H, alkyl, optionally substituted aryl, optionally substituted of Arola, optionally substituted arylsulfonyl and optionally substituted heteroaryl; Z is chosen from a covalent bond, -(CH2)r-, -O-, -SOt- , and-N((CH2)qR8)-; n is 0-4; p denotes 2-5; q represents 0 to 3; r represents 1 or 2; and t denotes 0-2.

Detailed description of the invention

In the first aspect of the present invention relates to a series of new compounds, which are inhibitors of the enzyme DP-IV and which are useful in the treatment of some human diseases. Compounds are described General formula 1:

In the General formula 1 X1denotes a divalent group selected from a sulfur atom (-S-), oxygen atom (-O-), su is thinley group (-SO-), sulfonyloxy group (-SO2-) and methylene group (-CH2-). X2denotes a divalent group selected from oxygen atom (-O-), sulfur atom (-S-) and methylene group (-CH2-). X3indicates either replaced aminogroup (-NR5-)or a carbonyl (>C=O) or thiocarbonyl group (>C=S).

R1denotes either a hydrogen atom (H)or a nitrile group (-CN).

R2and R3can independently from each other represent a hydrogen atom (H) or a lower alkyl group, or together they can make a chain of two to five methylene units -(CH2)p-where R takes values in the range from 2 to 5, forming together with the carbon atom to which they are attached, three-, four-, five - or six-membered ring. The parameter m can be 1, 2 or 3. In the case when m is greater than 1, each of the links of CR2R3may be the same or they may vary. For example, in the case when m equals 2, then (CR2R3)2can represent CH2CH2CH2C(Me)2With(Me)2CH2and other

The nature of R4depends on the value of parameter X3while the two groups are connected by an amide (CO-N), thioamides (CS-N) or sulfonamidnuyu (SO2-N) bond. So, in the case when X3denotes substituted aminogroup (-NR5-), R4 means R4Awhere R4Achoose from carbamoyl groups (R6R7NC(=O)), thiocarbamoyl groups (R6R7NC(=S), optionally modified with acyl groups (R8(CH2)qC(=O)), optional modified tjalling groups (R8(CH2)qC(=S), sulfanilic groups (R8(CH2)qSO2), optionally modified (alkyl or aryloxy)carbonyl groups (R8(CH2)qOC(=O)) and need not be modified (alkyl or aryloxy)thiocarbonyl groups (R8(CH2)qOC(=S)). In the context of the present description, the term "optionally modified" is used to indicate that some of the options R8beyond the definitions of the terms "alkyl", "acyl" and "aryl". The scope of R4Asets the scope of R8. Alternatively, in the case when X3denotes a carbonyl (>C=O) or thiocarbonyl (>C=S) group, R4is an R4Bwhere R4Bdenotes a substituted an amino group (R6R7N).

R5denotes a hydrogen atom (H) or a lower alkyl group. Preferably R5denotes N.

R6and R7can each, independently of one another, represent R8(CH2)q. Alternatively, they may together affect Iwate group (CH2)2-Z1-(CH2)2- or-CHR9-Z1-CH2-CR10-. In this case, Z1denotes a covalent bond, methylene or ethylidene group (-(CH2)r-where r has a value of 1 or 2), oxygen atom (-O-), sulfur atom or exelency a sulfur atom (-SOt-where t has a value of zero, 1 or 2) or replaced by aminogroup (-N((CH2)qR8)-), so that the group NR6R7is a pyrolidine, piperidine, peligrosamente, morpholino, not necessarily oxidized thiomorpholine or substituted pieperazinove ring. Z2indicates ortho-fenelonov group (-C6H4-), so that the group NR6R7represents tetrahydroisoquinoline.

R8selected from a hydrogen atom (H), lower alkyl groups, lower cycloalkyl group condensed with benzene ring (such as indayla group), acyl (lower alkyl) group, a di(lower alkyl)amino, di(lower alkyl)carbamoyl group, N-(lower alkyl)piperidinyl group, optionally substituted α-alkylbenzenes group, optionally substituted phenyl, naftilos or heteroaryl group and optionally substituted arolina (aryl-CO) or arylsulfonyl (aryl-SO2) group. In the above text matching is not necessary what's the substituents include lower alkyl, aryl, which may be further substituted by one or more methyl or triptoreline groups, hydroxy, lower alkyloxy, lower alkylsulfonyl, acyl, perforating, amino, lower alkylamino, di(lower alkyl)amino, aminoalkylindole, fluorine-, chlorine-, bromine-, triptorelin, nitro, cyano, carbamoyl, carboxy and lower allyloxycarbonyl group. In addition, two adjacent substituent can be connected with the formation of rings, condensed with parental aryl or heteroaryl ring.

R9and R10independently selected from hydrogen, carbamoyl, hydroxymethylene and cyanomethylene groups.

The parameter n denotes an integer and is selected from a range of values from zero to 4, and q is selected from a range of values from zero to 3.

Some compounds are intentionally excluded from the scope of the present invention. So, in the case when X2denotes methylene, X3denotes NH and R4means R8(CH2)qO(CO), when q=1, R8may not represent unsubstituted phenyl or phenyl substituted by a nitro-group. In General, it is preferable that, when X2denotes methylene, X3denotes NH and R4means R8(CH2)qAbout(FROM) when q=1 and R8denotes a substituted phenyl group, Deputy or substitute who must be selected from chlorine, methoxy and cryptomerias groups.

In the context of the present description, the term "lower alkyl", by itself or in such combinations as lower alkyloxy includes linear, branched and cyclic saturated hydrocarbon group with the number of carbon atoms of from one to six. Examples of lower alkyl groups include, but are not limited to the above list, methyl, ethyl, isopropyl, tert-butyl, neopentyl, cyclohexyl, cyclopentylmethyl, 2-(cyclopropyl)ethyl, 3,3-dimethylcyclobutyl and bicyclo[3.1.0]hexyl.

The term "heteroaryl" includes monocyclic five - and six-membered ring aromatic group with one or two heteroatoms, which are selected from nitrogen, oxygen and sulfur. So, heteroaryl groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolin, oxazolyl and isoxazolyl. Heteroaryl also includes derivatives of these rings condensed with benzene, such as chinoline, ethenolysis, honokalani, hintline, phthalazine, cinnoline, indolyl, isoindolyl, benzothiazolyl and others, as well as bicyclic group formed by condensation of two such monocyclic heteroaromatic groups.

The term "aryl" includes phenyl, naphthyl and heteroaryl.

Compounds of General formula 1 contain at least one stereogenic price is p, so that they can exhibit optical isomerism. All such isomers, including enantiomers, the diastereomers and epimer, the scope of the present invention. In addition, the invention includes such compounds as individual isomers and mixtures thereof, including racemates. Some compounds of General formula 1, including those containing heteroaryl group with a hydroxy or amino Deputy, may exist as tautomers. These tautomers, either individually or as mixtures, are also included in the scope of the present invention.

Compounds of General formula 1 contain at least one basic functional group. In this regard, they can form an additive salts of acids. The additive acid salts formed with pharmaceutically acceptable acids, are included in the scope of the present invention. Examples of acceptable acids include acetic acid, triperoxonane acid, citric acid, fumaric acid, benzoic acid, Paveway acid, methanesulfonate acid, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, etc.

Some compounds of General formula 1 contain an acid group and is able, therefore, to form salts with bases. Examples of such salts include salts of sodium, potassium and calcium, which are formed by reaction of the acid with sootvetstvujushchijemu, oxide, carbonate or bicarbonate of a metal. Similarly, tetraalkylammonium salt can be formed by reaction of the acid with of tetraalkylammonium hydroxide. Primary, secondary and tertiary amines, such as triethylamine, can form an additive salts with an acid. A special case is the formation of inner salt additive in the reaction between the acid group and the group of the primary amine within the same molecule, also known as zwitterions. All such salts, in the case of pharmaceutical acceptability, are included in the scope of the present invention.

In a preferred embodiment of the present invention R1denotes a nitrile group. In the case of this variant, it is preferable that the stereochemistry of the nitrile group corresponded to the one shown to the General formula 2:

In accordance with standard terminology, we have S configuration, when X1denotes methylene, and R configuration, when X1represents sulfur, oxygen, sulfinil or sulfonyl.

In another preferred embodiment, the stereochemistry at the center, adjacent to the primary amine, is represented the General formula 3. Thus, there is a S-configuration when X2denotes an oxygen atom or a methylene and the and aminogroup, and R configuration, when X2denotes a sulfur atom.

Within this variant of the invention, R1should, preferably, to provide a nitrile group, and more preferably, it should have the absolute configuration depicted General formula 4.

In another preferred variant of the invention, m is 1. More preferably, m is 1 and R2and R3represent independently hydrogen atoms or methyl groups. In the case when X2denotes a methylene group, more preferably, R2and R3were both hydrogens. In the case when X2denotes an oxygen atom, more preferably, one of R2and R3was hydrogen and the other methyl group. In the case when X2denotes a sulfur atom, more preferably R2and R3both were metal gruppami.

In another preferred embodiment of the invention X1stands for either S or methylene. More preferably, X1denotes S and R1denotes H, or X1denotes methylene, and R1denotes CN.

In yet another preferred embodiment of the invention X3denotes NH. More prepact the tion, X3denotes NH, m is 1, R2and R3both denote H, X2denotes methylene, and n is 1 or 2.

In yet another preferred embodiment of the invention R4means R8NHCO or R8CO and R8denotes optionally substituted heteroaryl group. More preferably, R8denotes unsubstituted heteroaryl group or a heteroaryl group, substituted by one or two groups selected from lower alkyl, lower alkyloxy, fluorine, chlorine and triptorelin groups.

In another preferred embodiment of the invention X3means WITH and R4means R8NH. More preferably, R8denotes optionally substituted heteroaryl group. Even more preferably, R8denotes unsubstituted heteroaryl group or a heteroaryl group, substituted by one or two groups selected from lower alkyl, lower alkyloxy, fluorine, chlorine and triptorelin groups.

In another preferred embodiment of the invention X3denotes NH and R4selected from R6R7N(CO), R8(CH2)qCO and R8(CH2)qSO2.

Particularly preferred compounds according to the present invention include:

(2S)-1-[Nω(pyrazinyl-2-bonil)-L-ornithine]pyrrolidin-2-carbonitrile,

(2S)-1-[Nω(pyrazinyl-2-carbonyl)-L-leinil]pyrrolidin-2-carbonitrile,

(2S)-1-[(2',3)-2'-amino-4'-(pyrazinyl-2"-carbylamine)butanoyl]pyrrolidin-2-carbonitrile,

(4R)-3-[Nω(pyrazinyl-2-carbonyl)-L-leinil]thiazolidin-4-carbonitrile,

(2S)-1-[Nω-(pyridyl-3-methyl)-L-glutaminyl]pyrrolidin-2-carbonitrile,

1-[Nω(pyrazinyl-2-carbonyl)-L-ornithine]pyrrolidin,

(2S)-1-[S-(acetamidomethyl)-L-cysteinyl]pyrrolidin-2-carbonitrile,

3-[Nω-(2-chloropyridin-3-carbonyl)-L-ornithine]thiazolidin,

1-[Nω-(2-chloropyridin-3-carbonyl)-L-ornithine]pyrrolidin and

(2S)-1-[Nω-(2-chloropyridin-3-carbonyl)-L-ornithine]pyrrolidin-2-carbonitrile,

3-[Nω(pyrazinyl-2-carbonyl)-L-ornithine]thiazolidin,

3-[Nω-(2-Hinckley)-L-leinil]thiazolidin,

3-[Nω-(2-Hinckley)-L-ornithine]taerigi,

(2S)-1-[Nω-(2-Hinckley)-L-ornithine]pyrrolidin-2-carbonitrile,

3-[Nω-(6-methylpyrazine-2-carbonyl)-L-ornithine]thiazolidin,

3-[Nω-(isoquinoline-3-carbonyl)-L-ornithine]thiazolidin,

3-[Nω-(6-triftormetilfosfinov)-L-ornithine]thiazolidin,

(2S)-1-[(2'R)-3'-(acetamidomethyl)-2'-amino-3'-methylbutanoyl]-pyrrolidin-2-carbonitrile,

(2S)-1-[S-(3-picolylamine)-L-cysteinyl]pyrrolidin-2-carbonitrile,

3-[Nω-(3-pyridi oxycarbonyl)-L-ornithine]thiazolidin,

3-[O-(3-chlorobenzylamino)serenil]thiazolidin and

3-[(2'S)-2'-amino-5'-oxo-5'-(1",2",3",4"-tetrahydroisoquinoline-2"-yl)pentanoyl]thiazolidin.

In a second aspect the present invention relates to pharmaceutical compositions for use in the treatment of people. The composition differs in that it contains, as active agent, at least one compound as described in the present invention. Such a composition is useful in the treatment of human diseases. Composition mainly includes one or more additional components selected from pharmaceutically acceptable excipients and pharmaceutically active agents other than those according to the present invention.

The composition may be solid or liquid form, depending on the intended route of administration. Examples of solid compositions include pills, tablets, capsules and powders for oral administration, suppositories for rectal or vaginal injection, powder for nasal or intra-lungs introduction and plasters for percutaneous or crosslist (such as transbukkalnye) introduction. Examples of liquid compositions include solutions and suspensions for intravenous, subcutaneous or intramuscular injection, and oral, nasal or intra-lungs injection. Particularly preferred form compositions which AI is a tablet for oral administration. Another preferred form, especially in urgent cases and in the management of patients in intensive care, is a sterile solution for intravenous injection.

The composition includes at least one compound according to the above description. The composition may contain more than one such connection, but mostly it is preferable to include only one. The number of compounds used in the composition should be such that the total daily dose of the active agent could be administered in one to four convenient standard doses. For example, the composition may be a tablet containing compound, in an amount equal to the total required daily dose and this pill may be taken once a day. Alternatively, the tablet may contain half (or one third or one quarter) of the daily dose and is taken twice (or three or four times a day. This tablet may also have a notch to facilitate dividing the dose, so that, for example, a pill that contains a full daily dose, could be broken into two halves and put into two portions. Preferably, tablet or other standard dosage form contains from 0.1 mg to 1 g of the active compound. More preferably, it contains from 1 mg to 250 mg

Composition mainly includes one ilible fillers, selected from known as pharmaceutically acceptable. Suitable fillers include, but are not limited to the above list, volumetric fillers, binders, diluents, solvents, preservatives and flavourings. In the context of the present invention as a suitable fillers also discusses agents, which modify the performance of the release composition, such as polymers that selectively dissolve in the intestine ("intersolubility coverage").

The composition may include, in addition to the compound according to the present invention, the second pharmaceutically acceptable active agent. For example, the composition may include anti-inflammatory agent, a growth stimulant, anti-inflammatory agent or an antiviral agent. Mainly, however, it is preferable that the composition contained only one active agent.

