Derivatives of aminomethylpyrrolidine with aromatic substitutes

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of aminomethylpyrrolidine of the formula (I) , their salts or hydrates wherein R1 represents aryl with from 6 to 10 carbon atoms or heteroaryl wherein heteroaryl is a five-membered ring or a six-membered ring and comprises from 1 to 2 heteroatoms taken among nitrogen, oxygen and sulfur atom; aryl and heteroaryl can comprise one or more substitutes taken among the group consisting of halogen atom or (C1-C6)-alkoxyl; each radical among R2, R3, R4, R5, R6, R7 and R8 represents hydrogen atom (H) independently; Q represents incomplete structure representing by the following formula: wherein R9 means (C3-C6)-cyclic alkyl that can be substituted with halogen atom; R10 means hydrogen atom (H); R11 means hydrogen atom (H), NH2; X1 means halogen atom; A1 represents incomplete structure representing by the formula (II): wherein X2 means hydrogen atom (H), halogen atom, halogenmethoxyl group, (C1-C6)-alkyl or (C1-C6)-alkoxyl group; X2 and above indicated R9 can be combined to form the ring structure and inclusion part of the main skeleton and such formed ring comprises oxygen, nitrogen or sulfur atom as a component atom of the ring and the ring can comprise (C1-C6)-alkyl as a substitute; Y means hydrogen atom (H). Compounds of the formula (I) elicit an antibacterial effect and can be used for preparing a therapeutic agent.

EFFECT: valuable medicinal properties of compounds.

2 tbl, 61 ex

 

The technical field

This invention relates to a synthetic quinolone antibacterial agent, which is useful as medical devices, veterinary drugs, drugs for use in aquaculture and antimicrobial preservative.

Thus, the invention relates to a synthetic quinolone antibacterial agent, in which the structure of the substituent in position 7 quinolone main skeleton or a suitable position (for example, position 7 1,4-dihydro-4-okahirongo skeleton, position 10 2,3-dihydro-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine skeleton, and the like) has a great influence on antibacterial activity, namely the quinolone derivative having as substituent 3-[1-amino-1-substituted aromatic group]methylpyrrolidine-1-yl that can provide an excellent antibacterial activity, and antibacterial agent and an antibacterial pharmaceutical compositions, which contain the connection.

The invention additionally relates to a synthetic quinolone antibacterial drug, namely 3-[1-amino-1-substituted aromatic group] methylpyrrolidine, which has a structure capable of providing excellent antibacterial act shall want to make, and is useful as an intermediate connection, and a secure connection.

Background of the invention

Since opening norfloksatsina was significantly improved antibacterial activity and pharmacokinetics of synthetic quinolone antibacterial agents, and now many of the compounds used in the clinical field as chemotherapeutic agents that are effective in the majority of systemic infectious diseases.

In recent years in the clinical field increased generation of bacteria with low sensitivity to synthetic quinolone antibacterial agents. For example, like Staphylococcus aureus (MRSA) and pneumococcus (PRSP), which are insensitive to antibiotics β -laktamovogo number, and enterococci (VRE), which are not sensitive to aminoglycoside antibacterial agents, an increasing number of cases where gram-positive bacteria, initially resistant to other means than synthetic quinolone antibacterial agents were also low-sensitivity to synthetic quinolone antibacterial agents. Therefore, in the area of the clinic requires the development of a tool having, in addition, high efficiency.

In addition, there was also a side effect, which is expressed in the fact that at the completion of the m the use of non-steroidal anti-inflammatory drugs appear cramps, as well as other side effects, such as toxicity and the like, thus, in this area requires the development of a synthetic quinolone antibacterial agent having, in addition, extra high security.

It is known that the structure of the substituents in position 7 and position 1 to a large extent are related to antibacterial activity, pharmacokinetics and safety of synthetic quinolone antibacterial agents. It is already known that quinolone derivative having as substituent 3-(aminomethyl)pyrrolidinyl in position 7 shows high antibacterial activity against gram-negative and gram-positive bacteria. For example, it is derived 7-[3-(aminomethyl)pyrrolidin-1-yl]chinolin-carboxylic acid [Journal of Medicinal Chemistry, vol. 29, p. 445 (1986)]. Also known derivative of 7-[3-(1-aminomethyl)pyrrolidin-1-yl]hinolincarbonova acid [Journal of Medicinal Chemistry, vol. 36, p. 871 (1993)], a derivative of 7-[3-(1-amino-1-methylethyl)pyrrolidin-1-yl]hinolincarbonova acid [Journal of Medicinal Chemistry, vol. 37, p. 733 (1994)], derived 7-[3-(1-aminoalkyl)pyrrolidin-1-yl] hinolincarbonova acid [Chemical & Pharmaceutical Bulletin, vol. 42, p. 1442 (1994)] and the like as derived hinolincarbonova acid having a substituent in the aminomethyl group, 3-(aminomethyl)pyrrolidin-1-yl.

However, to cover the firs in the aminomethyl group currently known 3-(aminomethyl)pyrrolidin-1-yl are only alkyl groups, and unknown quinolone compound having an aromatic group as a substituent, which relates to the present invention.

As an example you can refer to derivatives heylookaslongaswe acid having a cyclic substituent in the aminomethyl group, 3-(aminomethyl)pyrrolidin-1-yl, for example, JP-W-3-502452 (the term "JP-W"as used here means "not passed the examination published international patent application of Japan"), and it describes compounds represented by two General formulas shown below. However, a cyclic substituent in the aminomethyl group, 3-(aminomethyl)pyrrolidin-1-yl, described in this application is limited to cyclic alkyl, and not disclosed 3-[1-amino-1-substituted aromatic group]methylpyrrolidine-1-yl relating to this invention.

[In the above formula, R12represents alkyl having from 1 to 4 carbon atoms, vinyl, halogenated, hydroxyalkyl having from 2 to 4 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms, phenyl or phenyl substituted by halogen, alkyl, group NH2or HE, R14represents a straight, branched or cyclic lower alkyl having from 1 to 3 carbon atoms, and X3is CH, CF, CCl, CBr, N, F3, CNH2CNO2, R or COR' (in these formulas, R represents lower alkyl, and R' represents a hydrogen atom or lower alkyl)].

In the above formula, Z represents

(in which m is an integer from 0 to 4, and R15and R16each independently represents a hydrogen atom, lower alkyl or cycloalkyl). In this regard, the definition of the substituents and the like for the above two formulas are not the same for the compounds according to this invention, even if using the same notation.

In addition, in JP-W-9-503783 disclosed derivatives of 2-pyridonecarboxylic acid 4H-4-okahirongo skeleton and the like, represented by the following formula. However, quinolone compound according to this invention, having an aromatic substituent in the aminomethyl group, 3-(aminomethyl)pyrrolidin-1-yl relating to the invention, also not cited as an example in this application.

Disclosure of inventions

In light of the above, the inventors of this application have conducted intensive studies with the aim of obtaining excellent quinolone compounds. In the result, quite unexpectedly, it was found that the derivative substituted aromatic group aminomethylpyrrolidine represented by the formula (I)described below, its salts and their hydrates can exhibit a high antibacterial act shall want to make in relation to a wide range of gram-negative and gram-positive bacteria, including resistant to drugs bacteria, which ultimately led to the creation of this invention.

The inventors found that the compound represented by formula (I), in which the derivative substituted aromatic group aminomethylpyrrolidine is entered in position 10 2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine skeleton or position 7 6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-okahirongo skeleton, its salts and their hydrates, have excellent security, can exhibit a wide spectrum and excellent antibacterial activity against any of the gram-negative or gram-positive bacteria. At the same time it was found that it can exhibit a high antibacterial activity against resistant to the drugs gram-positive bacteria, including MRSA, PRSA and VPE, which is not expected before the invention.

Therefore, this invention relates to a compound represented by the following formula (I), its salts and their hydrates

{in which R1represents aryl having 6 to 10 carbon atoms, or heteroaryl,

where heteroaryl may be the five-membered ring or six-membered ring and can contain from 1 to 4 heteroatoms, optionally selected from nitrogen atom, oxygen atom and sulfur atom,

where d is installed aryl and heteroaryl can have one or more substituents, selected from the group consisting of alkyl having from 1 to 6 carbon atoms, halogen atom, hydroxyl, thiol, amino, nitro, cyano, carboxyl, carbamoyl, phenyl, alkoxyl having from 1 to 6 carbon atoms, alkylthio having from 1 to 6 carbon atoms, alkoxycarbonyl having from 2 to 6 carbon atoms, acyl having 2 to 5 carbon atoms and heteroaryl (this heteroaryl may be the five-membered ring or six-membered ring and can contain from 1 to 4 heteroatoms, optionally selected from nitrogen atom, oxygen atom and sulfur atom),

where mentioned among them, alkyl, alkoxyl, alkylthio, alkoxycarbonyl, acyl, phenyl and heteroaryl can have one or more substituents selected from the group consisting of halogen atom, hydroxyl, alkoxyl having from 1 to 6 carbon atoms, and alkylthio having from 1 to 6 carbon atoms, and

the amino group may have one or two substituent selected from the group consisting of formyl, alkyl having from 1 to 6 carbon atoms, acyl having 2 to 5 carbon atoms, and alkoxycarbonyl having from 2 to 5 carbon atoms,

R2and R3each independently represents a hydrogen atom or alkyl having from 1 to 6 carbon atoms,

where alkyl may have one or more substituents selected from the group consisting of hydroxyl, halogen atom, alkylthio, have from 1 to 6 carbon atoms, and alkoxyl having from 1 to 6 carbon atoms,

R4, R5and R6each independently represents a hydrogen atom, hydroxyl, a halogen atom, carbarnoyl, alkyl having from 1 to 6 carbon atoms, alkoxyl having from 1 to 6 carbon atoms, or akitio having from 1 to 6 carbon atoms,

where specified among them, the alkyl may have one or more substituents selected from the group consisting of hydroxyl, halogen atom and alkoxyl having from 1 to 6 carbon atoms,

R7and R8each independently represents a hydrogen atom or alkyl having from 1 to 6 carbon atoms,

Q represents a partial structure represented kedoya formula

[in which R9represents alkyl having from 1 to 6 carbon atoms, alkenyl having from 2 to 6 carbon atoms, halogenated having from 1 to 6 carbon atoms, cyclic alkyl having 3 to 6 carbon atoms which may have a Deputy, aryl which may have a Deputy, heteroaryl, which may have a Deputy, alkoxyl having from 1 to 6 carbon atoms, or alkylamino having from 1 to 6 carbon atoms,

R10represents a hydrogen atom or alkylthio having from 1 to 6 carbon atoms,

in which R10and above R9can be combined with the formation of the ring p is ktory the inclusion of the main skeleton, and thus formed ring may include a sulfur atom as a constituent ring atom, and the ring may have as a substituent alkyl having from 1 to 6 carbon atoms,

R11represents a hydrogen atom, amino, hydroxyl, thiol, halogenmethyl, alkyl having from 1 to 6 carbon atoms, alkenyl having from 2 to 6 carbon atoms, quinil having from 2 to 6 carbon atoms, or alkoxy having from 1 to 6 carbon atoms,

where the amino group may have one or two substituent selected from the group consisting of formyl, alkyl having from 1 to 6 carbon atoms, and acyl having from 2 to 6 carbon atoms,

when R11represents amino, hydroxyl or thiol, they can be protected by a protective group,

X1represents a halogen atom or a hydrogen atom,

And1represents a nitrogen atom or a partial structure represented by formula (II)

[in which X2represents a hydrogen atom, amino, a halogen atom, cyano, halogenmethyl, halogenmethyl, alkyl having from 1 to 6 carbon atoms, alkenyl having from 2 to 6 carbon atoms, quinil having from 2 to 6 carbon atoms, or alkoxy having from 1 to 6 carbon atoms,

where this among them, the amino group may have one or two substituent selected from the group consisting of formyl,alkyl, having from 1 to 6 carbon atoms, and acyl having 2 to 5 carbon atoms, and

X2and above R9can be combined with the formation of the ring structure by the inclusion of the main skeleton, and thus formed ring may include an oxygen atom, nitrogen atom and sulfur atom as a constituent ring atom, and the ring may have as a substituent alkyl having from 1 to 6 carbon atoms],

And2and3each independently represents a nitrogen atom or a carbon atom, and2and3and the carbon atom to which they are bound, form a partial structure

or incomplete structure

(in which > indicates the presence of 2 links with the nitrogen atom or carbon atom, the same will be used in future), and

Y represents a hydrogen atom, phenyl, acetoxymethyl, pivaloyloxymethyl, etoxycarbonyl, choline, dimethylaminoethyl, 5-indanyl, phthalidyl, 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl, 3-acetoxy-2-oxobutyl, alkyl having from 1 to 6 carbon atoms, alkoxymethyl having from 2 to 7 carbon atoms, or phenylalkyl (consisting of alkylene having from 1 to 6 carbon atoms, and phenyl)]}.

The invention also relates to the compound of formula (I), its salts or their hydrates, where Q in formula (I) has the structure is expressed by the formula:

or by the formula

(where A1, R9, R10, R11X1and Y have the meanings defined above);

the compound of formula (I), its salts or their hydrates, where Q in formula (I) has a structure represented by the formula:

(where A1, R9, R10, R11X1and Y have the meanings defined above);

the compound of formula (I), its salts or their hydrates, where Q in formula (I) is 6-carboxy-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazin-10-yl; [represented by the following formula:

the compound of formula (I), its salts or their hydrates, where Q in formula (I) is 8-amino-6-carboxy-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazin-10-yl;

[represented by the following formula;

the compound of formula (I), its salts or their hydrates, where Q in formula (I) is 3-carboxy-6-fluoro-1-[2-(3-fluoro-1-(R)-cyclopropyl]-1, 4-dihydro-4-oxo-1,8-naphthiridine-7-yl;

[represented by the following formula:

the compound of formula (I), its salts or their hydrates, where Q in formula (I) is 3-carboxy-8-chloro-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-7-yl;

p> [represented by the following formula:

the compound of formula (I), its salts or their hydrates, where Q in formula (I) is 3-carboxy-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoindole-7-yl;

[represented by the following formula:

the compound of formula (I), its salts or their hydrates, where Q in formula (I) is 3-carboxy-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoindole-7-yl;

[represented by the following formula:

the compound of formula (I), its salts or their hydrates, where Q in formula (I) is 3-carboxy-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-deformedarse-1,4-dihydro-4-oxoindole-7-yl; [represented by the following formula:

the compound of formula (I); its salts or their hydrates, where Q in formula (I) is 3-carboxy-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-deformedarse-1,4-dihydro-4-oxoindole-7-yl;

[represented by the following formula:

the compound of formula (I), its salts or their hydrates, where Q in formula (I) is 3-carboxy-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoindole-7-yl;

[represented by the following formula:

the compound of formula (I), its salts or ageratum, where Q in formula (I) is 5-amino-3-carboxy-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoindole-7-yl; [represented by the following formula:

the compound of formula (I), its salts or their hydrates, where Q in formula (I) is 5-amino-3-carboxy-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoindole-7-yl;

[represented by the following formula:

the compound of formula (I), its salts or their hydrates, where Q in formula (I) is 5-amino-3-carboxy-6,8-debtor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-7-yl;