In the third aspect of the invention relates to the use of the above-described compounds and compositions in the treatment of human diseases. This aspect can also be considered as an equivalent method of treatment of such diseases. Diseases that are sensitive to the specified treatment, are diseases in which inhibition of DP-IV or CD26 provides clinical improvement, direct or indirect, is th. Direct effects include blocking the activation of T lymphocytes. Indirect effects include potentiation of the activity of peptide hormones by preventing the collapse of such hormones. Examples of such diseases include, but are not limited to the above list, autoimmune and inflammatory diseases such as inflammatory bowel disease and rheumatoid arthritis, growth hormone deficiency, leading to low growth, polycystic ovarian syndrome, impaired glucose tolerance and type 2 diabetes. Especially preferred is the use of compounds and compositions in the treatment of impaired glucose tolerance and type 2 diabetes, as well as equally - method of treatment for these diseases through the introduction of an effective amount of a compound or composition described above.

The exact details of treatment, including determination of dosage, is established by the attending physician when taking into account the overall health of the patient and severity of the disease. For diseases such as inflammatory bowel disease, in which there are acute phase of active disease, divided latent periods, your doctor may choose a relatively high dose in the acute phase and a lower maintenance dose in the latent period. In chronic diseases, such as Dr who Abete type 2 impaired glucose tolerance, you may need a maintenance dose at the same level for a long period of time. In such cases, it may be a typical dosing regimen comprising the use of from one to four tablets per day, each of which contains from 0.1 mg to 1 g, and preferably from 1 mg to 250 mg of active compound.

Compounds according to the present invention can be obtained by means known in the field of chemistry methods. The way that you choose depends on the nature of the substituents present in the target molecule. In the description below, the indicated path synthesis for compounds in which m is 1. Compounds in which m=2 or 3, can be obtained using similar methods.

The original substance is typically derived α,ω-diaminoanisole 5 or derived aminocarbonyl acid 6.

PG1and PG2are "orthogonal" protective groups, which mask the reactivity of the amino groups and each of which can be selectively removed in the presence of another. Suitable groups are well known from the literature. PG3and PG4represent a protective group for carboxylic acids. They are chosen in such a way that they are orthogonal to each other and C is protective groups for amino groups. Suitable for PG3and PG4also well known from the literature. Derivatives deamination General formula 5 and derivatives iminodicarboxylic acids of General formula 6 are either manufactured products, or they can be obtained using the methods described in the literature. In practice, depending on the selected strategy, the starting material contains only two of the three present protective groups. Or will be absent PG3giving the possibility of introducing pyrolidine (or thiazolidinone or oxazolidinones) of residue, or is absent PG1or PG4allowing you to build a side chain.

Scheme a illustrates the introduction pyrrolidinone (or thiazolidinone or oxazolidinones) group as the first stage in the method of producing compounds according to the present invention.

Scheme And

Connection 5Aand 6Amatch 5 and 6, when PG3means a hydrogen atom (i.e., no protective group). The free carboxylic acid can be subjected to reaction with pyrrolidinone derivative 7 with the formation of amide 8 or 9. The reaction conditions for achieving the specified transformations are well described in the literature. Suitable reagents include carbodiimides, phosphorus reagents and alkylaromatic, and the reaction is s usually catalyzed by tertiary amine, such as triethylamine or dimethylaminopyridine.

The reaction depicted in scheme And available for all combinations of R1and X1. However, in the case when R1denotes a nitrile group, or when X1means sulfonyloxy or sulfonyloxy group, it may be convenient to modify the strategy as shown in schemes b and C.

Schema

Scheme

In the diagram To the group R1enter a primary amide and subsequently converted into the nitrile under the action of dehydrating agent such as triperoxonane anhydride. In the scheme With group X1impose tiefer and subsequently transformed into sulfoxide (a=1) or sulfon (a=2) under the action of an oxidant, such as periodate sodium. Modification strategies, privedennoi on the scheme, is impossible if X2denotes a sulfur atom.

Scheme D

In scheme D connection 5Dis a derivative of diaminoanisole 5 when ω-protective group denotes a hydrogen atom. The free amino group easily interacts with sulphonylchloride, acylchlorides and tionilhloridom, usually in the presence of a tertiary amine, to form sulfonamides 14, amides 15 and thioamides 16, respectively. Reagents mainly or available to the to such either can be obtained from the corresponding acids. The reaction depicted in scheme D, applicable mainly to all variations of the group R8(CH2)qprovided that some of substituents in the phenyl and heteroaryl rings, which are variations of the values of R8may need protection. Such deputies and their proper protection is mostly obvious to experts in the field of chemistry.

Scheme E

Reagents: (i) (COCl2; ii) CSCl2; (iii) R8(CH2)qOH; (iv) R6R7NH; v) R8(CH2)qOCOCl; vi) R8(CH2)qOCSCl; (vii) R6R7NCOCl; (viii) R6R7NCSCl.

Scheme E illustrates the conversion of the 5Dto carbamates and ureas and their thioanalogues. In the case when R5different from the hydrogen atom, the compound 5Dcan be converted into the corresponding carbamoylated 17 or thiocarbamoyl 18 by reaction with phosgene or thiophosgene. Can also be used with other reagents, which are known that they are functionally equivalent to the specified toxic reagents. In the case when R5denotes hydrogen, the resulting intermediate product is an isocyanate or isothiocyanate, which, however, acts equivalent to the corresponding chloride. Intermediate the products 17 and 18, as a rule, the rule does not distinguish, and subjected to direct processing of alcohols to form carbamates 19 and thiocarbamates 20. Processing the same specified intermediate products of amines leads to the formation of ureas 21 and thioureas 22. Alternatively, 5Dcan be directly subjected to the reaction with CHLOROFORMATES or chlorothioformate with getting carbamate or THIOCARBAMATE, or, in the case when neither R6or R7not denote hydrogen, chlorpropamide or chlorothioformate obtaining urea or thiourea. In the case when R6or R7represent a hydrogen atom, chloroformate or chlorothioformate can be unstable, and in this case, the use of isocyanate (e.g., R6-NCO) or isothiocyanate (for example, R6-NCS). As noted earlier in the discussion of scheme D, some deputies in the number of cases R8may require appropriate protection.

Scheme F

Scheme F illustrates the conversion of the side chain series aminocarbonyl acid. Acid 6Fwithout ω-protected groups can be in a variety of conditions subjected to reaction with the amine by amide formation 23. Condensation can be facilitated dehydrating reagent, such as carbodiimide or phosphate reagent. Alternatively, the acid can be the converted into a more reactive derivative, through this reaction, as processing oxalylamino or thionyl chloride, with the formation of the corresponding acid chloride, which will continue to interact directly with the amine. Tioned 24 can be obtained by treating the amide 23 reagent Losson (Lawesson''s reagent).

After the conversion is complete, remove all groups end protective group, highlight the product and purified using standard procedures.

Describes the basic methods is further illustrated with the help of non-limiting examples.

EXAMPLES

Reduction

Use the following abbreviations:
DMFN,N-dimethylformamide
hhour (s)
HPLChigh performance liquid chromatography
minminute(s)
Peter. etherthe fraction of petroleum ether, boiling at 60-80°
PyBOP®(benzotriazol-1 yloxy)triprolidine hexaphosphate
PyBroP®patrimonialization hexaphosphate
TFUtriperoxonane acid

EXAMPLE 1

Triptorelin (2S)-1-[Nω(pyrazinyl-2-carbonyl)-L-ornithine]PI is Raiden-2-carbonitrile

A. N-(2-nitrobenzenesulfonyl)-L-Proline

L-Proline (25 g, 217 mmol) dissolved in 2 M NaOH (110 ml, 220 mmol) and dioxane (120 ml). At the same time, and 2 M NaOH (110 ml, 220 mmol) is added slowly a solution of 2-nitrobenzenesulfonamide (42 g, 222 mmol) in dioxane (60 ml). After 2 hours of storage at room temperature, the reaction mixture was poured into water (500 ml) and filtered off the solid. Bring the pH value of the filtrate to 3 by addition of 2 M HCl and the solution extracted with ethyl acetate (3×500 ml). The combined organic extracts washed with water (4×200 ml)and saturated salt solution (1×200 ml), dried (Na2SO4) and evaporated in vacuo to obtain an orange solid, which was identified as N-(2-nitrobenzenesulfonyl)-L-Proline (58,1 g, 217 mmol, 100%).

Century Succinimidyl ester N-(2-nitrobenzenesulfonyl)-L-Proline

N-(2-nitrobenzenesulfonyl)-L-Proline (57,9 g, 216 mmol) was dissolved in CH2Cl2/DMF (9:1, 500 ml). Add N-hydroxysuccinimide (37,3 g, 324 mmol) and water soluble carbodiimide (51.8 g, 260 mmol). After 18 hours of incubation at room temperature the solvent is removed in vacuum and the residue is dissolved in ethyl acetate (1000 ml). The solution was washed with water (4×200 ml) and saturated salt solution (1×200 ml), dried (Na2SO4) and evaporated in vacuo to item is the receiving yellow solid, which identify as Succinimidyl ester N-(2-nitrobenzenesulfonyl)-L-Proline (78,9 g, 216 mmol, 100%).

C. N-(2-nitrobenzenesulfonyl)-L-prolinamide

Succinimidyl ester N-(2-nitrobenzenesulfonyl)-L-Proline (78,5 g, 215 mmol) dissolved in dioxane (500 ml). Add ammonia (35%, 100 ml). After stirring at room temperature for 2 hours, the reaction mixture was poured into water (700 ml). The precipitate is filtered off, washed with water (200 ml), dried over P2O5and re-crystallized from ethyl acetate/petroleum ether to obtain a yellow solid, which was identified as N-(2-nitrobenzenesulfonyl)-L-prolinamide (49,6 g, 185 mmol, 86%).

D. (2S)-N-(2-nitrobenzenesulfonyl)pyrrolidin-2-carbonitrile

N-(2-nitrobenzenesulfonyl)-L-prolinamide (49 g, 183 mmol) dissolved in dry THF (300 ml). The solution is cooled to 0°With, add triethylamine (36,7 g, 367 mmol) and then slowly add triperoxonane anhydride (77 g, 367 mmol). The pH value was adjusted to 9 by adding triethylamine. After 30 minutes the reaction mixture was diluted with ethyl acetate (500 ml), washed with water (1×200 ml) and saturated salt solution (1×200 ml), dried (Na2SO4) and evaporated in vacuo to obtain an orange oil, which was purified flash chromatography (eluent: 80% Peter. ether, 20% ethyl acetate) to give yellow solid, which which are identified as (2S)-N-(2-nitrobenzenesulfonyl)pyrrolidin-2-carbonitrile (38,9 g, 150 mmol, 82%).

That is, Hydrochloride, (2S)-pyrrolidin-2-carbonitrile

(2S)-N-(2-nitrobenzenesulfonyl)pyrrolidin-2-carbonitrile (38,5 g, 149 mmol) was dissolved in diethyl ether (200 ml). Slowly add 4 M HCl/dioxane (150 ml, 600 mmol). After 2 hours of storage at room temperature, the reaction mixture was poured into dielovy ether (1000 ml). The solid is filtered off, washed with diethyl ether (500 ml) and re-crystallized from methanol/diethyl ether to obtain white solid, which identify as hydrochloride, (2S)-pyrrolidin-2-carbonitrile (18,9 g, 142,5 mmol, 96%).

F. (2S)-1-[Nα-(tert-butyloxycarbonyl)-Nω(pyrazinyl-2-carbonyl)-L-ornithine]pyrrolidin-2-carbonitrile

Nα-(tert-butyloxycarbonyl)-Nω(pyrazinyl-2-carbonyl)-L-ornithin (2.5 g, 7.4 mmol) was dissolved in CH2Cl2(50 ml). This solution is cooled to 0°add hydrochloride (2S)-pyrrolidin-2-carbonitrile (1.2 g, 9.1 mmol) and PyBOP® (4.3 g, 8,23 mmol) and adjusting the pH to 9 by adding triethylamine. After 18 hours of incubation at a temperature of from 0°C to room temperature the solvent is removed in vacuum and the residue is dissolved in ethyl acetate (200 ml). The solution was washed with 0.3 M KHSO4(2×50 ml), a saturated solution of NaHCO3(2×50 ml), water (2×50 ml) and saturated salt solution (1×50 ml), the tub (Na 2SO4) and evaporated in vacuo to obtain a yellow oil. Specified oil purified flash chromatography (eluent: 80% acetate, 20% Peter. ether) to give a colorless oil, which was identified as (2S)-1-[Nα-(tert-butyloxycarbonyl)-Nω(pyrazinyl-2-carbonyl)-L-ornithine]pyrrolidin-2-carbonitrile (2,98 g, 7,16 mmol, 97%).

G. Triptorelin (2S)-1-[Nω(pyrazinyl-2-carbonyl)-L-ornithine]pyrrolidin-2-carbonitrile

(2S)-1-[Nα-(tert-butyloxycarbonyl)-Nω(pyrazinyl-2-carbonyl)-L-ornithine]pyrrolidin-2-carbonitrile (2.8 g, 6.7 mmol) dissolved in triperoxonane acid (5 ml). After 1 hour of incubation at room temperature the solvent is removed in vacuum. The residue is purified preparative HPLC (Vydak C18, 5 to 50% 0,1% TFU/acetonitrile in 0.1% TFU/water for 40 min with a volume flow rate of 3 ml/min). The fractions containing the product, lyophilized obtaining a colorless oil, which identifies as triptorelin (2S)-1-[Nω(pyrazinyl-2-carbonyl)-L-ornithine]pyrrolidin-2-carbonitrile (1.5 g, of 3.48 mmol, 52%).

[M+H]+=317,3.

EXAMPLE 2

Triptorelin (2S)-1-[Nω(pyrazinyl-2-carbonyl)-L-leinil]pyrrolidin-2-carbonitrile

A. (Nα-(tert-butyloxycarbonyl)-Nω-(9-fluorenylmethoxycarbonyl)-L-leinil)-L-Proline is d

Nα-(tert-butyloxycarbonyl)-Nω-(9-fluorenylmethoxycarbonyl)-L-lysine (5 g, of 10.7 mmol) dissolved in CH2Cl2(100 ml). The solution is cooled to 0°add L-prolinamide (1.78 g, 11.7 mmol) and PyBOP® (6.7 g, 12.8 mmol) and the pH is brought to 9 by adding triethylamine. After 18 hours of incubation at a temperature of from 0°C to room temperature the solvent is removed in vacuum and the residue is dissolved in ethyl acetate (200 ml). The solution was washed with 0.3 M KHSO4(2×50 ml), a saturated solution of NaHCO3(2×50 ml), water (2×50 ml) and saturated salt solution (1×50 ml), dried (Na2SO4) and evaporated in vacuo. The residue is purified with flash chromatography (eluent: 2% methanol, 98% chloroform) to give a colorless oil, which was identified as (Nα-(tert-butyloxycarbonyl)-Nω-(9-fluorenylmethoxycarbonyl)-L-leinil)-L-prolinamide (of 4.05 g, 7.2 mmol, 67%).