[represented by the following formula:

the compound of formula (I), its salts or their hydrates, where R1in the formula (I) represents aryl having 6 to 10 carbon atoms which may have a Deputy;

the compound of formula (I), its salts or their hydrates, where R1in the formula (I) represents aryl having 6 to 10 carbon atoms which may have a Deputy, and his aryl group is phenyl or naphthyl;

the compound of formula (I), its salts or their hydrates, where R1in the formula (I) represents heteroaryl, which may have a Deputy;

the compound of formula (I), its salts or their hydrates, where R1in the formula (I) represents heteroaryl, which can the be Deputy, and it heteroaryl group represents furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, imidazolyl, pyrazolyl, furutani, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl or tetrazine;

the compound of formula (I), its salts or their hydrates, where the compound of formula (I) represents the stereochemical net connection;

the compound of formula (I), its salts or their hydrates, where R9is cyclopropyl having a halogen atom as a substituent;

the compound of formula (I), its salts or their hydrates, where cyclopropyl having a halogen atom as a substituent, represents a 1,2-CIS-halogenlampen;

the compound of formula (I), its salts or their hydrates, where cyclopropyl having a halogen atom as a substituent, is pure stereochemical Deputy;

the compound of formula (I), its salts or their hydrates, where cyclopropyl having a halogen atom as a substituent, is (1R,2S)-2-halogenlampen;

the compound of formula (I), its salts or their hydrates, where the halogen atom of cyclopropyl having a halogen atom as a substituent is a fluorine atom; the compound of formula (I), its salts or their hydrates, where each of R4, R5, R6, R7and R8in the formula (I) represents a hydrogen atom;

the compound of formula (I), its salts or the hydrates, where R1in the formula (I) represents aryl having 6 to 10 carbon atoms which may have a Deputy, or heteroaryl of the five-membered ring or six-membered ring which contains from 1 to 4 heteroatoms, optionally selected from nitrogen atom, oxygen atom or sulfur atom, and may have a Deputy;

the compound of formula (I), its salts or their hydrates, where R1represents phenyl or naphthyl;

the compound of formula (I), its salts or their hydrates, where R1represents furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, imidazolyl, pyrazolyl, furutani, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl or tetrazine;

drug, which includes a compound of formula (I), its salts or hydrates as an active ingredient;

an antibacterial agent which comprises the compound of formula (I), its salts or hydrates as an active ingredient;

therapeutic agent for the treatment of infectious diseases, which comprises the compound of formula (I), its salts or hydrates as an active ingredient;

the method of treatment of a disease involving the introduction of the compounds of formula (I), its salts or hydrates;

the method of treatment of infectious diseases, including the introduction of the compounds of formula (I), its salts or hydrates;

method for producing a medicinal product, including the introduction in its composition the compounds of formula (I), its salts or hydrates as an active ingredient;

a method for producing an antibacterial agent, comprising introducing the composition of the compounds of formula (I), its salts or hydrates as an active ingredient;

method for producing a therapeutic agent for the treatment of infectious diseases, including the introduction in its composition the compounds of formula (I), its salts or hydrates as an active ingredient;

the use of the compounds of formula (I), its salts or hydrates upon receipt of the medication;

the use of the compounds of formula (I), its salts or hydrates when receiving antibacterial agent;

the use of the compounds of formula (I), its salts or hydrates when therapeutic agent for the treatment of infectious diseases;

and so on.

The invention also relates to each of the following items. I.e. the compound represented by the following formula, its salts and their hydrates

{in which R1represents aryl having 6 to 10 carbon atoms, or heteroaryl,

where heteroaryl may be the five-membered ring or six-membered ring and can contain from 1 to 4 heteroatoms, optionally selected the s from a nitrogen atom, oxygen atom and sulfur atom,

where these aryl and heteroaryl can have one or more substituents selected from the group consisting of halogen atom, hydroxyl, thiol, amino, nitro, cyano, carboxyl, carbamoyl, phenyl, alkyl having from 1 to 6 carbon atoms, alkoxyl having from 1 to 6 carbon atoms, alkylthio having from 1 to 6 carbon atoms, alkoxycarbonyl-La, having from 2 to 6 carbon atoms, acyl having 2 to 5 carbon atoms, and heteroaryl (this heteroaryl may be the five-membered ring or six-membered ring and can contain from 1 to 4 heteroatoms, optionally selected from nitrogen atom, oxygen atom and sulfur atom),

where mentioned among them, alkyl, alkoxyl, alkylthio, alkoxycarbonyl, acyl, phenyl and heteroaryl can have one or more substituents selected from the group consisting of halogen atom, hydroxyl, alkoxyl having from 1 to 6 carbon atoms, and alkylthio having from 1 to 6 carbon atoms, and

the amino group may have one or two substituent selected from the group consisting of formyl, alkyl having from 1 to 6 carbon atoms, acyl having 2 to 5 carbon atoms, and alkoxycarbonyl having from 2 to 5 carbon atoms,

R222represents a hydrogen atom, alkyl having from 1 to 6 carbon atoms, or aminosidine group,

R3represents the atom of water is entering or alkyl, having from 1 to 6 carbon atoms,

where an alkyl group, R222and R3may have one or more substituents selected from the group consisting of hydroxyl, halogen atom, alkylthio having from 1 to 6 carbon atoms, and alkoxyl having from 1 to 6 carbon atoms,

R4, R5and R6each independently represents a hydrogen atom, hydroxyl, a halogen atom, carbarnoyl, alkyl having from 1 to 6 carbon atoms, alkoxyl having from 1 to 6 carbon atoms, or akitio having from 1 to 6 carbon atoms,

where specified among them, the alkyl may have one or more substituents selected from the group consisting of hydroxyl, halogen atom and alkoxyl having from 1 to 6 carbon atoms,

R7and R8each independently represents a hydrogen atom or alkyl having from 1 to 6 carbon atoms, and

Q' represents aminoethanol group];

the compound of the above formula, its salts or their hydrates, where aminosidine group is a protective group selected from the group consisting of alkoxycarbonyl, which may have a Deputy, orelkinoservisa, which may have a Deputy, acyl, which may have a Deputy, alkyl which may have a Deputy, aralkyl, which may have a Deputy, and substituted silyl groups;

the compound of the above formula (I), its salts or their hydrates, where aminosidine group is a protective group selected from the group consisting of tert-butoxycarbonyl, 2,2,2-trichlorocarbanilide and similar alkoxycarbonyl groups; benzyloxycarbonyl, para-methoxybenzylidene, para-nitrobenzisoxazole and similar aracelikarsaalyna groups; acetyl, methoxyacetyl, TRIFLUOROACETYL, chloroacetyl, pivaloyl, formyl, benzoyl and the like acyl groups; tert-butyl, benzyl, para-nitrobenzyl, para-methoxybenzyl, triphenylmethyl and similar alkyl groups or Uralkalij groups; methoxymethyl, tert-butoxymethyl, tetrahydropyranyl, 2,2,2-trichloroacetyl and similar simple esters; trimethylsilyl, isopropylimidazole, tert-butyldimethylsilyl, tribenzylamine, tert-butyldiphenylsilyl and such substituted silyl groups;

the compound of the above formula, its salts or hydrates, in which R222and Q' are not the same;

the compound of the above formula, its salts or hydrates, in which R1represents aryl having 6 to 10 carbon atoms which may have a Deputy;

the compound of the above formula, its salts or hydrates, in which R1represents aryl having 6 to 10 carbon atoms which may have a Deputy, and his aryl group I have is a phenyl or naphthyl;

the compound of the above formula, its salts or hydrates, in which R1is heteroaryl, which may have a Deputy;

the compound of the above formula, its salts or hydrates, in which R1is heteroaryl, which may have a Deputy, and his heteroaryl group represents furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, imidazolyl, pyrazolyl, furutani, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl or tetrazine;

the compound of the above formula, its salts or hydrates, in which each of R4, R5, R6, R7and R8represents a hydrogen atom;

and so on.