C. (2S)-1-(Nα-(tert-butyloxycarbonyl)-Nω-(9-fluorenylmethoxycarbonyl)-L-leinil)pyrrolidin-2-carbonitrile

(Nα-(tert-butyloxycarbonyl)-Nω-(9-fluorenylmethoxycarbonyl)-L-leinil)-L-prolinamide (3,95 g, 7,02 mmol) dissolved in anhydrous THF (100 ml). The solution is cooled at 0°With, add triethylamine (1.4 g, 14 mmol) and then slowly add triperoxonane anhydride (2,97 g, 14.1 mmol). The value of the N lead up to 9, adding triethylamine. After 30 min the reaction mixture was diluted with ethyl acetate (100 ml), washed with water (1×50 ml) and saturated salt solution (1×50 ml), dried (Na2SO4) and evaporated in vacuo to obtain an orange oil. The residue is purified with flash chromatography (eluent: 60% Peter. ether, 40% ethyl acetate) to give colorless oil, which was identified as (2S)-1-(Nα-(tert-butyloxycarbonyl)-Nω-(9-fluorenylmethoxycarbonyl)-L-leinil)pyrrolidin-2-carbonitrile (3.3 grams, 6,11 mmol, 87%).

C. (2S)-1-(Nα-(tert-butyloxycarbonyl)-L-leinil)pyrrolidin-2-carbonitrile

(2S)-1-(Nα-(tert-butyloxycarbonyl)-Nω-(9-fluorenylmethoxycarbonyl)-L-leinil)pyrrolidin-2-carbonitrile (3.1 g, 5.7 mmol) dissolved in THF (80 ml). Add diethylamine (20 ml). After 2 h of incubation at room temperature the solvent is removed in vacuum. The residue is purified with flash chromatography (eluent: 90% chloroform, 7% methanol, 3% triethylamine) to give a colorless oil, which was identified as (2S)-1-(Nα-(tert-butyloxycarbonyl)-L-leinil)pyrrolidin-2-carbonitrile (1.63 g, of 5.03 mmol, 89%).

D. (2S)-1-(Nα-(tert-butyloxycarbonyl)-Nω(pyrazinyl-2-carbonyl)-L-leinil)pyrrolidin-2-carbonitrile

(2S)-1-(Nα-(tert-butyloxycarbonyl)-L-leinil)pyrrolidin-2-carbonitrile (100 mg, 0.31 mmol) is astonaut in CH 2Cl2/DMF (9:1, 20 ml). To the specified solution at 0°add the hydrate of 1-hydroxybenzotriazole (84 mg, of 0.62 mmol), water-soluble carbodiimide (76 mg, 0.38 mmol), 2-pyrazinecarboxamide acid (43 mg, 0.35 mmol) and triethylamine (65 mg, of 0.65 mmol). After 18 h of incubation at room temperature the solvent is removed in vacuum and the residue is dissolved in ethyl acetate (70 ml). This solution was washed with 0.3 M KHSO4(2×20 ml), a saturated solution of NaHCO3(2×20 ml), water (2×20 ml) and saturated salt solution (1×20 ml), dried (Na2SO4) and evaporated in vacuo to obtain a yellow oil. The residue is purified with flash chromatography (eluent: 2% methanol, 98% chloroform) to give a colorless oil, which was identified as (2S)-1-(Nα-(tert-butyloxycarbonyl)-Nω(pyrazinyl-2-carbonyl)-L-leinil)pyrrolidin-2-carbonitrile (124 mg, 0.29 mmol, 93%).

E. Triptorelin (2S)-1-[Nω(pyrazinyl-2-carbonyl)-L-leinil]pyrrolidin-2-carbonitrile

(2S)-1-(Nα-(tert-butyloxycarbonyl)-Nω(pyrazinyl-2-carbonyl)-L-leinil)pyrrolidin-2-carbonitrile (110 mg, 0.26 mmol) dissolved in triperoxonane acid (5 ml). After 1 hour of incubation at room temperature the solvent is removed in vacuum. The residue is purified preparative HPLC (Vydac C18, 5 to 50% 0,1% TFU/acetonitrile in 0.1% TFU/water for 40 min with the volumes of the major flow of 3 ml/min). The fractions containing the product, lyophilized obtaining a colorless oil, which identifies as Triptorelin (2S)-1-[Nω(pyrazinyl-2-carbonyl)-L-leinil]pyrrolidin-2-carbonitrile (66 mg).

[M+H]+=331,1.

EXAMPLE 3

Triptorelin (4R)-3-[Nω(pyrazinyl-2-carbonyl)-L-leinil]thiazolidin-4-carbonitrile

A. (4R)-3-(tert-butyloxycarbonyl)thiazolidin-4-carboxamid

(4R)-3-(tert-butyloxycarbonyl)thiazolidin-4-carboxylic acid (12.5 g, 54.1 mmol) was dissolved in CH2Cl2/DMF (9:1, 150 ml). To the specified solution at 0°add the hydrate of 1-hydroxybenzotriazole (14.6 g, 108 mmol) and water soluble carbodiimide (13,0 g, 65 mmol). After 1 hour of incubation at 0°add ammonia (35%, 50 ml). After 1 hour of incubation at a temperature of from 0°C to room temperature the solvent is removed in vacuum and the residue is dissolved in ethyl acetate (500 ml). The solution was washed with 0.3 M KHSO4(2×100 ml), a saturated solution of NaHCO3(2×100 ml), water (2×100 ml) and saturated salt solution (1×100 ml), dried (Na2SO4) and evaporated in vacuo to obtain a yellow oil. The residue is purified with flash chromatography (eluent: 2% methanol, 98% chloroform) to give a colorless oil, which was identified as (4R)-3-(tert-butyloxycarbonyl)thiazolidin-4-carboxamid (8,9 g, 38,4 IMO the e l e C 71%).

Century Hydrochloride (4R)-thiazolidin-4-carboxamide

(4S)-3-(tert-butyloxycarbonyl)thiazolidin-4-carboxamid (8.6 g, 37,1 mmol) was dissolved in 4 M HCl/dioxane (50 ml). After incubation for 1 hour at room temperature the solvent is evaporated in vacuum to obtain a white solid, which identify as hydrochloride (4R)-thiazolidin-4-carboxamide (6.2 g, to 36.8 mmol, 99%).

C. (4R)-3-[Nα-(tert-butyloxycarbonyl)-Nω-(9-fluorenylmethoxycarbonyl)-L-leinil]thiazolidin-4-carboxamid

Nα-(tert-butyloxycarbonyl)-Nω-(9-fluorenylmethoxycarbonyl)-L-lysine (5 g, of 10.7 mmol) dissolved in CH2Cl2(100 ml). This solution is cooled to 0°add hydrochloride (4R)-thiazolidin-4-carboxamide (1.78 g, 11.7 mmol) and PyBOP® (6.7 g, 12.8 mmol) and bring the triethylamine pH value to 9. After incubation for 18 hours at a temperature of from 0°C to room temperature the solvent is removed in vacuum and the residue is dissolved in ethyl acetate (200 ml). The solution was washed with 0.3 M KHSO4(2×50 ml), a saturated solution of NaHCO3(2×50 ml), water (2×50 ml) and saturated salt solution (1×50 ml), dried (Na2SO4) and evaporated in vacuo to obtain a yellow oil. The residue is purified with flash chromatography (eluent: 2% methanol, 98% chloroform) to give a colorless oil, to the / establishment, which identified as (4R)-3-[N α-(tert-butyloxycarbonyl)-Nω-(9-fluorenylmethoxycarbonyl)-L-leinil]thiazolidin-4-carboxamid (2,81 g, 4.8 mmol, 44%).

D. (4R)-3-[Nα-(tert-butoxycarbonyl)-Nω-(9-fluorenylmethoxycarbonyl)-L-leinil]thiazolidin-4-carbonitrile

(4R)-3-[Nα-(tert-butyloxycarbonyl)-Nω-(9-fluorenylmethoxycarbonyl)-L-leinil]thiazolidin-4-carboxamide (2.7 g, 4.7 mmol) dissolved in anhydrous THF (100 ml). The solution is cooled to 0°With, add triethylamine (1.0 g, 10 mmol) and then slowly add triperoxonane anhydride (2.0 g, 9.5 mmol). The pH value was adjusted to 9 by adding triethylamine. After 30 min the reaction mixture was diluted with ethyl acetate (100 ml), washed with water (1×50 ml) and saturated salt solution (1×50 ml), dried (Na2SO4) and evaporated in vacuo. The residue is purified with flash chromatography (eluent: 60% Peter. ether, 40% ethyl acetate) to give colorless oil, which was identified as (4R)-3-[Nα-(tert-butyloxycarbonyl)-Nω-(9-fluorenylmethoxycarbonyl)-L-leinil]thiazolidin-4-carbonitrile (2.14 g, 3,81 mmol, 82%).

That is, (4R)-3-[Nα-(tert-butyloxycarbonyl)-L-leinil]thiazolidin-4-carbonitrile

(4R)-3-[Nα-(tert-butyloxycarbonyl)-Nω-(9-fluorenylmethoxycarbonyl)-L-leinil]thiazolidin-4-carbonitrile (1,9 g, 3.4 mmol) dissolved in THF (40 ml). Doba is by diethylamine (10 ml). After 2 h of incubation at room temperature the solvent is removed in vacuum. The residue is purified with flash chromatography (eluent: 90% chloroform, 7% methanol, 3% triethylamine) to give a colorless oil, which was identified as (4R)-3-[Nα-(tert-butyloxycarbonyl)-L-leinil]thiazolidin-4-carbonitrile (863 mg, 2.5 mmol, 75%).

F. (4R)-3-[Nα-(tert-butyloxycarbonyl)-Nω(pyrazinyl-2-carbonyl)-L-leinil]thiazolidin-4-carbonitrile

(4R)-3-[N-(tert-butyloxycarbonyl)-L-leinil]thiazolidin-4-carbonitrile (100 mg, 0.29 mmol) dissolved in CH2Cl2(20 ml). To the specified solution at 0°add 2-pyrazinecarboxamide acid (43 mg, 0.35 mmol) and PyBOP® (170 mg, 0.33 mmol) and adjusting the pH to 9 by adding triethylamine. After 18 h of incubation at room temperature the solvent is removed in vacuum and the residue is dissolved in ethyl acetate (70 ml). The solution was washed with 0.3 M KHSO4(2×20 ml), a saturated solution of NaHCO3(2×20 ml), water (2×20 ml) and saturated salt solution (1×20 ml), dried (Na2SO4) and evaporated in vacuo. The residue is purified with flash chromatography (eluent: 2% methanol, 98% chloroform) to give a colorless oil, which was identified as (4R)-3-[Nα-(tert-butyloxycarbonyl)-Nω(pyrazinyl-2-carbonyl)-L-leinil]thiazolidin-4-carbonitrile (112 mg, 0.25 mmol, 86%).

G. Triflora the Etat (4R)-3-[N ω(pyrazinyl-2-carbonyl)-L-leinil]thiazolidin-4-carbonitrile

(4R)-3-[Nα-(tert-butyloxycarbonyl)-Nω(pyrazinyl-2-carbonyl)-L-leinil]thiazolidin-4-carbonitrile (110 mg, 0.26 mmol) dissolved in triperoxonane acid (5 ml). After incubation for 1 hour at room temperature the solvent is removed in vacuum. The residue is purified preparative HPLC (Vydac C18, 5 to 50% 0,1% TFU/acetonitrile in 0.1% TFU/water for 40 min with a volume flow rate of 3 ml/min). The fractions containing the product, lyophilized obtaining a colorless oil, which identifies as triptorelin (4R)-3-[Nω(pyrazinyl-2-carbonyl)-L-leinil]thiazolidin-4-carbonitrile (57 mg).

[M+H]+=349,1.

EXAMPLE 4

The dihydrochloride (2S)-1-[Nω-(pyridyl-3-methyl)-L-glutaminyl]pyrrolidin-2-carbonitrile

D. (2S)-1-[N-(tert-butyloxycarbonyl)-Oω-methyl-L-glutamyl]pyrrolidin-2-carbonitrile

N-(tert-butyloxycarbonyl)-Oω-methyl-L-glutamic acid (1.0 g, a 3.83 mmol) dissolved in CH2Cl2/DMF (9:1, 20 ml). To the specified solution at 0°add the hydrate of 1-hydroxybenzotriazole (788 mg, of 5.84 mmol), water-soluble carbodiimide (877 mg, of 4.38 mmol), hydrochloride, (2S)-pyrrolidin-2-carbonitrile (609 mg, 4.6 mmol) and triethylamine (65 mg, of 0.65 mmol). After incubation for 18 h at pace is the atur 0° With up to room temperature the solvent is removed in vacuum and the residue is dissolved in ethyl acetate (70 ml), and then this solution was washed with 0.3 M KHSO4(2×20 ml), a saturated solution of NaHCO3(2×20 ml), water (2×20 ml) and saturated salt solution (1×20 ml), tub (Na2SO4) and evaporated in vacuo. The residue is purified with flash chromatography (eluent: 50% ethyl acetate, 50% Peter. ether) to give a brown oil, which was identified as (2S)-1-[N-(tert-butyloxycarbonyl)-Oω-methyl-L-glutamyl]pyrrolidin-2-carbonitrile (290 mg, 0.86 mmol, 22%).

C. (2S)-1-[N-(tert-butyloxycarbonyl)-L-glutamyl]pyrrolidin-2-carbonitrile

(2S)-1-[N-(tert-butyloxycarbonyl)-Oω-methyl-L-glutamyl]pyrrolidin-2-carbonitrile (250 mg, of 0.74 mmol) dissolved in dioxane (5 ml). Added 1 M lithium hydroxide (1.1 ml, 1.1 mmol). After incubation for 1 hour at room temperature the solvent is removed in vacuum and the residue is dissolved in ethyl acetate (70 ml). This solution was washed with 1 M KHSO4(2×20 ml), water (2×20 ml) and saturated salt solution (1×20 ml), dried (Na2SO4) and evaporated in vacuo to obtain a colorless oil, which was identified as (2S)-1-[N-(tert-butyloxycarbonyl)-L-glutamyl]pyrrolidin-2-carbonitrile (200 mg, 0.61 mmol, 83%).

C. (2S)-1-[Nα-(tert-butyloxycarbonyl)-Nω-(pyridyl-3-meth is l)-L-glutaminyl]pyrrolidin-2-carbonitrile

(2S)-1-[N-(tert-butyloxycarbonyl)-L-glutamyl]pyrrolidin-2-carbonitrile (30 mg, 0,093 mmol) dissolved in CH2Cl2/DMF (9:1, 10 ml). To the specified solution at 0°add the hydrate of 1-hydroxybenzotriazole (21 mg, 0.16 mmol), water-soluble carbodiimide (21 mg, 0,105 mmol), 3-(aminomethyl)pyridine (11 mg, 0.1 mmol) and triethylamine (20 mg, 0.2 mmol). After incubation for 18 hours at a temperature of from 0°C to room temperature the solvent is removed in vacuum and the residue is dissolved in ethyl acetate (70 ml). The solution was washed with 0.3 M KHSO4(2×20 ml), a saturated solution of NaHCO3(2×20 ml), water (2×20 ml) and saturated salt solution (1×20 ml), dried (Na2SO4) and evaporated in vacuo to obtain a yellow oil. The residue is purified with flash chromatography (eluent: 5% methanol, 97% chloroform) to give a colorless oil, which was identified as (2S)-1-[Nα-(tert-butyloxycarbonyl)-Nω-(pyridyl-3-methyl)-L-glutaminyl]pyrrolidin-2-carbonitrile (16.6 mg, 0.04 mmol, 44%).