The invention also relates to each of the following items. I.e. the compound represented by the following formula, its salts or hydrates

[in which R1represents aryl having 6 to 10 carbon atoms, or heteroaryl,

where heteroaryl may be the five-membered ring or six-membered ring and can contain from 1 to 4 heteroatoms, optionally selected from nitrogen atom, oxygen atom and sulfur atom,

where these aryl and heteroaryl can have one or more substituents selected from the group consisting of halogen atom, hydroxyl, thiol, amino, nitro, cyano, carboxyl is, carbamoyl, phenyl, alkyl having from 1 to 6 carbon atoms, alkoxyl having from 1 to 6 carbon atoms, alkylthio having from 1 to 6 carbon atoms, alkoxycarbonyl having from 2 to 6 carbon atoms, acyl having 2 to 5 carbon atoms, and heteroaryl (this heteroaryl may be the five-membered ring or six-membered ring and can contain from 1 to 4 heteroatoms, optionally selected from nitrogen atom, oxygen atom and sulfur atom),

where mentioned among them, alkyl, alkoxyl, alkylthio, alkoxycarbonyl, acyl, phenyl and heteroaryl can have one or more substituents selected from the group consisting of halogen atom, hydroxyl, alkoxyl having from 1 to 6 carbon atoms, and alkylthio having from 1 to 6 carbon atoms and

the amino group may have one or two substituent selected from the group consisting of formyl, alkyl having from 1 to 6 carbon atoms, acyl having 2 to 5 carbon atoms, and alkoxycarbonyl having from 2 to 5 carbon atoms,

R222represents a hydrogen atom, alkyl having from 1 to 6 carbon atoms, or aminosidine group,

R3represents a hydrogen atom or alkyl having from 1 to 6 carbon atoms,

where an alkyl group, R222and R3may have one or more substituents selected from the group consisting of hydroxyl, halogen atom, ALK is LTI, having from 1 to 6 carbon atoms, and alkoxyl having from 1 to 6 carbon atoms,

R4, R5and R6each independently represents a hydrogen atom, hydroxyl, a halogen atom, carbarnoyl, alkyl having from 1 to 6 carbon atoms, alkoxyl having from 1 to 6 carbon atoms, or akitio having from 1 to 6 carbon atoms,

where specified among them, the alkyl may have one or more substituents selected from the group consisting of hydroxyl, halogen atom and alkoxyl having from 1 to 6 carbon atoms, and

R7and R8each independently represents a hydrogen atom or alkyl having from 1 to 6 carbon atoms];

the compound of the above formula, its salts or hydrates, in which aminosidine group is a protective group selected from the group consisting of alkoxycarbonyl, which may have a Deputy, orelkinoservisa, which may have a Deputy, acyl, which may have a Deputy, alkyl which may have a Deputy, aralkyl, which may have a Deputy, and substituted silyl groups;

the compound of the above formula, its salts or hydrates, in which aminosidine group is a protective group selected from the group consisting of tert-butoxycarbonyl, 2,2,2-trichlorocarbanilide and similar alkoxycarbonyl groups; benzyloxy the onila, para-methoxybenzylidene, para-nitrobenzisoxazole and similar aracelikarsaalyna groups; acetyl, methoxyacetyl, TRIFLUOROACETYL, chloroacetyl, pivaloyl, formyl, benzoyl and the like acyl groups; tert-butyl, benzyl, para-nitrobenzyl, para-methoxybenzyl, triphenylmethyl and similar alkyl groups or Uralkalij groups; methoxymethyl, tert-butoxymethyl, tetrahydropyranyl, 2,2,2-trichloroacetyl and like ethers; trimethylsilyl, isopropylimidazole, tert-butyldimethylsilyl, tribenzylamine, tert-butyldiphenylsilyl and such substituted silyl groups;

the compound of the above formula, its salts or hydrates, in which R1represents aryl having 6 to 10 carbon atoms which may have a Deputy;

the compound of the above formula, its salts or hydrates, in which R1represents aryl having 6 to 10 carbon atoms which may have a Deputy, and his aryl group is phenyl or naphthyl;

the compound of the above formula, its salts or hydrates, in which R1is heteroaryl, which may have a Deputy;

the compound of the above formula, its salts or hydrates, in which R1is heteroaryl, which may have a Deputy, and heteroaryl group is and represents furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, imidazolyl, pyrazolyl, furutani, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl or tetrazine;

the compound of the above formula, its salts or hydrates, in which each of R4, R5, R6, R7and R8represents a hydrogen atom;

and so on.

The invention also relates to a method for producing a quinolone compounds, including the removal of Q' from the compounds represented by the following formula, its salts and their hydrates

[in which R1represents aryl having 6 to 10 carbon atoms, or heteroaryl,

where heteroaryl may be the five-membered ring or six-membered ring and can contain from 1 to 4 heteroatoms, optionally selected from nitrogen atom, oxygen atom and sulfur atom,

where these aryl and heteroaryl can have one or more substituents selected from the group consisting of halogen atom, hydroxyl, thiol, amino, nitro, cyano, carboxyl, carbamoyl, phenyl, alkyl having from 1 to 6 carbon atoms, alkoxyl having from 1 to 6 carbon atoms, alkylthio having from 1 to 6 carbon atoms, alkoxycarbonyl having from 2 to 6 carbon atoms, acyl having 2 to 5 carbon atoms, and heteroaryl (this heteroaryl can be five-membered what olicom or six-membered ring and may include from 1 to 4 heteroatoms, optionally selected from nitrogen atom, oxygen atom and sulfur atom),

where mentioned among them, alkyl, alkoxyl, alkylthio, alkoxycarbonyl, acyl, phenyl and heteroaryl can have one or more substituents selected from the group consisting of halogen atom, hydroxyl, alkoxyl having from 1 to 6 carbon atoms, and alkylthio having from 1 to 6 carbon atoms, and

the amino group may have one or two substituent selected from the group consisting of formyl, alkyl having from 1 to 6 carbon atoms, acyl having 2 to 5 carbon atoms, and alkoxycarbonyl having from 2 to 5 carbon atoms,

R222represents a hydrogen atom, alkyl having from 1 to 6 carbon atoms, or aminosidine group,

R3represents a hydrogen atom or alkyl having from 1 to 6 carbon atoms,

where an alkyl group, R222and R3may have one or more substituents selected from the group consisting of hydroxyl, halogen atom, alkylthio having from 1 to 6 carbon atoms, and alkoxyl having from 1 to 6 carbon atoms,

R4, R5and R6each independently represents a hydrogen atom, hydroxyl, a halogen atom, carbarnoyl, alkyl having from 1 to 6 carbon atoms, alkoxyl having from 1 to 6 carbon atoms, or akitio having from 1 to 6 carbon atoms,

where specified among them, the alkyl may who have one or more substituents, selected from the group consisting of hydroxyl, halogen atom and alkoxyl having from 1 to 6 carbon atoms,

R7and R8each independently represents a hydrogen atom or alkyl having from 1 to 6 carbon atoms,

Q' represents aminosidine group],

if necessary, separation and purification,

and its subsequent interaction with the compound of the formula (III):

[in which X1represents a halogen atom or a hydrogen atom,

X4represented by the Deputy, acting as leaving groups, such as fluorine atom, chlorine atom, bromine atom, substituted or unsubstituted phenylsulfonyl or substituted or unsubstituted alkylsulfonyl having from 1 to 3 carbon atoms,

Y1represents a hydrogen atom, phenyl, acetoxymethyl, pivaloyloxymethyl, etoxycarbonyl, choline, dimethylaminoethyl, 5-indanyl, phthalidyl, 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl, 3-acetoxy-2-oxobutyl, alkyl having from 1 to 6 carbon atoms, alkoxymethyl having from 2 to 7 carbon atoms, or phenylalkyl (consisting of alkylene having from 1 to 6 carbon atoms, phenyl) or boron Deputy represented by the formula (IV):

-B(Y)11Y12(IV)

(in which each of the Y11and Y12represents a fluorine atom or alkylcarboxylic having from 2 to 4 atoms of plastics technology : turning & is Yes),

R9represents alkyl having from 1 to 6 carbon atoms, alkenyl having from 2 to 6 carbon atoms, halogenated having from 1 to 6 carbon atoms, cyclic alkyl having 3 to 6 carbon atoms which may have a Deputy, aryl which may have a Deputy, heteroaryl, which may have a Deputy, alkoxyl having from 1 to 6 carbon atoms, or alkylamino having from 1 to 6 carbon atoms,

R10represents a hydrogen atom or alkylthio having from 1 to 6 carbon atoms,

where R10and above R9can be combined with the formation of the ring structure by the inclusion of the main skeleton, and thus formed ring may include a sulfur atom as a constituent ring atom, and the ring may have as a substituent alkyl having from 1 to 6 carbon atoms,

R11represents a hydrogen atom, amino, hydroxyl, thiol, halogenmethyl, alkyl having from 1 to 6 carbon atoms, alkenyl having from 2 to 6 carbon atoms, quinil having from 2 to 6 carbon atoms, or alkoxy having from 1 to 6 carbon atoms,

where the amino group may have one or two substituent selected from the group consisting of formyl, alkyl having from 1 to 6 carbon atoms, and acyl having from 2 to 6 carbon atoms,

when R11represents amino, hydrox the l or thiol, they can be protected by a protective group,

And1represents a nitrogen atom or a partial structure represented by formula (II)

[in which X2represents a hydrogen atom, amino, a halogen atom, cyano, halogenmethyl, halogenmethyl, alkyl having from 1 to 6 carbon atoms, alkenyl having from 2 to b carbon atoms, quinil having from 2 to 6 carbon atoms, or alkoxy having from 1 to 6 carbon atoms,

where this among them, the amino group may have one or two substituent selected from the group consisting of formyl, alkyl having from 1 to 6 carbon atoms, and acyl having 2 to 5 carbon atoms, and

X2and above R9can be combined with the formation of the ring structure by the inclusion of the main skeleton, and thus formed ring may include an oxygen atom, nitrogen atom and sulfur atom as a constituent ring atom, and the ring may have as a substituent alkyl having from 1 to 6 carbon atoms)],

or with the compound represented by formula (V):

(in which X1X4, R9, R10, R11And1and Y have the meanings given above)

in the presence of a base and then conducting remove the protection, if necessary.

The invention also Rel is referring to the method for producing a quinolone compounds, including the interaction of the compounds represented by the following formula, its salts or hydrates

(in which R1represents aryl having 6 to 10 carbon atoms, or heteroaryl,

where heteroaryl may be the five-membered ring or six-membered ring and can contain from 1 to 4 heteroatoms, optionally selected from nitrogen atom, oxygen atom and sulfur atom,

where these aryl and heteroaryl can have one or more substituents selected from the group consisting of halogen atom, hydroxyl, thiol, amino, nitro, cyano, carboxyl, carbamoyl, phenyl, alkyl having from 1 to 6 carbon atoms, alkoxyl having from 1 to 6 carbon atoms, alkylthio having from 1 to 6 carbon atoms, alkoxycarbonyl having from 2 to 6 carbon atoms, acyl having 2 to 5 carbon atoms, and heteroaryl (this heteroaryl may be the five-membered ring or six-membered ring and may include from 1 to 4 heteroatoms, optionally selected from nitrogen atom, oxygen atom and sulfur atom),

where mentioned among them, alkyl, alkoxyl, alkylthio, alkoxycarbonyl, acyl, phenyl and heteroaryl can have one or more substituents selected from the group consisting of halogen, hydroxyl, alkoxyl having from 1 to 6 carbon atoms, and alkylthio having from 1 to 6 atoms angle of the ode, and

the amino group may have one or two substituent selected from the group consisting of formyl, alkyl having from 1 to 6 carbon atoms, acyl having 2 to 5 carbon atoms, and alkoxycarbonyl having from 2 to 5 carbon atoms,

R222represents a hydrogen atom, alkyl having from 1 to 6 carbon atoms, or aminosidine group,

R3represents a hydrogen atom or alkyl having from 1 to 6 carbon atoms,

where an alkyl group, R222and R3may have one or more substituents selected from the group consisting of hydroxyl, halogen atom, alkylthio having from 1 to 6 carbon atoms, and alkoxyl having from 1 to 6 carbon atoms,

R4, R5and R6each independently represents a hydrogen atom, hydroxyl, a halogen atom, carbarnoyl, alkyl having from 1 to 6 carbon atoms, alkoxyl having from 1 to 6 carbon atoms, or akitio having from 1 to 6 carbon atoms,

where specified among them, the alkyl may have one or more substituents selected from the group consisting of hydroxyl, halogen atom and alkoxyl having from 1 to 6 carbon atoms,

R7and R8each independently represents a hydrogen atom or alkyl having from 1 to 6 carbon atoms)

with the compound represented by formula (III):

[in which X1 represents a halogen atom or a hydrogen atom,

X4represented by the Deputy, acting as leaving groups, such as fluorine atom, chlorine atom, bromine atom, substituted or unsubstituted phenylsulfonyl, or substituted or unsubstituted alkylsulfonyl having from 1 to 3 carbon atoms,

Y1represents a hydrogen atom, phenyl, acetoxymethyl, pivaloyloxymethyl, etoxycarbonyl, choline, dimethylaminoethyl, 5-indanyl, phthalidyl, 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl, 3-acetoxy-2-oxobutyl, alkyl having from 1 to 6 carbon atoms, alkoxymethyl having from 2 to 7 carbon atoms, or phenylalkyl consisting of alkylene having from 1 to 6 carbon atoms, and phenyl, or boron Deputy represented by the formula (IV):

(Y11)Y12(IV)

(in which each of the Y11and Y12represents a fluorine atom or alkylcarboxylic having from 2 to 4 carbon atoms),

R9represents alkyl having from 1 to 6 carbon atoms, alkenyl having from 2 to 6 carbon atoms, halogenated having from 1 to 6 carbon atoms, cyclic alkyl having 3 to 6 carbon atoms which may have a Deputy, aryl which may have a Deputy, heteroaryl, which may have a Deputy, alkoxyl having from 1 to 6 carbon atoms, or alkylamino having from 1 to 6 carbon atoms,

R1 represents a hydrogen atom or alkylthio having from 1 to 6 carbon atoms,

where R10and above R9can be combined with the formation of the ring structure by the inclusion of the main skeleton, and thus formed ring may include a sulfur atom as a constituent ring atom, and the ring may have as a substituent alkyl having from 1 to 6 carbon atoms,

R11represents a hydrogen atom, amino, hydroxyl, thiol, halogenmethyl, alkyl having from 1 to 6 carbon atoms, alkenyl having from 2 to 6 carbon atoms, quinil having from 2 to 6 carbon atoms, or alkoxy having from 1 to 6 carbon atoms,

where the amino group may have one or two substituent selected from the group consisting of formyl, alkyl having from 1 to 6 carbon atoms, and acyl having from 2 to 6 carbon atoms,

when R11represents amino, hydroxyl or thiol, they can be protected by a protective group,

And1represents a nitrogen atom or a partial structure represented by formula (II):

(in which X2represents a hydrogen atom, amino, a halogen atom, cyano, halogenmethyl, halogenmethyl, alkyl having from 1 to 6 carbon atoms, alkenyl having from 2 to 6 carbon atoms, quinil having from 2 to 6 carbon atoms, or alkoxy having from 1 to 6 carbon atoms,

where this among them, the amino group may have one or two substituent selected from the group consisting of formyl, alkyl having from 1 to 6 carbon atoms, and acyl having 2 to 5 carbon atoms, and

X2and above R9can be combined with the formation of the ring structure by the inclusion of the main skeleton, and thus formed ring may include an oxygen atom, nitrogen atom and sulfur atom as a constituent ring atom, and the ring may have as a substituent alkyl having from 1 to 6 carbon atoms)],

or with the compound represented by formula (V):

(in which X1X4, R9, R10, R11And1and Y have the meanings given above)

in the presence of a base and then conducting remove the protection, if necessary.

(A variant implementation of the invention)

Describes the substituents in the compound of the invention represented by the formula (I).

Deputy R1represents an aromatic group (an aromatic Deputy). The connection according to the invention is characterized by the fact that this provision is aromatic Deputy. This aromatic Deputy may be a hydrocarbon group (an aryl or heterocyclic group (heteroaryl). In the case of the hydrocarbon group is s, it can be monocyclic or bicyclic. In the case of the heterocyclic group, it may be monocyclic or bicyclic. In the case of a monocyclic heterocyclic group she represents a five-membered or six-membered ring, and in the case of a bicyclic heterocyclic group it is benzododecinium ring system, or different from it, and as an example 6-5-condensed ring system or 6-6-condensed ring system. In addition, in the case of a heterocyclic system, the number of incoming is 1-4 heteroatoms, optionally selected from nitrogen atom, oxygen atom and sulfur atom.

I.e. the substituent R1represents an aromatic Deputy, such as aryl having from 6 to 10 carbon atoms, or heteroaryl.

In this case, heteroaryl is five-membered ring or six-membered ring and can contain from 1 to 4 heteroatoms, optionally selected from nitrogen atom, oxygen atom and sulfur atom.