D. Dihydrochloride (2S)-1-[Nω-(pyridyl-3-methyl)-L-glutaminyl]pyrrolidin-2-carbonitrile

(2S)-1-[Nα-(tert-butyloxycarbonyl)-Nω-(pyridyl-3-methyl)-L-glutaminyl]pyrrolidin-2-carbonitrile (17 mg, 0.04 mmol) was dissolved in 4 M HCl/dioxane (5 ml). After incubation for 1 hour at room temperature the solvent is removed in Vacu the IU to obtain white solids, which identifies as the dihydrochloride (2S)-1-[Nω-(pyridyl-3-methyl)-L-glutaminyl]pyrrolidin-2-carbonitrile (17 mg, 0.04 mmol, 100%).

[M+H]+=316,2.

EXAMPLE 5

Triptorelin 1-[Nω(pyrazinyl-2-carbonyl)-L-ornithine]pyrrolidine

A. 1-[Nω(benzyloxycarbonyl)-Nα-(tert-butyloxycarbonyl)-L-ornithine]pyrrolidin

Nω(benzyloxycarbonyl)-Nα-(tert-butyloxycarbonyl)-L-ornithine (5.49 g, 15 mmol) dissolved in CH2Cl2/DMF (9:1, 100 ml). To the specified solution at 0°add the hydrate of 1-hydroxybenzotriazole (3,37 g, 22 mmol), water-soluble carbodiimide (of 3.46 g, 18 mmol), pyrrolidine (1.28 g, 18 mmol) and triethylamine (200 mg, 20 mmol). After incubation for 18 hours at a temperature of from 0°C to room temperature the solvent is removed in vacuum and the residue is dissolved in ethyl acetate (200 ml). The solution was washed with 0.3 M KHSO4(2×50 ml), a saturated solution of NaHCO3(2×50 ml), water (2×50 ml) and saturated salt solution (1×50 ml), dried (Na2SO4) and evaporated in vacuo. The residue is purified with flash chromatography (eluent: 90% acetate, 10% Peter. ether) to give a colorless oil, which was identified as 1-[Nω(benzyloxycarbonyl)-Nα-(tert-butyloxycarbonyl)-L-ornithine]pyrrolidin (5,15 g, 12.3 mm is l, 82%).

C. 1-[Nα-(tert-butyloxycarbonyl)-L-ornithine]pyrrolidin

1-[Nω(benzyloxycarbonyl)-Nα-(tert-butyloxycarbonyl)-L-ornithine]pyrrolidin (2.15 g, 5,13 mmol) dissolved in methanol (80 ml). This solution hydronaut over 10% Pd/C (400 mg). After 2 hours the catalyst is filtered off and washed with methanol (50 ml). The combined filtrates evaporated in vacuo to obtain not quite white solid, which was identified as 1-[Nα-(tert-butyloxycarbonyl)-L-ornithine]pyrrolidin (1.35 g, 4,74 mmol, 94%).

C. 1-[Nα-(tert-butyloxycarbonyl)-Nω(pyrazinyl-2-carbonyl)-L-ornithine]pyrrolidin

1-[Nα-(tert-butyloxycarbonyl)-L-ornithine]pyrrolidine (100 mg, 0.35 mmol) dissolved in CH2Cl2(20 ml). To the specified solution at 0°With added PyBrop® (195 mg, 0.04 mmol), 2-pyrazinecarboxamide acid (50 mg, 0.4 mmol) and triethylamine (100 mg, 1.0 mmol). After incubation for 18 hours at a temperature of from 0°C to room temperature the solvent is removed in vacuum and the residue is dissolved in ethyl acetate (70 ml). The solution was washed with 0.3 M KHSO4(2×20 ml), a saturated solution of NaHCO3(2×20 ml), water (2×20 ml) and saturated salt solution (1×20 ml), dried (Na2SO4) and evaporated in vacuo. The residue is purified with flash chromatography (eluent: 3% methanol, 97% of CHL is reform) to give a sticky white solid, which is identified as 1-[Nα-(tert-butyloxycarbonyl)-Nω(pyrazinyl-2-carbonyl)-L-ornithine]pyrrolidine (90 mg, 0.25 mmol, 66%).

D. Triptorelin 1-[Nω(pyrazinyl-2-carbonyl)-L-ornithine]pyrrolidine

1-[Nα-(tert-butyloxycarbonyl)-Nω(pyrazinyl-2-carbonyl)-L-ornithine]pyrrolidine (90 mg, 0.23 mmol) was dissolved in 4 M HCl/dioxane (15 ml). After incubation for 45 min at room temperature the solvent is removed in vacuum. The residue is purified by the method of preparative HPLC (Vydac C18, 5 to 50% 0,1% TFU/acetonitrile in 0.1% TFU/water for 40 min with a volume flow rate of 3 ml/min). The fractions containing the product, lyophilized obtaining a colorless oil, which identifies as triptorelin 1-[Nω(pyrazinyl-2-carbonyl)-L-ornithine]pyrrolidine (51 mg).

[M+H]+=292,1.

EXAMPLE 6

Triptorelin 3-[Nω(pyrazinyl-2-carbonyl)-L-ornithine]thiazolidine

A. 3-[Nα-(tert-butyloxycarbonyl)-Nω-(9-fluorenylmethoxycarbonyl)-L-ornithine]thiazolidin

Nα-(tert-butyloxycarbonyl)-Nω-(9-fluorenylmethoxycarbonyl)-L-ornithine (2,73 g, 6 mmol) dissolved in CH2Cl2/DMF (9:1, 100 ml). To the specified solution at 0°C add the hydrate of 1-hydroxybenzotriazole (1,53 g, 10 mmol), vodorastvorimostew (1,34 g, 7 mmol), thiazolidine (1.28 g, 18 mmol) and triethylamine (80 mg, 8 mmol). After incubation for 18 hours at a temperature of from 0°C to room temperature the solvent is removed in vacuum and the residue is dissolved in ethyl acetate (100 ml). The solution was washed with 0.3 M KHSO4(2×25 ml), a saturated solution of NaHCO3(2×25 ml), water (2×25 ml) and saturated salt solution (1×25 ml), dried (Na2SO4) and evaporated in vacuo. The residue is purified with flash chromatography (eluent: 75% acetate, 25% Peter. ether) to give white solid, which was identified as 3-[Nα-(tert-butyloxycarbonyl)-Nω-(9-fluorenylmethoxycarbonyl)-L-ornithine]thiazolidin (2.55 g, is 4.85 mmol, 81%).

Century 3-[Nα-(tert-butyloxycarbonyl)-L-ornithine]thiazolidin

3-[Nα-(tert-butyloxycarbonyl)-Nω-(9-fluorenylmethoxycarbonyl)-L-ornithine]thiazolidin (1,15 g, 2,13 mmol) dissolved in acetonitrile (20 ml). Add diethylamine (5 ml). After incubation for 90 min at room temperature the solvent is removed in vacuo and the residue purified flash chromatography (eluent: 90% chloroform, 7% methanol, 3% triethylamine) to obtain a slightly yellow oil, which was identified as 3-[Nα-(tert-butyloxycarbonyl)-L-ornithine]thiazolidin (530 mg, 1,67 mmol, 78%).

C. 3-[Nα-(tert-butyloxycarbonyl)-Nω (pyrazinyl-2-carbonyl)-L-ornithine]thiazolidin

3-[Nα-(tert-butyloxycarbonyl)-L-ornithine]thiazolidin (80 mg, 0.27 mmol) dissolved in CH2Cl2(20 ml). To the specified solution at 0°With added PyBroP® (146 mg, 0.3 mmol), 2-pyrazinecarboxamide acid (37 mg, 0.3 mmol) and triethylamine (90 mg, 0.9 mmol). After incubation for 18 hours at a temperature of from 0°C to room temperature the solvent is removed in vacuum and the residue is dissolved in ethyl acetate (70 ml). The solution was washed with 0.3 M KHSO4(2×20 ml), a saturated solution of NaHCO3(2×20 ml), water (2×20 ml) and saturated salt solution (1×20 ml), dried (Na2SO4) and evaporated in vacuo. The residue is purified with flash chromatography (eluent: 3% methanol, 97% chloroform) to give a sticky white solid, which was identified as 3-[Nα-(tert-butyloxycarbonyl)-Nω(pyrazinyl-2-carbonyl)-L-ornithine]thiazolidin (45 mg, 0.11 mmol, 41%).

D. Triptorelin 3-[Nω(pyrazinyl-2-carbonyl)-L-ornithine]thiazolidine

3-[Nα-(tert-butyloxycarbonyl)-Nω(pyrazinyl-2-carbonyl)-L-ornithine]thiazolidin (45 mg, 0.11 mmol) was dissolved in 4 M HCl/dioxane (10 ml). After incubation for 45 min at room temperature the solvent is removed in vacuum. The residue is purified by the method of preparative HPLC (Vydac C18, 5 to 50% 0,1% TFU/AC is lonitrile 0.1% TFU/water for 40 min with a volume flow rate of 3 ml/min). The fractions containing the product, lyophilized obtaining a colorless oil, which identifies as triptorelin 3-[Nω(pyrazinyl-2-carbonyl)-L-ornithine]thiazolidine (14 mg).

[M+H]+=310,0.

EXAMPLE 7

Triptorelin (2S)-1-[S-(acetamidomethyl)-L-cysteinyl]pyrrolidin-2-carbonitrile

A. (2S)-1-[S-(acetamidomethyl)-N-(tert-butyloxycarbonyl)-L-cysteinyl]pyrrolidin-2-carbonitrile

S-(acetamidomethyl)-N-(tert-butyloxycarbonyl)-L-cysteine (660 mg, and 2.26 mmol) dissolved in CH2Cl2(30 ml). To the specified solution at 0°add hydrochloride (2S)-pyrrolidin-2-carbonitrile (250 mg, 1,89 mmol) and PyBOP® (1.3 g, 2.49 mmol) and bring the pH to 9 by adding triethylamine. After incubation for 18 hours at a temperature of from 0°C to room temperature the solvent is removed in vacuum and the residue is dissolved in ethyl acetate (150 ml). The solution was washed with 0.3 M KHSO4(2×30 ml), a saturated solution of NaHCO3(2×30 ml), water (2×30 ml) and saturated salt solution (1×30 ml), dried (Na2SO4) and evaporated in vacuo. The residue is purified with flash chromatography (eluent: 75% acetate, 25% Peter. ether) to give a colorless oil, which was identified as (2S)-1-[S-(acetamidomethyl)-N-(tert-butyloxycarbonyl)-L-cysteinyl]pyrrolidin-2-carbonitrile (650 mg, of 1.76 mmol, 78%).

Century is triftoratsetata (2S)-1-[S-(acetamidomethyl)-L-cysteinyl]pyrrolidin-2-carbonitrile

(2S)-1-[S-(acetamidomethyl)-N-(tert-butyloxycarbonyl)-L-cysteinyl]pyrrolidin-2-carbonitrile (610 mg, of 1.65 mmol) dissolved in triperoxonane acid (30 ml). After incubation for 1 hour at room temperature the solvent is removed in vacuum to obtain a colorless oil, which identifies as triptorelin (2S)-1-[S-(acetamidomethyl)-L-cysteinyl]pyrrolidin-2-carbonitrile (620 mg, of 1.61 mmol, 98%).

[M+H]+=271,0.

EXAMPLE 8

Triptorelin (2S)-1-[(2'R)-3'-(acetamidomethyl)-2'-amino-3'-methylbutanoyl]pyrrolidin-2-carbonitrile

A. (2S)-1-[(2'R)-3'-(acetamidomethyl)-2'-(tert-butyloxycarbonyl)-3'-methylbutanoyl]pyrrolidin-2-carbonitrile

S-(acetamidomethyl)-N-(tert-butyloxycarbonyl)penicillamine (720 mg, 2.25 mmol) was dissolved in CH2Cl2(30 ml). To the specified solution at 0°C add hydrochloride (2S)-pyrrolidin-2-carbonitrile (270 mg, 2.04 mmol) and PyBOP® (1.3 g, 2.49 mmol) and bring the pH to 9 by adding triethylamine. After incubation for 18 hours at a temperature of from 0°C to room temperature the solvent is removed in vacuum and the residue is dissolved in ethyl acetate (150 ml). The solution was washed with 0.3 M KHSO4(2×30 ml), a saturated solution of NaHCO3(2×30 ml), water (2×30 ml) and saturated salt solution (1×30 ml), dried (Na2SO4) and evaporated the vacuum. The residue is purified with flash chromatography (eluent: 75% acetate, 25% Peter. ether) to give a colorless oil, which was identified as (2S)-1-[(2'R)-3'-(acetamidomethyl)-2'-(tert-butyloxycarbonyl)-3'-methylbutanoyl]pyrrolidin-2-carbonitrile (742 mg, of 1.86 mmol, 83%).

Century Triptorelin (2S)-1-[(2'R)-3'-(acetamidomethyl)-2'-amino-3'-methylbutanoyl]pyrrolidin-2-carbonitrile

(2S)-1-[(2'R)-3'-(acetamidomethyl)-2'-(tert-butyloxycarbonyl)-3'-methylbutanoyl]pyrrolidin-2-carbonitrile (710 mg, 1.78 mmol) was dissolved in triperoxonane acid (30 ml). After incubation for 1 hour at room temperature the solvent is removed in vacuum to obtain a colorless oil, which identifies as triptorelin (2S)-1-[(2'R)-3'-(acetamidomethyl)-2'-amino-3'-methylbutanoyl]-pyrrolidin-2-carbonitrile (560 mg, of 1.36 mmol, 76%).

[M+H]+=299,1.

EXAMPLE 9

Triptorelin (2S)-1-[Nω-(2-chloropyridin-3-carbonyl)-L-ornithine]pyrrolidin-2-carbonitrile

A. (2S)-1-(Nα-(tert-butyloxycarbonyl)-L-Omnitel)pyrrolidin-2-carbonitrile

(2S)-1-(Nα-(tert-butyloxycarbonyl)-L-arnitel]pyrrolidin-2-carbonitrile receive according to the method described for lysine derivative in example 2.

C. (2S)-1-(Nα-(tert-butyloxycarbonyl)-Nω-(2-chloropyridin-3-carbonyl)-L-Omnitel)aerolysin-2-carb is nitrile

(2S)-1-(Nα-(tert-butyloxycarbonyl)-L-Omnitel)pyrrolidin-2-carbonitrile (80 mg, 0.26 mmol) dissolved in CH2Cl2(20 ml). To the specified solution was added 2-chloropyridin-3-carbonylchloride (55 mg, 0.32 mmol) and bring the pH to 9 by adding triethylamine. After incubation for 18 h at room temperature the solvent is removed in vacuum and the residue is dissolved in ethyl acetate (70 ml). The solution was washed with 0.3 M KHSO4(2×20 ml), a saturated solution of NaHCO3(2×20 ml), water (2×20 ml) and saturated salt solution (1×20 ml), dried (Na2SO4) and evaporated in vacuo. The residue is purified with flash chromatography (eluent: 95% acetate, 5% pet. ether) to give a colorless oil, which was identified as (2S)-1-(Nα-(tert-butyloxycarbonyl)-Nω-(2-chloropyridin-3-carbonyl)-L-Omnitel)pyrrolidin-2-carbonitrile (60 mg, 0.14 mmol, 53%).