These aryl and heteroaryl can have one or more substituents selected from the group consisting of halogen atom, hydroxyl, thiol, amino, nitro, cyano, carboxyl, carbamoyl, phenyl, alkyl having from 1 to 6 carbon atoms, alkoxyl having from 1 to 6 carbon atoms, alkylthio having from 1 to 6 carbon atoms, alkoxycarbonyl having from 2 to 6 atomo the carbon acyl having 2 to 5 carbon atoms, and heteroaryl (five-membered ring or six-membered ring which contains from 1 to 4 heteroatoms, optionally selected from nitrogen atom, oxygen atom and sulfur atom).

Alkyl, alkoxyl, alkylthio, alkoxycarbonyl, acyl, phenyl and heteroaryl as substituents of aryl or heteroaryl can have one or more substituents selected from the group consisting of halogen atom, hydroxyl, alkoxyl having from 1 to 6 carbon atoms, and alkylthio having from 1 to 6 carbon atoms.

In addition, the amino group may have one or two substituent selected from the group consisting of formyl, alkyl having from 1 to 6 carbon atoms, acyl having 2 to 5 carbon atoms, and alkoxycarbonyl having from 2 to 5 carbon atoms.

As an example, aryl having from 6 to 10 carbon atoms, and as an aromatic substituent that can result phenyl, pentalene, naphthyl, azulene and the like, of which phenyl, 1-naphthyl and 2-naphthyl are preferred.

As an example of heteroaryl of the five-membered ring or six-membered ring which contains from 1 to 4 heteroatoms, optionally selected from nitrogen atom, oxygen atom and sulfur atom, as an aromatic substituent that can result in a furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, it is detail, pyrazolyl, furutani, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl, tetrazini or the like. Among them, preferred are 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-oxazolyl, 2-thiazolyl, 2-imidazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2 pirimidil, 4 pirimidil, 5 pirimidil and 3-pyridazinyl. As more preferred examples are 2-furyl, 3-furyl, 2-thienyl, 2-oxazolyl, 2-thiazolyl, 2-imidazolyl, 2-pyridyl and 4-pyridyl.

The substituent in the aryl rings of data and heteroaryl can be selected from the group consisting of halogen atom, hydroxyl, thiol, amino, nitro, cyano, carboxyl, carbamoyl, phenyl, alkyl having from 1 to 6 carbon atoms, alkoxyl having from 1 to 6 carbon atoms, alkylthio having from 1 to 6 carbon atoms, alkoxy-carbonyl having from 2 to 6 carbon atoms, acyl having 2 to 5 carbon atoms, and heteroaryl (this heteroaryl may be the five-membered ring or six-membered ring, which contains from 1 to 4 heteroatoms, selected optional ie of nitrogen atom, oxygen atom and sulfur atom). Among these groups, preferred are alkyl, alkoxyl, alkylthio, halogen atom, hydroxyl, amino, carbarnoyl, alkoxycarbonyl and phenyl, are especially preferred substituents are alkyl, alkoxyl, alkylthio, halogen atom, hydroxyl and amino group

Describes substituted aryl and substituted heteroaryl when alkyl, alkoxyl, allylthiourea, halogen atom, hydroxyl and amino group are preferred as the substituents in the aryl ring and heteroaryl.

When the aryl or heteroaryl have as a substituent alkyl, the alkyl may be straight or branched, having from 1 to 6 carbon atoms, it is preferable examples include methyl, ethyl, straight-propyl and isopropyl.

When the alkyl has as a substituent a halogen atom, the alkyl may be straight or branched, having from 1 to 6 carbon atoms, and a fluorine atom is preferable as the replacement of the halogen atom. In terms of the number of fluorine atoms, it can be anything from monotomidae to perversione. His examples include MonitorMaster, deformity, trifluoromethyl, 2,2,2-triptorelin and the like.

When alkyl optionally has as a substituent a hydroxyl, alkyl may be straight or branched, having from 1 to 6 carbon atoms. Although the position of substitution of the hydroxyl not specifically limited, it may be preferable to substitution on the terminal carbon atom of the alkyl. As alkyl with hydroxyl, preferred are those having up to 3 carbon atoms, and preferred hydroxymethyl, 2-hydroxyethyl, 2-hydrox is propyl, 3-hydroxypropyl, and the like.

When alkyl optionally has as a substituent alkoxy, the alkyl may be straight or branched, having from 1 to 6 carbon atoms, and replacement alkoxyl may also be straight or branched, having from 1 to 6 carbon atoms. Although the position of substitution by alkoxyl not specifically limited, it may be preferable to substitution on the terminal carbon atom of the alkyl. Preferred are alkoxymethyl, alkoxyethyl and alkoxyaryl as alkyl having alkoxyl, and preferably alkoxyl can have up to 3 carbon atoms. More preferred examples include methoxymethyl, ethoxymethyl and methoxyethyl.

When alkyl optionally has as Deputy allylthiourea, the alkyl may be straight or branched, having from 1 to 6 carbon atoms, and the replacement allylthiourea can also be straight or branched, having from 1 to 6 carbon atoms. Although the position of substitution by alkylthiophene not specifically limited, it may be preferable to substitution on the terminal carbon atom of the alkyl. As alkyl having allylthiourea, are preferred alkylthiomethyl, alkylthiomethyl and alkylthiomethyl, and preferably allylthiourea may have from 1 to 3 carbon atoms. Preferable examples in luchot methylthiomethyl, ethylthiomethyl and methylthioethyl.

In the above aryl and heteroaryl having as substituent "alkyl which may have a substitute, the number of alkyl groups can be anything from monotomidae to parallelomania. When there are two or more alkyl, they may be the same or different. In the case of replacement akiliyi the group is mono-, di - and tizanidine.

When the aryl and heteroaryl have as a substituent alkoxy, this alkoxy may be straight or branched, having from 1 to 6 carbon atoms, and preferred examples include methoxy and amoxil.

When alkoxyl additionally has as a substituent a halogen atom, alkoxy may be straight or branched, having from 1 to 6 carbon atoms, and a fluorine atom is preferable as the replacement of the halogen atom. In terms of the number of fluorine atoms, it can be anything from monotomidae to perversione. His examples include monitormanager, diformitatii, trifloromethyl, 2,2,2-triptoreline and the like.

When alkoxyl additionally has as a substituent a hydroxyl, alkoxy may be straight or branched, having from 1 to 6 carbon atoms. Although the position of substitution of the hydroxyl not specifically limited, it may be preferable to substitute Konz is the first carbon atom of alkoxyl. As alkoxyl with hydroxyl, preferred are those having up to 3 carbon atoms, and preferred 1-hydroxyethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 3-hydroxypropoxy and the like.

When alkoxyl additionally has as Deputy CNS group, alkoxy may be straight or branched, having from 1 to 6 carbon atoms, and replacing CNS group may be straight or branched, having from 1 to 6 carbon atoms. Although the position of substitution of the CNS group are not specifically limited, it may be preferable to substitution on the terminal carbon atom of alkoxyl. As alkoxyl with CNS group, are preferred alkoxymethyl and alkoxyalkyl, and alkoxy may preferably having up to 3 carbon atoms. More preferred examples include 2-methoxyethoxy and 2-ethoxyethoxy.

When alkoxyl additionally has as Deputy allylthiourea, alkoxy may be straight or branched, having from 1 to 6 carbon atoms, and the replacement allylthiourea can also be straight or branched, having from 1 to 6 carbon atoms. Although the position of substitution by alkylthiophene not specifically limited, it may be preferable to substitution on the terminal atom angle is ode of alkoxyl. As alkoxyl with allylthiourea is preferred alkylthiomethyl, and allylthiourea may preferably have from 1 to 3 carbon atoms. More preferred examples include 2-methylthiouracil and 2-ethylthioethyl.

In the above aryl and heteroaryl having as substituent "alkoxyl, which may have a substitute, the number of CNS groups can be anything from monotomidae to peralkaline. When there are two or more alkoxyl, they may be the same or different. In the case of substitution of the CNS group is mono-, di - and trisamine.

When the aryl and heteroaryl have as a substituent allylthiourea, allylthiourea may be straight or branched, having from 1 to 6 carbon atoms, and preferred examples include metalcorp and ethylthiourea.