C. Triptorelin (2S)-1-[Nω-(2-chloropyridin-3-carbonyl)-L-ornithine]pyrrolidin-2-carbonitrile

(2S)-1-[Nα-(tert-butyloxycarbonyl)-Nω-(2-chloropyridin-3-carbonyl)-L-ornithine]pyrrolidin-2-carbonitrile (60 mg, 0.14 mmol) dissolved in triperoxonane acid (5 ml). After incubation for 1 hour at room temperature the solvent is removed in vacuum. The residue is purified by the method of preparative HPLC (Vydac C18, 5 to 50% 0,1% TFU/acetonitrile in 0.1% of the FU/water for 40 min with a volume flow rate of 3 ml/min). The fractions containing the product, lyophilized obtaining a white solid, which identifies as Triptorelin (2S)-1-[Nω-(2-chloropyridin-3-carbonyl)-L-ornithine]pyrrolidin-2-carbonitrile (52 mg).

[M+H]+=350,1.

EXAMPLE 10

Hydrochloride of 1-[Nω-(2-chloropyridin-3-carbonyl)-L-ornithine]pyrrolidine

A. 1-(Nα-(tert-butyloxycarbonyl)-Nω-(2-chloropyridin-3-carbonyl)-L-Omnitel)pyrrolidin

1-(Nα-(tert-butyloxycarbonyl)-L-Omnitel)pyrrolidine (20 mg, 0,069 mmol) dissolved in CH2Cl2(5 ml). To the specified solution was added 2-chloropyridin-3-carbonylchloride (14 mg, 0,076 mmol) and bring the pH to 9 by adding triethylamine. After incubation for 1 hour at room temperature the solvent is removed in vacuum and the residue is dissolved in ethyl acetate (70 ml). The solution was washed with 0.3 M KHSO4(2×20 ml), a saturated solution of NaHCO3(2×20 ml), water (2×20 ml) and saturated salt solution (1×20 ml), dried (Na2SO4) and evaporated in vacuo. The residue is purified with flash chromatography (eluent: 10% methanol, 90% dichloromethane) to give a colorless oil, which was identified as 1-(Nα-tert-butyloxycarbonyl)-Nω-(2-chloropyridin-3-carbonyl)-L-Omnitel)pyrrolidine (19 mg, 0.045 mmol, 63%).

C. the Hydrochloride of 1-[N#x003C9; -(2-chloropyridin-3-carbonyl)-L-ornithine]pyrrolidine

1-[Nα-(tert-butyloxycarbonyl)-Nω-(2-chloropyridin-3-carbonyl)-L-ornithine] pyrrolidine (19 mg, 0.045 mmol) was dissolved in 4 M HCl/dioxane (10 ml). After incubation for 45 min at room temperature the solvent is removed in vacuum to obtain a white solid, which identify as hydrochloride 1-[Nω-(2-chloropyridin-3-carbonyl)-L-ornithine]pyrrolidine (15 mg).

[M+H]+=325,1.

EXAMPLE 11

Hydrochloride 3-[Nω-(2-chloropyridin-3-carbonyl)-L-ornithine]thiazolidine

A. 3-(Nα-(tert-butyloxycarbonyl)-Nω-(2-chloropyridin-3-carbonyl)-L-Omnitel)thiazolidin

3-(Nα-(tert-butyloxycarbonyl)-L-Omnitel)thiazolidin (136 mg, 0.45 mmol) dissolved in CH2Cl2(10 ml). To the specified solution was added 2-chloropyridin-3-carbonylchloride (88 mg, 0.5 mmol) and bring the pH to 9 by adding triethylamine. After incubation for 1 hour at room temperature the solvent is removed in vacuum and the residue is dissolved in ethyl acetate (70 ml). The solution was washed with 0.3 M KHSO4(2×20 ml), a saturated solution of NaHCO3(2×20 ml), water (2×20 ml) and saturated salt solution (1×20 ml), dried (Na2SO4) and evaporated in vacuo. The residue is purified flash chromatogr is FIA (eluent: 1.5% methanol, 98,5% dichloromethane) to give a colorless oil, which was identified as 3-(Nα-(tert-butyloxycarbonyl)-Nω-(2-chloropyridin-3-carbonyl)-L-Omnitel)thiazolidin (30 mg, 0,068 mmol, 15%).

Century Hydrochloride 3-[Nω-(2-chloropyridin-3-carbonyl)-L-ornithine]thiazolidine

3-[Nα-(tert-butyloxycarbonyl)-Nω-(2-chloropyridin-3-carbonyl)-L-ornithine]thiazolidin (30 mg, 0,068 mmol) was dissolved in 4 M HCl/dioxane (10 ml). After incubation for 45 min at room temperature the solvent is removed in vacuum to obtain a white solid, which identify as hydrochloride 1-[Nω-(2-chloropyridin-3-carbonyl)-L-ornithine]thiazolidine (25 mg).

[M+H]+=342,1.

EXAMPLE 12

Triptorelin (2S)-1-[S-(3-picolylamine)-L-cysteinyl]pyrrolidin-2-carbonitrile

A. S-(benzyloxycarbonylamino)-N-(tert-butyloxycarbonyl)-L-cysteine

N-(tert-butyloxycarbonyl)-L-cysteine (3.5 g, 15.8 mmol), benzyl-2-bromoacetate (3.7 g, 16,1 mmol) and triethylamine (1.8 g, 18,1 mmol) dissolved in THF (100 ml). After incubation for 18 h at room temperature, the reaction mixture was diluted with ethyl acetate (100 ml), washed with 0.3 M KHSO4, a saturated solution of NaHCO3, water and saturated salt solution, dried (Na2SO4) and evaporated. The residue is purified by flash-chromate what graphy (eluent: 95% chloroform, 4% methanol, 1% acetic acid) to give a colorless oil, which was identified as S-(benzyloxycarbonylamino)-N-(tert-butyloxycarbonyl)-L-cysteine (5,2 g, 14.1 mmol, 89%).

C. (2S)-1-[S-(benzyloxycarbonylamino)-N-(tert-butyloxycarbonyl)-L-cysteinyl]pyrrolidin-2-carbonitrile

S-(benzyloxycarbonylamino)-N-(tert-butyloxycarbonyl)-L-cysteine (5.10 g, of 13.8 mmol) dissolved in CH2Cl2(200 ml). This solution is cooled to 0°add hydrochloride (2S)-pyrrolidin-2-carbonitrile (2.1 mg, 15.8 mmol) and PyBOP (8.0 g, of 15.3 mmol) and bring the pH to 9 by adding triethylamine. After incubation for 18 hours at a temperature of from 0°C to room temperature the solvent is removed in vacuum and the residue is dissolved in ethyl acetate (150 ml). The solution was washed with 0.3 M KHSO4(1×50 ml), a saturated solution of NaHCO3(1×50 ml), water (1×50 ml) and saturated salt solution (1×50 ml), dried (Na2SO4) and evaporated in vacuo to obtain a yellow oil. Specified oil purified flash chromatography (eluent: 40% ethyl acetate, 60% Peter. ether) to give a colorless oil, which was identified as (2S)-1-[S-(benzyloxycarbonylamino)-N-(tert-butyloxycarbonyl)-L-cysteinyl]pyrrolidin-2-carbonitrile (of 5.82 g, 13,0 mmol, 94%).

C. (2S)-1-[N-(tert-butyloxycarbonyl)-S-(carboxymethyl)-L-cysteinyl]pyrrolidin-2-carbonitrile

(2S)-1-[S-(Benzino icarbonell)-N-(tert-butyloxycarbonyl)-L-cysteinyl]pyrrolidin-2-carbonitrile (1.31 g, 2.9 mmol) dissolved in THF (100 ml). Add an aqueous solution of lithium hydroxide (1 M, 3.5 ml, 3.5 mmol). After incubation for 3 hours at room temperature, the reaction mixture was diluted with ethyl acetate (100 ml), washed with 1 M citric acid, water and saturated salt solution, dried (Na2SO4) and evaporated in vacuo to obtain a colorless oil. Specified oil purified flash chromatography (eluent: 97% chloroform, 2% methanol, 1% acetic acid) to give a colorless oil, which was identified as (2S)-1-[N-(tert-butyloxycarbonyl)-S-(carboxymethyl)-L-cysteinyl]pyrrolidin-2-carbonitrile (860 mg, 2.4 mmol, 82%).

D. (2S)-1-[N-(tert-butyloxycarbonyl)-S-(3-picolylamine)-L-cysteinyl]pyrrolidin-2-carbonitrile

(2S)-1-[N-(tert-butyloxycarbonyl)-S-(carboxymethyl)-L-cysteinyl]pyrrolidin-2-carbonitrile (150 mg, 0.42 mmol) dissolved in CH2Cl2(20 ml). This solution is cooled to 0°add 3-(aminomethyl)pyridine (53 mg, 0.5 mmol) and PyBOP (270 mg, 0.52 mmol) and bring the pH to 9 by adding triethylamine. After incubation for 18 hours at a temperature of from 0°C to room temperature the solvent is removed in vacuum and the residue is dissolved in ethyl acetate (70 ml). Next, this solution was washed with 0.3 M KHSO4(1×20 ml), a saturated solution of NaHCO3(1×20 ml), water (1×20 ml) and saturated concrete is salt (1× 20 ml), dried (Na2SO4) and evaporated in vacuo to obtain a yellow oil. Specified oil purified flash chromatography (eluent: 96% chloroform, 4% methanol) to give a colorless oil, which was identified as (2S)-1-[N-(tert-butyloxycarbonyl)-S-(3-picolylamine)-L-cysteinyl]pyrrolidin-2-carbonitrile (170 mg, 0.38 mmol, 91%).

E. Triptorelin (2S)-1-[S-(3-picolylamine)-L-cysteinyl]pyrrolidin-2-carbonitrile

(2S)-1-[N-(tert-butyloxycarbonyl)-S-(3-picolylamine)-L-cysteinyl]pyrrolidin-2-carbonitrile (130 mg, 0.29 mmol) dissolved in triperoxonane acid (10 ml). After incubation for 1 hour at room temperature the solvent is removed in vacuum to obtain a white solid, which identifies as triptorelin (2S)-1-[S-(3-picolylamine)-L-cysteinyl]pyrrolidin-2-carbonitrile (116 mg, 0.25 mmol, 86%).

[M+H]+=348,2.

EXAMPLE 13

Hydrochloride 3-[Nω-(2-Hinckley)-L-leinil]thiazolidine

A. 3-[Nα-(tert-butyloxycarbonyl)-Nω-(2-Hinckley)-L-leinil]thiazolidin

3-[Nα-(tert-butyloxycarbonyl)leinil]thiazolidin (128 mg, 0.4 mmol) dissolved in CH2Cl2(10 ml). Add 2-hinoksalinovym (85 mg, 0.44 mmol) and potassium carbonate (45,8 mg, 0.3 mmol). The reaction mixture was stirred at room the Oh temperature for 18 h and then the solvent is removed in vacuum. The residue is purified with flash chromatography (eluent: 99.5% chloroform, 0.5% methanol) to give a colorless oil, which was identified as 3-[Nα-(tert-butyloxycarbonyl)-Nω-(2-Hinckley)-L-leinil]thiazolidin (140 mg, 0,296 mmol, 74%).

Century Hydrochloride 3-[Nω-(2-Hinckley)-L-leinil]thiazolidine

3-[Nα-(tert-butyloxycarbonyl)-Nω-(2-Hinckley)-L-leinil]thiazolidin (140 mg, 0,296 mmol) was dissolved in 4 M HCl/dioxane (20 ml). After stirring for 1 hour at room temperature the solvent is removed in vacuum to obtain a white solid, which identify as hydrochloride 3-[Nω-(2-Hinckley)-L-leinil]thiazolidine (128 mg, 0,296 mmol, 100%).

[M+H]+=374,2.

EXAMPLE 14

Hydrochloride 3-[Nω-(3-pyridylcarbonyl)-L-ornithine]thiazolidine

A. 3-[Nα-(tert-butyloxycarbonyl)-Nω-(3-pyridylcarbonyl) L ornithine]thiazolidin

3 Hydroxypyridine (14,9 mg, was 0.138 mmol) dissolved in CH2Cl2(20 ml). Add at 0°With phosgene (20% solution in toluene, 0,335 ml, 0,685 mmol) and pyridine (14 mg, of 0.182 mmol). After 90 min the solvent is removed in vacuo and the residue dissolved in CH2Cl2(20 ml). Add 3-[Nα-(tert-butyloxycarbonyl)ornithine]thiazolidin (42 mg, was 0.138 mmol) and triethylamine 28 mg, 0.28 mmol). The reaction mixture is stirred for 18 hours and then the solvent is removed in vacuum. The residue is purified with flash chromatography (eluent: 97% chloroform, 3% methanol) to give a colorless oil, which was identified as 3-[Nα-(tert-butyloxycarbonyl)-Nω-(3-pyridylcarbonyl)-L-ornithine]thiazolidin (16 mg, of 0.038 mmol, 27%).

Century Hydrochloride 3-[Nω-(3-pyridylcarbonyl)-L-ornithine]thiazolidine

3-[Nα-(tert-butyloxycarbonyl)-Nω-(3-pyridylcarbonyl)-L-ornithine] thiazolidin (16 mg, of 0.038 mmol) was dissolved in 4 M HCl/dioxane (20 ml). After incubation for 1 hour at room temperature the solvent is removed in vacuum to obtain a white solid, which identify as hydrochloride 3-[Nω-(3-pyridylcarbonyl)-L-ornithine]thiazolidine (14 mg, of 0.038 mmol, 100%).

[M+H]+=325,1.

EXAMPLE 15

Hydrochloride 3-[O-(3-chlorobenzylamino)serenil]thiazolidine

A. 3-[N-(tert-butyloxycarbonyl)-L-serinol]thiazolidin

N-(tert-butyloxycarbonyl)-L-serine (2.1 g, 10.2 mmol) dissolved in CH2Cl2/DMF (9:1, 50 ml). Add at 0°With thiazolidin (650 mg, and 11.2 mmol), hydroxybenzotriazole (2.8 g, of 20.7 mmol) and water soluble carbodiimide (3,9 g of 19.5 mmol). The pH value was adjusted to 8 by adding N-methylmorpholine. The reaction is th the mixture is stirred at room temperature for 18 hours, the solvent is removed in vacuum and the residue is dissolved in ethyl acetate (150 ml). The solution was washed with 0.3 M KHSO4(1×50 ml), a saturated solution of NaHCO3(1×50 ml), water (1×50 ml) and saturated salt solution (1×50 ml), dried (Na2SO4) and evaporated in vacuo to obtain a white solid, which was identified as 3-[N-(tert-butyloxycarbonyl)-L-serinol]thiazolidin (2.15 g, 7,78 mmol, 76%).