When allylthiourea has as a substituent a halogen atom, allylthiourea may be straight or branched, having from 1 to 6 carbon atoms, and a fluorine atom is preferable as the halogen atom. In terms of the number of fluorine atoms, it can be anything from monoelement to perversione. Her examples include monitorsetup, deformationof, triptoreline, 2,2,2-Cryptor-ethylthiourea and the like.

When Ala is tighrope additionally has as a substituent a hydroxyl, allylthiourea may be straight or branched, having from 1 to 6 carbon atoms. Although the position of substitution of the hydroxyl not specifically limited, it may be preferable to substitution on the terminal carbon atom of ancilliary. As ancilliary with hydroxyl, preferred are those having up to 3 carbon atoms, and preferred 1-hydroxyethylthio, 2-hydroxymethylpropane, 2-hydroxypropionate, 3-hydroxypropionate and the like.

When allylthiourea additionally has as a substituent alkoxy, allylthiourea may be straight or branched, having from 1 to 6 carbon atoms, and replacement alkoxyl may also be straight or branched, having from 1 to 6 carbon atoms. Although the position of substitution by alkoxyl not specifically limited, it may be preferable to substitution on the terminal carbon atom of alkylthio group. As ancilliary with alkoxyl, are preferred alkoxygroup and alkoxygroup, and alkoxyl may preferably having up to 3 carbon atoms. More preferred examples include 2-methoxyaniline and 2-amoxicillinum.

When allylthiourea additionally has as Deputy allylthiourea, allylthiourea can be direct or once evennou, having from 1 to 6 carbon atoms, and the replacement allylthiourea can also be straight or branched, having from 1 to 6 carbon atoms. Although the position of substitution by alkylthiophene not specifically limited, it may be preferable to substitution on the terminal carbon atom of ancilliary. As ancilliary with allylthiourea, the preferred alkylthiomethyl, and allylthiourea may preferably have from 1 to 3 carbon atoms. More preferred examples include 2-methylthioethyl and 2-ethylthioethyl.

In these aryl and heteroaryl having as substituent "allylthiourea, which may have a substitute, the number of alkylthiols can be anything from monotomidae to paralleltimeline. When there are two or more alkylthio, they may be the same or different. Monozameschennaya suitable as alkylthiophene.

When the aryl and heteroaryl have as a substituent a halogen atom, preferred are a fluorine atom, a chlorine atom and a bromine atom as the halogen atom. The fluorine atom is particularly preferred, and the number of fluorine atoms in this case can be anything from monotomidae to perversione.

Their examples include 2-forfinal, 3-forfinal, 4-forfinal, 2,4-differenl, 2, 5-differenl, 2,6-ditto is phenyl, 3,4-differenl, 3,5-differenl, 2,4,6-tryptophanyl, 3,4,5-tryptophanyl, 2,3,5,6-tetrafluorophenyl, pentafluorophenyl, 4-fluoro-1-naphthyl, 7-fluoro-1-naphthyl, 3-fluoro-2-pyridyl, 6-fluoro-2-pyridyl, 2,4,5,6-titrator-3-pyridyl, 2,3,5,6-titrator-4-pyridyl and the like.

When the aryl and heteroaryl have as a substituent a hydroxyl, aryl, substituted hydroxyl is preferred, and substituted phenyl are particularly preferred. As example 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2,4-dihydroxyphenyl and the like.

When the aryl and heteroaryl have as a substituent an amino group, substituted amino group, the aryl is preferred, and a substituted amino group of a phenyl are particularly preferred. In this case, the amino group may have 1 or 2 substituent selected from the group consisting of formyl, alkyl having from 1 to 6 carbon atoms, acyl having 2 to 5 carbon atoms, and alkoxycarbonyl having from 2 to 5 carbon atoms, and monoalkylbenzenes phenyl, dialkylaminomethyl phenyl (alkyl group in this case may be the same or different) and acylaminoalkyl phenyl are preferred.

As an example, 2-AMINOPHENYL, 3-AMINOPHENYL, 4-AMINOPHENYL, 2-methylaminophenol, 4-methylaminophenol, 2-dimethylaminophenyl, 4-dimethylaminophenyl, 4-acetoxyl nofeel and the like.

When the aryl and heteroaryl have two or more substituents, their combination can be a combination, optionally selected from the group consisting of halogen atom, hydroxyl, thiol, amino, nitro, cyano, carboxyl, carbamoyl, phenyl, alkyl having from 1 to 6 carbon atoms, alkoxyl having from 1 to 6 carbon atoms, alkylthio having from 1 to 6 carbon atoms, alkoxycarbonyl having from 2 to 6 carbon atoms, acyl having 2 to 5 carbon atoms, and heteroaryl (five-membered ring or six-membered ring and contains from 1 to 4 heteroatoms, optionally selected from nitrogen atom, oxygen atom and sulfur atom), but it is preferable that one of them was selected from alkyl, alkoxyl, halogen atom, hydroxyl and amino. As the halogen atom, the fluorine atom is particularly preferred.

As examples of the case where the aryl and heteroaryl have two or more substituents, it is possible to produce 2-fluoro-4-hydroxy-phenyl, 3-amino-4,6-differenl, 4,6-debtor-3-methylaminophenol, 2,6-debtor-4-methoxyphenyl, 4-fluoro-2-were, 4-hydroxy-3, 5dimethylphenyl, 3,5-dimethyl-4-methoxyphenyl, 6-amino-3,5-debtor-2-pyridyl, 5-chloro-6-methyl-4-pyrimidinyl and so similar.

In this regard, the carbon atom is linked to R1becomes asymmetric carbon, forming isomers, and these isomers are included in this invention.

In addition, the substituent R1represents a (substituted) phenyl or burilovo type (substituted) heteroaryl of the five-membered ring or six-membered ring containing 1-4 heteroatoms, optionally selected from nitrogen atom, oxygen atom and sulfur atom (the term "(substituted)" means that there may be a Deputy), it forms the isomers arising from axial chirality, and all of such isomers are included in this invention.

The substituents R2and R3each independently represents a hydrogen atom or alkyl having from 1 to 6 carbon atoms, and alkyl may have one or more substituents selected from the group consisting of hydroxyl, halogen atom, alkylthio having from 1 to 6 carbon atoms, and alkoxyl having from 1 to 6 carbon atoms.

In the case of alkyl he may be straight or branched, having from 1 to 6 carbon atoms, and preferred examples include methyl, ethyl, straight-propyl and isopropyl.

When alkyl optionally has as a substituent a hydroxyl, alkyl may be straight or branched, having from 1 to 6 carbon atoms. Although the position of substitution of the hydroxyl not specifically limited, it may be preferable to substitution on the terminal carbon atom of the alkyl. As alkyl with hydroxyl, deletemin are those with up to 3 of the atoms is of Pereda, and preferred hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, and the like.

When alkyl optionally has as a substituent a halogen atom, the alkyl may be straight or branched, having from 1 to 6 carbon atoms, and a fluorine atom is preferable as the halogen atom. In terms of the number of fluorine atoms, it can be anything from monotomidae to perversione. His examples include MonitorMaster, deformity, trifluoromethyl, 2,2,2-triptorelin and the like.

When alkyl optionally has as Deputy allylthiourea, the alkyl may be straight or branched, having from 1 to 6 carbon atoms, and the replacement allylthiourea can also be straight or branched, having from 1 to 6 carbon atoms. Although the position of substitution by alkylthiophene not specifically limited, it may be preferable to substitution on the terminal carbon atom of the alkyl. As alkyl having allylthiourea, are preferred alkylthiomethyl, alkylthiomethyl and alkylthiomethyl, and preferably allylthiourea may have from 1 to 3 carbon atoms. More preferred examples include methylthiomethyl, ethylthiomethyl and methylthioethyl.

When the alkyl has as a substituent alkoxy, the alkyl may be straight or branched, having from 1 to 6 the volume of carbon and replacement alkoxyl may also be straight or branched, having from 1 to 6 carbon atoms. Although the position of substitution by alkoxyl not specifically limited, it may be preferable to substitution on the terminal carbon atom of the alkyl. As alkyl having alkoxyl, are preferred alkoxymethyl, alkoxyethyl and alkoxyaryl, and preferably alkoxyl can have up to 3 carbon atoms. More preferred examples include methoxymethyl, ethoxymethyl and methoxyethyl.