Century 3-[N-(tert-butyloxycarbonyl)-O-(3-chlorobenzylamino)-L-serinol]thiazolidin

3-[N-(tert-butyloxycarbonyl)-L-serinol]thiazolidin (110 mg, 0.48 mmol) dissolved in DMF (10 ml) and added 1,1'-carbonyldiimidazole (71 mg, 0.43 mmol). After incubation for 2 hours at room temperature, add 3-chlorobenzylamino (62 mg, 0.4 mmol). After another 18 hours, add EtOAc (200 ml). This solution was washed with 0.3 M KHSO4(1×50 ml), a saturated solution of NaHCO3(1×50 ml), water (4×50 ml) and saturated salt solution (1×50 ml), dried (Na2SO4) and evaporated in vacuo to obtain a yellow oil. Specified oil purified flash chromatography (eluent: 40% ethyl acetate, 60% Peter. ether) to give a colorless oil, which was identified as 3-[N-(tert-butyloxycarbonyl)-O-(3-chlorobenzylamino)-L-serinol]thiazolidin (158 mg, 0.36 mmol, 90%).

C. the Hydrochloride of 3-[O-(3-chloraniline)-L-serinol]thiazolidine

3-[-(tert-butyloxycarbonyl)-O-(3-chlorobenzylamino)-L-serinol]thiazolidin (140 mg, 0.32 mmol) was dissolved in 4 M HCl/dioxane (20 ml). After stirring for 1 hour at room temperature the solvent is removed in vacuum to obtain a white solid, which identify as hydrochloride 3-[O-(3-chlorobenzylamino)-L-serinol]thiazolidine (115 mg, 0.3 mmol, 94%).

[M+H]+=344,1.

Connection of other examples that are listed in the following tables are in accordance with the methods described above.

H
TABLE 1

Examples 16-162
ExamplenR8(CH2)qR1X1
161CNCH2
172CNCH2
181NS
192NS
201CNS
212CNS
221NCH2/sub>
232NCH2
241CNCH2
252CNCH2
261HS
272HS
281CNCH2
292CNCH2
301HS
312HS
321CNCH2
332CNCH2
341HS
352HS
361CNCH2
372CNCH2
381S

ExamplenR8(CH2)qR1X1
391CNCH2
402CNCH2
411NS
422NS
431CNCH2
442CNCH2
451NS
462NS
471CNCH2
482CNCH2
491NS
502NS
511CN522CNCH2
531NS
542NS
551CNCH2
562CNCH2
571NS
582NS
591CNCH2
602CNCH2
611NS
622NS
631CNCH2
642CNCH2
651NS
662NS
671 CNCH2
682CNCH2
691NS
702NS

ExamplenR8(CH2)qR1X1
711CNCH2
722CNCH2
731NS
742NS
751CNCH2
762CNCH2
771NS
782NS
791CNCH2
802CNCH2
1NS
822NS
831CNCH2
842CNCH2
851NS
862NS
871CNCH2
882CNCH2
891NS
902NS
911CNCH2
922CNCH2
931NS
942NS
951CNCH2
962CNWith the 2
971NS
982NS
991CNCH2
1002CNCH2
1011NS
1022NS

ExamplenR8(CH2)qR1X1
1031CNCH2
1042CNCH2
1051NS
1062NS
1071CNCH2
1082CNCH2
1091NS
1102N S
1111CNCH2
1122CNCH2
1131NS
1142NS
1151CNCH2
1162CNCH2
1171NS
1182NS
1191CNCH2
1202CNCH2
1211NS
1222NS
1231CNCH2
1242CNCH2
1251NS
2NS
1271NS
1281NS
1292NS
1301NS
1312NS

ExamplenR8(CH2)qR1X1
1321HS
1331NS
1341HS
1351NS
1361HS
1371 NS
1381NS
1391NS
1401NS
1411NS

ExamplenR8(CH2)qR1X1
1421HS
1431HS
1441HCH2
1451HCH2
1461HCH2
1471 HCH2
1481HS
1491HS
1502HS
1511HS
1522HS
1531HS
1541HS

ExamplenR8(CH2)qR1X1
1551HS
1561HS
1571HS
1581 HS
1591HS
1601HS
1611HS
1621HCH2

TABLE 2

Examples 163-250
ExamplenR6R7NR1X1
1631CNCH2
1642CNCH2
1651HS
1662HS
1671CNS
1682CNS
1691HCH2
1702HCH2
1711CNCH2
1722CNCH2
1731HS
1742HS
1751CNCH2
1762CNCH2
1771HS
1782HS
1791CNCH2
1802CNCH2
1811HS
1822HS
1831CNCH2
1842CN CH2
1851HS
1862HS

ExamplenR6R7NR1X1
1871CNCH2
1882CNCH2
1891HS
1902HS
1911NH2CNCH2
1922CNCH2
1931HS
1942HS
1951CNCH2
1962CNCH2
1971HS
1982HS
199 1CNCH2
2002CNCH2
2011HS
2022HS
2031CNCH2
2042CNCH2
2051HS
2062HS
2071CNCH2
2082CNCH2
2091HS
2102HS
2111CNCH2
2122CNCH2
2131HS
2142HS
2151CNCH2
2162CNCH2
2171HS
2182HS

ExamplenR6R7NR1X1
2191CNCH2
2202CNCH2
2211HS
2222NS
2231CNCH2
2242CNCH2
2251HS
2262HS
2271CNCH2
2282CNCH2
2291HS
2302HS
2311CNCH2
2322CNCH2
2331HS
2342HS
2351CNCH2
2362CNCH2
2371HS
2382HS
2391CNCH2
2402CNCH2
2411HS
2422HS
2431CNCH2/sub>
2442CNCH2
2451HS
2462HS
2471CNCH2
2482CNCH2
2481HS
2502HS

TABLE 3

Examples 251-266
ExamplenR6R7NR1X1
2511CNCH2
2522CNCH2
2531NS
2542NS
2551CNCH2
2562CNCH2
2571NS
2582NS
2591CNCH2
2602CNCH2
2611HS
2622HS
2631CNS
2642CNS
2651HCH2
2662HCH2

2
TABLE 4

Examples 267-318
ExamplenR8(CH2)qR1X1
2671CNCH2
268CNCH2
2691CNS
2702CNS
2711CNCH2
2722CNCH2
2731CNCH2
2742CNCH2
2751CNCH2
2762CNCH2
2771CNCH2
2782CNCH2
2791CNCH2
2802CNCH2
2811 HCH2
2822HCH2

ExamplenR8(CH2)qR1X1
2831NCH2
2842NCH2
2851NCH2
2862NCH2
2871NS
2882NS
2891NS
2902NS
2911NS
2922NS
2931 CNCH2
2942CNCH2
2951CNCH2
2962CNCH2
2971CMCH2
2982CNCH2
2991CNCH2
3002CNCH2
3011CNCH2
3022CNCH2
3031CNCH2
3042CNCH2

ExamplenR8(CH2)q R1X1
3051CNCH2
3062CNCH2
3071HS
3082HS
3091HS
3102HS
3111HS
3122HS
3131HS
3142HS
3151HS
3162HS
3171HS
3182HS
TABLE 5

Examples 319-378
ExampleR4BR1X1
319NH2CNCH2

ExampleR4BR1X1
320CNCH2
321CNCH2
322 CNCH2
323CNCH2
324CNCH2
325CNCH2
326CNCH2
327NCH2
328NCH2
329NS
330NS
331NS

ExampleR4BR1X1
332HS
333CNSN 2
334CNCH2
335CNS
336CNS
337CNCH2
338CNCH2
339CNCH2
340CNCH2
341HS
342HS
343HS

ExampleR4BR1X1
344NS
345 NS
346NS
347NS
348NS
349NS
350NS
351NS
352NS
353NS

N
ExampleR4BR1X1
354NS
355NS
356NS
357S
358NS
359NS
360NS
361NCH2
362NCH2
363NS

td align="center"> N
ExampleR4BR1X1
364HS
365NS
366HS
367NS
368HS
369S
370NS
371NS
372NS
373NS

ExampleR4BR1X1
374NS
375NS
376NCH2
377NCH2
378NCH2
TABLE 6

Examples 379-418
ExamplenR8(CH2)qR1X1
3791CNCH2
3802CNCH2
3811CNCH2
3822CNCH2

1
ExamplenR8(CH2)qR1X1
3831CNCH2
3842CNCH2
3851CNCH2
3862CNCH2
3871 CNCH2
3882CNCH2
3891CNCH2
3902CNCH2
3911CNCH2
3922CNCH2
3931CNCH2
3942CNCH2
3951NCH2
3962NCH2
3971NS
3982NS
3991CNS
4002CNS
401CNCH2
4022CNCH2
4031CNCH2
4042CNCH2
4051CNCH2
4062CNCH2
4071CNCH2
4082CNCH2

ExamplenR8(CH2)qR1X1
4091CNCH2
4102CNCH2
4111 CNCH2
4122CNCH2
4131NS
4142NS
4151NS
4162NS
4171NS
4182NS
TABLE 7

Examples 419-438
ExamplemR6R7N
4191
4201
4211

ExamplemR6R7N
4221
4231
4241
4252
4263
4271
4282
4293
4301
4312
4323
4332
4343
4352
4363
4372
4383

TABLE 8

Examples 439-450
ExamplenR8(CH2)qR1X1
4391CNCH2
4402CNCH2
4411CNCH2
4422CNCH2
4431NS
4442NS
4451CNCH2
4462CNCH2
4471CNCH2
4482CNCH2
4491 CNCH2
4502CNCH2

EXAMPLE 451

Determination of the activity

Assess the ability of compounds to inhibit DP IV, using the analysis methods described in WO 95/15309. All compounds described in the preceding examples, are competitive inhibitors of DP-IV with values of Kiless than 300 nm.

EXAMPLE 452

The definition of activity in vivo

Antidiabetic effect of the selected compounds was shown in obese rats of Zucker (Zucker) using standard oral test glucose tolerance. Control rats probe is inserted through the glucose solution and determine the plasma glucose level. These rats exhibit pronounced hyperglycemia. Compounds according to the present invention is dissolved in a solution of glucose in different concentrations, so that the rats could receive different doses of the compounds simultaneously with glucose provocation. Hyperglycemic deviation is reduced dependent on the dose in animals receiving from 0.1 to 100 mg/kg of the inhibitor of DP-IV.

EXAMPLE 453

The pharmaceutical composition

Tablets containing 100 mg of the compound from example 1 as an active ingredient, is obtained using the following components:

Connection example 1200,0 g
Corn starch71,0 g
Hydroxypropylcellulose18.0 g
Calcium carboxymethylcellulose13,0 g
Magnesium stearate3.0 g
Lactose195.0 g
Only500.0 g

The source components are mixed and then pressed to obtain 2000 tablets 250 mg, each containing 100 mg of the compound from example 1.

From the above description it is seen that the compounds according to the present invention are inhibitors of DP-IV, and, accordingly, we should expect that they will be useful as drugs in the treatment of impaired glucose tolerance, type II diabetes and other diseases in which inhibition of the specified enzyme leads to a weakening of the corresponding primary pathology or reduce symptoms.

The present invention defines the following claims.

1. A compound selected from derivatives of formula 1, their tautomers and stereoisomers and pharmaceutically acceptable salts of these derivatives, tautomers and isomers

where X1selected from a sulfur atom and a methylene group;/p>

X2selected from O, S or methylene;

X3indicates either NR5or carbonyl group;

R1denotes either a hydrogen atom or a nitrile group;

R2and R3chosen independently from N and C1-C6of alkyl;

R4means R4Awhen X3denotes NR5and R4Bwhen X3denotes a carbonyl group;

R4Aselected from R6R7NC(=O)R6R7NC(=S), R8(CH2)qC(=O)

R8(CH2)qC(=S), R8(CH2)qSO2and R8(CH2)qOC(=O);

R4Bmeans R6R7N;

R5denotes N;

R6and R7chosen independently of R8(CH2)qor together they form

-(CH2)2-Z1-(CH2)2- or-CHR9-Z2-CH2-CHR10-;

R8selected from H, C1-C4of alkyl, cycloalkyl condensed with a benzene ring, acyl, dialkylamino, dialkylamino, N-alkylpiperidines, optionally substituted aryl, optionally substituted α-alkylbenzene, optionally substituted of Arola, optionally substituted arylsulfonyl and optionally substituted heteroaryl, which represents a monocyclic five-and six-membered ring aromatic group with one or two heteroatoms, which are selected from nitrogen, oxygen and sulfur, and derivatives of these rings fused with benzene;

R9and R10chosen independently from H, carbamoyl, hydroxymethyl and cyanomethyl;

Z1chosen from -(CH2)r-, -O -, and-N((CH2)qR8)-;

Z2denotes optionally substituted orthophenylene group;

m is 1-3;

n is 0-4;

R denotes 2-5;

q denotes 0 to 3; and

r denotes 1 or 3;

provided that when X2denotes CH2X3denotes NH and R4means R8CH2O(CO), R8is not unsubstituted phenyl or nitrophenyl; and provided that when X1denotes CH2, R1denotes H, X2denotes CH2X3denotes NH and R4means R8(CH2)qC(=O)R8(CH2)qwill not be the stands or ethyl.

2. The compound according to claim 1, where R1denotes a nitrile group.

3. The compound according to claim 2, where the stereochemistry of the nitrile group is represented by formula 2

4. The compound according to claim 1 or 2, where the stereochemistry of the center, adjacent to the primary amine corresponds to the S configuration represented by the formula 3

5. The compound according to claim 4, where R1denotes a nitrile group and the stereochemistry of the nitrile group is represented by formula 4

6. The compound according to any one of the preceding paragraphs, where m = 1.

7. The compound according to any one of the preceding paragraphs, where R2and R3means independently H or methyl.

8. The compound according to any one of the preceding paragraphs, where m is 1, X2denotes-CH2and R2and R3both represent N.

9. The compound according to any one of claims 1 to 7, where m = 1, X2represents-O - and one of R2and R3denotes methyl and the other represents N.

10. The compound according to any one of claims 1 to 7, where m = 1, X2represents-S -, and R2and R3both represent methyl.

11. The compound according to any one of the preceding paragraphs, where X3denotes NH.

12. Connection to item 11, where m = 1, R2and R3denote N and n = 1 or 2.

13. The connection section 12, where R4means R2CO or R8NHCO and R8denotes optionally substituted heteroaryl.

14. The compound according to any one of claims 1 to 7, where m = 1, X2denotes-CH2-, R2and R3both represent H, n = 0 and X3means.

15. The connection 14, where R4means R6NH.

16. The connection indicated in paragraph 15, where R6denotes optionally substituted hetero is the Rila mountains.

17. The connection 13 or 16, where the specified heteroaryl group not substituted or substituted in one or two positions, and these substituents selected from C1-C6of alkyl, C1-C6alkyloxy, fluorine, chlorine and triptorelin group.

18. The compound according to claim 1, where R1denotes CN and X1denotes CH2.

19. The compound according to claim 1, where R1denotes N and X1denotes S.

20. The compound according to claim 1, where X3denotes NH and R4selected from R6R7N(CO), R8(CH2)qCO and R8(CH2)qSO2.

21. The compound according to claim 1, which is selected from

(2S)-1-[Nω(pyrazinyl-2-carbonyl)-L-ornithine]pyrrolidin-2-carbonitrile,

(2S)-1-[Nω(pyrazinyl-2-carbonyl)-L-leinil]pyrrolidin-2-carbonitrile,

(2S)-1-[(2'S)-2'-amino-4'-(pyrazinyl-2"-carbylamine)butanoyl]pyrrolidin-2-carbonitrile,

(4R)-3-[Nω(pyrazinyl-2-carbonyl)-L-leinil]thiazolidin-4-carbonitrile,

(2S)-1-[Nω-(pyridyl-3-methyl)-L-glutaminyl]pyrrolidin-2-carbonitrile,

1-[Nω(pyrazinyl-3-carbonyl)-L-ornithine]pyrrolidine,

(2S)-1-[S-(acetamidomethyl)-L-cysteinyl]pyrrolidin-2-carbonitrile,

3-[Nω-(2-chloropyridin-3-carbonyl)-L-ornithine]thiazolidine,

1-[Nω-(2-chloropyridin-3-carbonyl)-L-is retinyl]pyrrolidine,

(2S)-1-[Nω-(2-chloropyridin-3-carbonyl)-L-ornithine]pyrrolidin-2-carbonitrile,

3-[Nω(pyrazinyl-2-carbonyl)-L-ornithine]thiazolidine,

3-[Nω-(2-Hinckley)-L-leinil]thiazolidine,

3-[Nω-(2-Hinckley)-L-ornithine]thiazolidine,

(2S)-1-[Nω-(2-Hinckley)-L-ornithine]pyrrolidin-2-carbonitrile,

3-[Nω-(6-methylpyrazine-2-carbonyl)-L-ornithine]thiazolidine,

3-[Nω-(isoquinoline-3-carbonyl)-L-ornithine]thiazolidine,

3-[Nω-(6-triftormetilfosfinov)-L-ornithine]thiazolidine,

(2S)-1-[(2'R)-3'-(acetamidomethyl)-2'-amino-3'-methylbutanoyl]pyrrolidin-2-carbonitrile,

(2S)-1-[S-(3-picolylamine)-L-cysteinyl]pyrrolidin-2-carbonitrile,

3-[Nω-(3-pyridylcarbonyl)-L-ornithine]thiazolidine,

3-[O-(3-chlorobenzylamino)serenil]thiazolidine and

3-[(2'S)-2'-amino-5'-oxo-5'-(1",2",3",4"-tetrahydroisoquinoline-2"-yl)pentanoyl]thiazolidine.

22. The compound according to any one of claims 1 to 21 for obtaining a pharmaceutical composition intended for treating at least one disease group, including type 2 diabetes, impaired glucose tolerance, growth hormone deficiency, polycystic ovary syndrome and autoimmune and inflammatory diseases the project.



 

Same patents:

FIELD: organic chemical, pharmaceuticals.

SUBSTANCE: invention relates to new compounds having JAK3 kinase inhibitor activity, methods for production thereof, intermediates, and pharmaceutical composition containing the same. In particular disclosed are aromatic 6,7-disubstituted 3-quinolinecarboxamide derivatives of formula I and pharmaceutically acceptable salts thereof useful in production of drugs for treatment of diseases mediated with JAK3. In formula n = 0 or 1; X represents NR3 or O; Ar is selected from phenyl, tetrahydronaphthenyl, indolyl, pyrasolyl, dihydroindenyl, 1-oxo-2,3-dihydroindenyl or indasolyl, wherein each residue may be substituted with one or more groups selected from halogen, hydroxy, cyano, C1-C8-alkoxy, CO2R8, CONR9R10 C1-C8-alkyl-O-C1-C8-alkyl, etc., wherein R-groups are independently hydrogen atom or C1-C8-alkyl; meanings of other substitutes are as define in description.

EFFECT: new compounds having value biological properties.

17 cl, 222 ex

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

SUBSTANCE: invention relates to a method for preparing an antidiabetic agent pioglitazone of the formula (I): . Method involves condensation of 4-substituted phenol or phenolate of the general formula (II): wherein R represents organic radical comprising amino-group and chosen from group comprising group of the general formula: -NHRa (IIa) wherein Ra means hydrogen atom or protective group that is removed before the following treatment, and group of the general formula: wherein Rb represents carboxyl group as free acid or as salt or ester; M represents hydrogen atom or alkaline metal with pyridine base of the general formula (III): wherein Z means a removing group distinguishing from halogen atom and wherein the following steps are carried out: (a) diazotization reaction of amino-group as a moiety of organic radical R; (b) conversion of diazotized radical R to derivative of 2-halogenpropionate or 2-halogenpropionitrile of the formula: wherein Rb is determined above; X represents halogen atom; (c) cyclization of derivative of 2-halogenpropionate or 2-halogenpropionitrile with thiourea, and (d) hydrolysis of imine prepared. In case when R represents group of the formula (IIa) method involves firstly carrying out the condensation reaction followed by carrying out steps (a)-(d) to obtain agent of the formula (I); or in case when R represents group of the formula (IIb) then method involves firstly carrying out steps (a)-(d) followed by condensation with pyridine base of the general formula (III) to obtain agent of the formula (I). Also, invention describes compounds of the formula (V): wherein Ra represents a protective group chosen from group comprising acyl, n-alkoxycarbonyl, tert.-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, 2-cyanoethoxycarbonyl as an intermediate substance in synthesis of compound of the formula (I).

EFFECT: improved preparing method of agent.

12 cl, 5 ex

FIELD: organic chemistry, medicine, virology, pharmacy.

SUBSTANCE: invention relates to new non-nucleoside inhibitors of reverse transcriptase activity of the formula (1): wherein R1 represents oxygen atom (O), sulfur atom (S); R2 represents optionally substituted nitrogen-containing heterocycle wherein nitrogen atom is at position 2 relatively to the bond with (thio)urea; R3 represents hydrogen atom (H), (C1-C3)-alkyl; R4-R7 are chosen independently from hydrogen atom (H), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, halogen-(C1-C6)-alkyl, (C1-C6)-alcanoyl, halogen-(C1-C6)-alcanoyl, (C1-C6)-alkoxy-, halogen-(C1-C6)-alkoxy-group, hydroxy-(C1-C)-alkyl, cyano-group, halogen atom, hydroxy-group; X represents group of the formula: -(CHR8)-D-(CHR8)m- wherein D represents -O or -S-; R8 represents hydrogen atom (H); n and m represent independently 0, 1 or 2, and to its pharmaceutically acceptable salts. Also, invention relates to a pharmaceutical composition based on these compounds possessing inhibitory effect with respect to activity of HIV-1 reverse transcriptase, and to using these compounds in preparing medicinal agents used in treatment of HIV-1 and to intermediates compounds.

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

45 cl, 1 tbl, 57 ex

FIELD: organic chemistry, medicine, cosmetics, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): wherein R1 means radical of the following formulae: (a) or (b) wherein R2 and R3 are similar or different and mean hydrogen atom, alkyl with 10-12 carbon atoms, aryl, radical -OR7; X means a binding fragment of the following formula: -(CH2)m-(Z)n-(CO)p-(W)q- wherein a binding fragment can be read from the left to the right or inversely; R4 means alkyl with 1-12 carbon atoms, aryl, aralkyl, heteroaryl or 9-fluorenylmethyl; Y means radical -CH2 or sulfur atom; R5 means hydroxyl, alkoxyl with 1-6 carbon atoms, radical -NH-OH or radical -N(R8)(R9); R6 means alkyl with 1-12 carbon atoms, radical -OR10 or radical -(CH2)r-COR11; R7 means hydrogen tom or aralkyl; Z means oxygen atom or radical -NR12; W means oxygen atom, radical -NR13 or radical -CH2; m, n, p and q are similar or different and can mean 0 or 1 under condition that the sum (m + n + p + q) = 2 or above, and when p = 0 then n or q = 0; R8 means hydrogen atom; R9 means hydrogen atom or aryl; r means 0 or 1; R10 means alkyl with 1-12 carbon atoms; R11 means hydroxyl or radical -OR14; R12 means hydrogen atom or alkyl with 1-12 carbon atoms; R13 means hydrogen atom or alkyl with 1-12 carbon atoms; R14 means alkyl with 1-12 carbon atoms; and optical and geometric isomers of abovementioned compounds of the formula (I), and their salts also. These compounds are useful as activating agents of receptors of type PPAR-γ in pharmaceutical compositions designated for using in medicine, in particular, in dermatology, in treatment of cardiovascular diseases and related to immunity of diseases and/or diseases associated with lipid metabolism, and in cosmetic compositions also.

EFFECT: valuable properties of compounds and compositions.

19 cl, 1 tbl, 2 dwg, 37 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to substituted bicyclic heterocyclic compounds of the formula (I): their tautomeric forms, stereoisomers, polymorphous forms, pharmaceutically acceptable salts and pharmaceutically acceptable solvates wherein groups R1, R2, R3 and R4, and groups R5 and R6 when they are bound with carbon atom they represent hydrogen, halogen atom, hydroxy-group, alkyl, alkoxy-group; R5 and R6 as a single group or both can represent also an oxo-group when they are bound with carbon atom; when R5 and R6 are bound with nitrogen atom then they represent hydrogen atom, hydroxy-group or such unsubstituted groups as alkyl, alkoxy-group, aralkyl. X means oxygen or sulfur atom; Ar means phenylene, naphthylene or benzofuryl. Proposed compounds can be used against obesity and hypercholesterolemia. Also, the invention describes methods for preparing compounds, pharmaceutical compositions, method for treatment and using compounds proposed.

EFFECT: valuable medicinal properties of compounds and compositions.

52 cl, 77 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I) and pharmaceutical composition based on thereof possessing properties of ligand binding with adenosine receptors selectively. Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable properties of compounds.

6 cl, 375 ex

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

SUBSTANCE: invention relates to new derivatives of 4-aminopiptidine of the general formula (I): wherein R1 means (C1-C6)-alkyl, -(CH2)m-Y-Z11 or -(CH2)m-Z12 wherein Z11 means (C1-C6)-alkyl; Z12 means bis-phenyl, (C3-C7)-cycloalkyl, (C3-C7)-heterocycloalkyl with 1 or 2 heteroatoms taken among nitrogen (N) or oxygen (O) atoms, possibly substituted phenyl, naphthyl, possibly substituted (C5-C9)-heteroaryl wherein heteroatoms are taken among N; or Z12 means ; Y means O; or R1 means ; R2 means -C(Y)-NHX1, -C(O)X2 or -SO2X3; R3 means hydrogen atom (H), (C1-C4)-alkyl, (C2-C4)-alkenyl, possibly substituted heteroarylalkyl or -C(Y)-NHX1, -(CH2)n-C(O)X2 or -SO2X3 wherein X1-X3 have different values. Also, invention describes methods for preparing indicated substances by synthesis in liquid and solid phase. These compounds possessing good affinity to definite subtypes of somatostatin receptors can be used in treatment of pathological states or diseases caused by one or some somatostatin receptors.

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

14 cl, 4 tbl, 778 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of isoquinoline carboxamide of the formula (I):

and to their pharmaceutically acceptable salts wherein R1 means hydrogen atom, hydroxy-group or -NHR2 wherein R2 means alkyl, arylalkyl, heterocyclylalkyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, arylalkylcarbonyl, heterocyclylalkylcarbonyl that comprises one or some heteroatoms taken among nitrogen and oxygen atoms, alkyloxycarbonyl, arylalkyloxycarbonyl, heterocyclylalkyloxycarbonyl that comprises one or some heteroatoms taken among nitrogen atom, heterocyclyl that comprises one or some heteroatoms taken among nitrogen and sulfur atoms, alkylsulfonyl, arylsulfonyl or the group of the formula:

R3 and R4 mean alkyl independently of one another; R5 means alkyl; or R4 and R5 in common with carbon and sulfur atoms to which they are bound form a heterocycle; R6 means alkyl; R13 means hydrogen atom or the group of the formula:

R15 means aryl under condition that if R3, R4 and R5 form methyl, R6 forms tert.-butyl then R13 means hydrogen atom, and if R15 means phenyl then R2 doesn't mean benzyloxycarbonyl and 2-quinoline carbonyl (other values of radicals are given in cl. 1 of the invention claim). Also, invention relates to a medicinal agent based on these compounds used in treatment of HIV-mediated diseases. Invention provides preparing new compounds and a medicinal agent based on thereof in aims for treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and medicinal agent.

14 cl, 11 tbl, 173 ex

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention elates to novel derivatives of uracil of the formula [I] possessing herbicide activity, a herbicide composition based on thereof and to a method for control of weeds. In derivatives of uracil of the formula [I] the group Q-R3 represents a substituted group taken among:

wherein a heterocyclic ring can be substituted with at least a substitute of a single species taken among the group involving halogen atom, (C1-C6)-alkyl-(C1-C6)-alkoxy; Y represents oxygen, sulfur atom, imino-group or (C1-C3)-alkylimino-group; R1 represents (C1-C3)-halogenalkyl; R2 represents (C1-C3)-alkyl; R3 represents OR7, SR8 or N(R9)R10; X1 represents halogen atom, cyano-group, thiocarbamoyl or nitro-group; X2 represents hydrogen or halogen atom wherein each among R7, R8 and R10 represents independently carboxy-(C1-C6)-alkyl and other substitutes given in the invention claim; R9 represents hydrogen atom or (C1-C6)-alkyl. Also, invention relates to intermediate compounds used in preparing uracil derivatives.

EFFECT: improved preparing method, valuable properties of compounds.

40 cl, 16 sch, 12 tbl, 65 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to derivatives of piperidine of the general formula (I): in free form or as a salt wherein Ar1 means phenyl substituted with one or some halogen atoms; Ar2 means phenyl or naphthyl that can be unsubstituted or substituted with one or some substitutes chosen from the group comprising halogen atom, cyano-, hydroxy-, nitro-group, (C1-C8)-alkyl, (C1-C8)-halogenalkyl, (C1-C8)-alkoxy-group or (C1-C8)-alkoxycarbonyl; R1 means hydrogen atom or (C1-C8)-alkyl optionally substituted with hydroxy-,(C1-C8)-alkoxy-, acyloxy-group, -N(R2)R3, halogen atom, carboxy-group, (C1-C8)-alkoxycarbonyl, -CON(R4)R5 or monovalence cyclic organic group; each among R2 and R3 and independently of one another means hydrogen atom or (C1-C8)-alkyl, or R2 means hydrogen atom and R3 means acyl or -SO2R6, or R and R3 in common with nitrogen atom to which they are bound form 5- or 6-membered heterocyclic group; each among R4 and R5 and independently of one another means hydrogen atom or (C1-C8)-alkyl, or R4 and R in common with nitrogen atom to which they are bound form 5- or 6-membered heterocyclic group; R6 means (C1-C8)-alkyl, (C1-C8)-halogenalkyl or phenyl optionally substituted with (C1-C8)-alkyl; n means 1, 2, 3 or 4 under condition that when Ar1 means para-chlorophenyl and R1 means hydrogen atom then Ar2 doesn't mean phenyl or para-nitrophenyl. Compounds of the formula (I) possess the inhibitory CCR-3 activity and can be used in medicine.

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

7 cl, 47 ex

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes new substituted derivatives of pyrazole of the general formula (I): wherein n = 0 or 1; group A represents independently hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, cycloalkyl group with 3-6 carbon atoms or phenyl group having substituting groups optionally; group D represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkoxy-group with 1-4 carbon atoms, cycloalkyl group with 3-6 carbon atoms, halogen atom, alkoxycarbonyl group with 1-4 carbon atoms, alkylsulfonyl group with 1-4 carbon atoms or phenyl group; group E represents hydrogen atom, halogen atom or phenyl group; groups R1 and R2 both represent halogen atom; group R3 represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkynyl group with 2-4 carbon atoms or benzyl group; groups R4 and R5 are similar or different and each represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, cycloalkyl group with 3-8 carbon atoms that can be substituted with alkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkynyl group with 2-4 carbon atoms, cyanomethyl group or phenyl group; or each R4 and R5 group means benzyl group; or each R4 and R5 group represents α- or β-phenethyl group having substituting groups at benzyl ring optionally. Indicated substituting groups represent alkoxy-groups with 1-4 carbon atoms wherein indicated substituting groups substitute hydrogen atom at the arbitrary positions 0-2 of the benzyl ring; or groups R4 and R5 form in common 5-membered or 6-membered aliphatic ring wherein the indicated ring can be substituted with alkyl groups with 1-4 carbon atoms and indicated ring can comprise one or two heteroatoms chosen from nitrogen oxygen and sulfur atom, and a method for their preparing. Also, invention describes herbicide compositions based on compound of the formula (I). Invention provides preparing herbicide compositions showing the strong herbicide effect and broad herbicide spectrum of their effect.

EFFECT: improved preparing method, valuable properties of derivatives and compositions.

7 cl, 6 tbl, 3 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention relates to a new biologically active compound of 4-oxoquinoline that is useful as an anti-HIV agent and to its pharmaceutically acceptable salt. Invention describes an anti-HIV agent comprising compound of 4-oxoquinoline represented by the following formula [I] or its pharmaceutically acceptable salt as an active component wherein ring Cy represents phenyl group, naphthyl group or pyridyl group and each this group is substituted optionally with 1-5 substituted chosen from the following group A wherein A represents the group consisting of cyano-group, phenyl group, nitro-group, halogen atom, (C1-C4)-alkyl group, halogen-(C1-C4)-alkyl group, halogen-(C1-C4)-alkoxy-group, -ORa1, -SRa1, -NRa1Ra2, -CONRa1Ra2, -SO2NRa1Ra2, -NRa1CORa3, -SO2Ra3, -NRa1SO2Ra3 and -COORa1 wherein Ra1 and Ra2 are similar or different and each represents hydrogen atom, (C1-C4)-alkyl group or benzyl group, and Ra3 represents (C1-C4)-alkyl group; R1 represent a substitute chosen from the following group B, or (C1-C10)-alkyl group optionally substituted with 1-3 substitutes chosen from halogen atom and the following group B wherein the group B represents the group consisting of phenyl group optionally substituted with phenyl group or 1-5 halogen atoms; (C3-C6)-cycloalkyl group, imidazolyl group, benzothiophenyl group, thiazolyl group optionally substituted with 1-3 (C1-C6)-alkyl groups, morpholinyl group, pyridyl group, -ORa4, -SRa4, -NRa4Ra5, -CONRa4Ra5, -SO2NRa4Ra5, -CORa6, -NRa4CORa6, -SO2Ra6, -NRa4SO2Ra6, -COORa4 and -NRa5COORa6 wherein Ra4 and Ra5 are similar or different and each represents hydrogen atom, (C1-C4)-alkyl group or phenyl group; Ra6 represents (C1-C4)-alkyl group; R2 represents hydrogen atom or (C1-C4)-alkyl group; R31 represents hydrogen atom, cyano-group, hydroxy-group, halogen atom or (C1-C4)-alkoxy-group; X represents -C-R32, and Y represents -C-R33 or nitrogen atom wherein R32 and R33 are similar or different and each represents hydrogen atom, cyano-group, halogen atom, pyrrolidinyl group, (C1-C10)-alkyl group optionally substituted with 1-3 halogen atoms, -ORa7, -SRa7, -NRa7Ra8, -NRa7CORa9, -COORa10 or -N=CH-NRa10Ra11 wherein Ra7 and Ra8 are similar or different and each represents hydrogen atom, phenyl group or (C1-C10)-alkyl group optionally substituted with (C3-C6)-cycloalkyl group or hydroxy-group; Ra9 represents (C1-C4)-alkyl group and Ra10 and Ra11 are similar or different and each represents hydrogen atom or (C1-C4)-alkyl group. Also, invention describes compound of the formula (III) given in the invention description, integrase inhibitor, antiviral agent, ant-HIV composition, anti-HIV agent, using compound of 4-oxoqionoline, method for inhibition of integrase activity, method for prophylaxis or treatment of viral infectious disease, pharmaceutical composition used for inhibition of integrase activity, antiviral composition and commercial package (variants). Invention provides the development of a pharmaceutical agent possessing inhibitory effect on activity of integrase.

EFFECT: valuable medicinal properties of compound, agent and composition.

40 cl, 7 tbl, 250 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes derivatives of substituted triazoldiamine of the formula (I): wherein R1 represents (C1-C4)-alkyl, phenyl possibly substituted with halogen atom, amino-group substituted with -SO2-(C1-C4)-alkyl, imidazolyl, 1,2,4-triazolyl, imidazolidinone, dioxidoisothiazolidinyl, (C1-C4)-alkylpiperazinyl, residue -SO2- substituted with amino-group, (C1-C4)-alkylamino-group, (C1-C4)-dialkylamino-group, pyridinylamino-group, piperidinyl, hydroxyl or (C1-C4)-dialkylamino-(C1-C3)-alkylamino-group; R2 represents hydrogen atom (H); or R1 represents H and R2 means phenyl possibly substituted with halogen atom or -SO2-NH2; X represents -C(O)-, -C(S)- or -SO2-;R3 represents phenyl optionally substituted with 1-3 substitutes comprising halogen atom and nitro-group or 1-2 substitutes comprising (C1-C4)-alkoxy-group, hydroxy-(C1-C4)-alkyl, amino-group or (C1-C4)-alkyl possibly substituted with 1-3 halogen atoms by terminal carbon atom; (C3-C7)-cycloalkyl possibly substituted with 1-2 groups of (C1-C4)-alkyl; thienyl possibly substituted with halogen atom, (C1-C4)-alkyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C2-C4)-alkenyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, pyrrolyl, pyridinyl or amino-group substituted with -C(O)-C1-C4)-alkyl; (C1-C4)-alkyl substituted with thienyl or phenyl substituted with halogen atom; (C2-C8)-alkynyl substituted with phenyl; amino-group substituted with halogen-substituted phenyl; furyl, isoxazolyl, pyridinyl, dehydrobenzothienyl, thiazolyl or thiadiazolyl wherein thiazolyl and thiadiazolyl are substituted possibly with (C1-C4)-alkyl; to their pharmaceutically acceptable salts, a pharmaceutical composition based on thereof and a method for its preparing. New compounds possess selective inhibitory effect on activity of cyclin-dependent kinases and can be used in treatment of tumor diseases.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and composition.

16 cl, 3 tbl, 26 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing heterocyclic compounds describing by the general formula (I): . Invention describes a method for preparing compounds of the formula (I) wherein R1 represents hydrogen atom or alkyl group; A represents ethylene group that can be substituted with alkyl or trimethylene group that can be substituted with alkyl; D represents nitro- or cyano-group; X represents oxygen or sulfur atom, or the group of the formula: or wherein R3 represents hydrogen atom or alkyl group; Z represents 2-chloropyrid-5-yl. Method involves interaction of compound of the formula (II): wherein A, D and X abovementioned values with a base in the presence of diluting agent followed by interaction of the reaction mixture with a mixture consisting of 2-chloro-5-chloromethylpyridine/2-chloro-5-methylpyridine with corresponding hydrochlorides.

EFFECT: simplified technology, enhanced yield of end product.

4 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to water-soluble azole compounds that can be used in biology and medicine. Invention describes a water-soluble azole compound of the formula (I):

or its pharmaceutically acceptable salt wherein each R and R1 means independently hydrogen atom or (C1-C6)-alkyl; A means group of the formula:

wherein R3 represents phenyl group with one or more halide atoms as substitutes; R4 represents hydrogen atom or -CH3; R5 represents hydrogen atom or in common with R4 it can represent =CH2; R6 represents 5- or 6-membered nitrogen-containing cycle that can comprise if necessary as substituted one or more groups taken among halogen atom, =O group, phenyl substituted with one or more groups taken among -CN, -(C6H4)-OCH2-CF2-CHF2 and -CH=CH-(C6H4)-OCH2-CF2-CHF2 or phenyl substituted with one or more groups taken among halogen atom and methylpyrazolyl group. Also, invention describes a method for preparing a water-soluble azole compound. Invention provides preparing new compounds that can be useful in medicine.

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

4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a prophylactic or therapeutic agent used against hyperlipidemia and comprising as an active component the heterocyclic compound of the formula [1]:

or its pharmaceutically acceptable salt wherein R1 represents aryl optionally substituted with similar or different one-three groups taken among alkyl, halogenalkyl, trihalogen alkyl, alkoxy-group and halogen atom; Het represents bivalent aromatic heterocyclic group of the formula [5]:

wherein X represents oxygen, sulfur atom or NR6 wherein R6 represents hydrogen atom or alkyl; R2 represents hydrogen atom, alkyl or trihalogenalkyl; D represents alkylene and alkenylene; E represents group of the formulae [3] or [4] wherein Y represents oxygen or sulfur atom; R3 and R4 are similar or different and each represents hydrogen atom or alkyl; p = 1; Z represents carboxy-group, alkoxycarbonyl, cyano-group or 1H-5-tetrazolyl. Also, invention relates to new compounds belonging to group of above enumerated heterocyclic compounds of the formula [1] that show effect reducing blood triglycerides level, low density lipoprotein cholesterol, glucose and insulin or effect enhancing high density lipoprotein cholesterol and effect reducing the atherogenic effect. Therefore, these compounds can be used in prophylaxis or treatment of hyperlipidemia, arteriosclerosis, heart ischemic disease, brain infarction, rheocclusion after percutaneous intraluminal coronary angioplasty, diabetes mellitus and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 170 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing compound of the formula: . Method involves interaction of compound of the formula: with compound of the formula: wherein Q means chlorine or bromine atom in the presence of solvent or diluting agent, an interphase catalyst and a base wherein solvent or diluting agent represent carbonic acid esters, an interphase catalyst represents ammonium quaternary salt, and a base represents carbonate. Method provides inhibition of process in formation of undesirable isomers.

EFFECT: improved preparing method.

1 cl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indol-3-yl of the formula (I):

wherein each A and B represents independently of one another oxygen atom (O), NH, CONH, NHCO or a direct bond; X means (C1-C2)-alkylene or a direct bond; R1 means hydrogen atom (H); R2 means hydrogen atom (H); R3 means NHR6, -NR6-C(=NR6)-NHR6, -C(=NR6)-NHR6, -NR6-C(=NR9)-NHR6, -C(=NR9)-NHR6 or Het1; each R4 and R5 represents independently of one another hydrogen atom (H); R7 means -(CH2)o-Ar, Het, OR6; R6 means hydrogen atom (H); R7 means (C1-C10)-alkyl, (C3-C10)-cycloalkyl; R8 means Hal, NO2 (nitro-group), CN (cyano-group), Z, -(CH2)o-Ar, COOR1, OR1, CF3, OCF3, NHR1; R9 means CN or NO2; Z means (C1-C6)-alkyl; Ar means aryl that can represent unsubstituted, monosubstituted, or polysubstituted R8; Hal means F, Cl, Br, J; Het means saturated, partially or completely saturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members wherein 1 or 2 nitrogen atom (N) and/or 1 or two sulfur atom (S) present, and heterocyclic radical can be monosubstituted with phenyl; Het1 means saturated, partially or completely unsaturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members and from 1 to 4 nitrogen atoms (N) that can be unsubstituted or monosubstituted NHX, or oxo-group; n = 0, 1 or 2; m = 0, 1, 2, 3, 4, 5 or 6; o means 0, 1 or 2; and their physiologically acceptable salts and solvates. Compounds of the formula (I) elicit intergin-inhibitory effect that allows their using as components of pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds.

11 cl, 4 sch, 1 tbl, 34 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to epothilones with modified thiazole substituent, methods for production thereof and pharmaceutical composition capable of cell growth inhibiting containing the same. Claimed compounds have general formula I , wherein P-Q represents double carbon bond or epoxy; R represents H, C1-C6-alkyl; G represents ; R1 represents and ; G1 and G2 represent hydrogen; G3 represents O, S, and NZ1; G4 represents H, optionally substituted C1-C6-alkyl, OZ2, Z2C=O and Z4SO2; G5 represents halogen, N3, CN, NC, heteroaryl containing nitrogen or oxygen, and heterocycle; G6 represents H, C1-C6-alkyl, or OZ5, wherein Z5 represents H, C1-C6-alkyl; G9 represents oxygen; Z1 represents H, optionally substituted C1-C6-alkyl, optionally substituted acyl; Z2 represents optionally substituted C1-C6-alkyl or aryl; Z4 represents optionally substituted aryl.

EFFECT: new epothilones capable of cell growth inhibiting.

19 cl, 39 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to series of new compounds that are inhibitors of enzyme dipeptidyl peptidase IV. Invention proposes a compound chosen from derivatives of the formula (1) its tautomers and stereomers and pharmaceutically acceptable salts of indicated derivatives, tautomers and isomers wherein R1 represents hydrogen atom (H) or -CN; X1 represents sulfur atom (S), oxygen atom (O), -SO2 or -CH2; X2 represents -CO, -CH2 or a covalent bond; Het represents nitrogen-containing heterocycle; n = 1-5. Invention proposes a pharmaceutical composition possessing properties of inhibitor of enzyme dipeptidyl peptidase IV, and a method for treatment of at least one diseases among diabetes mellitus type 2, reduced tolerance to glucose, growth hormone deficiency, polycystic ovary syndrome and autoimmune and inflammatory diseases. Invention provides preparing series of inhibitors of dipeptidyl peptidase IV showing the improved affinity to enzyme, preparing pharmaceutical compositions and their using in treatment of some human diseases including the reduced tolerance to glucose and diabetes mellitus of type 2.

EFFECT: valuable biochemical and medicinal properties of inhibitors.

14 cl, 6 tbl, 123 ex

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