R4, R5and R6each independently represents a hydrogen atom, hydroxyl, a halogen atom, carbarnoyl, alkyl having from 1 to 6 carbon atoms, alkoxyl having from 1 to 6 carbon atoms, or alkylthio having from 1 to 6 carbon atoms, and listed among them, the alkyl may have one or more substituents selected from the group consisting of hydroxyl, halogen atom and alkoxyl having from 1 to 6 carbon atoms. In addition, R5and R6join in polymethene chain, having from 3 to 6 carbon atoms (forming spiracular system together with the ring pyrrolidine), hydroxyimino or alkylenediamines having from 1 to 6 carbon atoms.

As the halogen atom is preferable fluorine atom or a chlorine atom.

As for the alkyl, it may be direct or razwell is authorized, having from 1 to 6 carbon atoms, and preferred examples include methyl, ethyl, straight-propyl and isopropyl.

As alkoxyl, it may be straight or branched, having from 1 to 6 carbon atoms, and preferred examples include methoxy and amoxil.

As for Citigroup, it may be straight or branched, having from 1 to 6 carbon atoms, and preferred examples include methylthiazole and ethylthiourea.

When the hydroxyl is present as a substituent in the alkyl having from 1 to 6 carbon atoms, the alkyl may be straight or branched. Although the position of substitution of the hydroxyl not specifically limited, it may be preferable to substitution on the terminal carbon atom of the alkyl. Preferred examples of the substituted hydroxyl alkyl having from 1 to 6 carbon atoms include hydroxymethyl, 2-hydroxyethyl and 3-hydroxypropyl.

As the halogen atom of the alkyl having halogen atom, preferred are fluorine atoms and chlorine, and fluorine atom is particularly preferred. The alkyl may be straight or branched.

In containing alkoxyl the alkyl having from 1 to 6 carbon atoms, each alkyl group may be straight or branched, and preferred are alkoxymethyl or alkoxyethyl. As more preferred is part of the examples methoxymethyl, ethoxymethyl and 2-methoxyethyl.

When the substituents R5and R6combined with education polymethene chain, a ring of three six-membered rings is newly added to the ring pyrrolidine education spericolata patterns. As for the size of the newly formed ring, it is preferred ring cyclopropyl or ring cyclobutyl having 2 or 3 carbon atoms.

In addition, when the substituents R5and R6United in alkylenediamines, represented by the following formula:

the alkyl may be straight or branched. As alkyloxybenzoic are preferred methoxyimino and toksikologiya.

The substituents R7and R8each independently represents a hydrogen atom or alkyl having from 1 to 6 carbon atoms. As for the alkyl, it may be straight or branched, having from 1 to 6 carbon atoms, and preferably is stands, ethyl, direct propylene or isopropyl. Preferred is when each of them represents a hydrogen atom.

Q represents a partial structure represented by the following formula:

In this structural formula, And2and3each independently represents a nitrogen atom or an atom of carbon is a, and2and3and the carbon atoms to which they are linked, associated with formation of incomplete patterns

or incomplete patterns

Condensed heterocyclic partial structure represented by the following formula:

or the following formula:

is preferred as the structure of Q.

Deputy R9represents alkyl having from 1 to 6 carbon atoms, alkenyl having from 2 to 6 carbon atoms, halogenated having from 1 to 6 carbon atoms, cyclic alkyl having 3 to 6 carbon atoms which may have a Deputy, aryl which may have a Deputy, heteroaryl, which may have a Deputy, alkoxyl having from 1 to 6 carbon atoms, or alkylamino having from 1 to 6 carbon atoms.

In this case, particularly preferred is ethyl as alkyl having from 1 to 6 carbon atoms. As alkenyl having from 2 to 6 carbon atoms, preferred is vinyl or 1-Isopropenyl. 2-Feratel is preferred as halogenoalkane having from 1 to 6 carbon atoms. Cyclopropyl is especially preferred as the cyclic alkyl, and halogen atom, ESP the NGOs fluorine atom, is preferred as the substituent of the cyclic alkyl.

Examples of aryl which may have a Deputy, include phenyl or similar group which may have 1 to 3 substituent selected from the group consisting of, for example, fluorine atom, chlorine atom, bromine atom and the like, halogen atom, hydroxyl, amino, nitro, alkyl having from 1 to 6 carbon atoms, and alkoxyl having from 1 to 6 carbon atoms, and preferred examples include phenyl, 2-forfinal, 4-forfinal, 2,4-differenl, 2-fluoro-4-hydroxyphenyl, 3-amino-4,6-differenl and 4,6-debtor-3-methylaminophenol. The aryl can be identical with the aryl substituent R1or it may differ.

Heteroaryl is derived five-membered or six-membered aromatic heterocyclic compound that includes one or more heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom. This heteroaryl may be identical with heteroaryl Deputy R1or it may differ. As an example of heteroaryl Deputy R9you can lead pyridyl, pyrimidyl and the like. As Deputy in these rings preferred are alkyl, halogen atom or the like. Especially preferred is 6-amino-3,5-debtor-2-pyridyl.

Methoxyl is preferably the m as alkoxyl, having from 1 to 6 carbon atoms. Methylaminopropyl is preferred as alkylamino having from 1 to 6 carbon atoms.

As Deputy R9preferred are cyclic alkyl or halogenosilanes. Among these groups, preferred are cyclopropyl or 2-halogenic-propyl. As the halogen atom is preferable fluorine atom.

Deputy R10represents a hydrogen atom or allylthiourea having from 1 to 6 carbon atoms, or R9and R10can be merged to form a hydrocarbon ring structure by the inclusion of the main skeleton (namely, the inclusion of the carbon atom to which R10connected and And2). Thus formed ring may include a sulfur atom as a constituent atom, and the ring may optionally have a substituent alkyl having from 1 to 6 carbon atoms. Thus formed ring may have a size of four-membered ring to a six-membered ring, and the ring may be saturated or unsaturated. As examples of the condensed ring structure formed thereby, can cause the following:

Deputy X1represents a halogen atom or a hydrogen atom, and fluorine atom is before occhialini in the case of the halogen atom. Among these atoms, a fluorine atom or a hydrogen atom are preferred as Deputy.

Deputy R11represents a hydrogen atom, amino group, hydroxyl, thiol, halogenmethyl, alkyl having from 1 to 6 carbon atoms, alkenyl having from 2 to 6 carbon atoms, quinil having from 2 to 6 carbon atoms, and alkoxy having from 1 to 6 carbon atoms, and mentioned among them, the amino group may have one or two substituent selected from the group consisting of formyl, alkyl having from 1 to 6 carbon atoms, and acyl having from 2 to 6 carbon atoms.

As for the alkyl, it may be straight or branched, having from 1 to 6 carbon atoms, and preferred examples include methyl, ethyl, straight-propyl and isopropyl. Alkenyl may be straight or branched, having from 2 to 6 carbon atoms, and it is preferably vinyl. As quinil, it may be straight or branched, having from 2 to 6 carbon atoms, it preferably represents ethinyl. The fluorine atom is particularly preferred as the halogen in halogenmethyl group, and the number can be from 1 to 3. Alkoxyl may have from 1 to 6 carbon atoms, and preferably represents methoxy.

Deputy R11preferably represents a hydrogen atom, alkyl or amine is, of which methyl or unsubstituted amino group are preferred.

When the substituent R11represents amino, hydroxyl or thiol, they can be protected commonly used protective groups.

Examples of such protective groups include tert-butoxycarbonyl, 2,2,2-trichlorocyanuric and the like (substituted) alkoxycarbonyl group; benzyloxycarbonyl, para-methoxybenzeneboronic, para-nitrobenzenesulfonyl and the like (substituted)aracelikarsaalyna group; acetyl, methoxyacetyl, TRIFLUOROACETYL, chloroacetyl, pivaloyl, formyl, benzoyl and the like (substituted)acyl groups; tert-butyl, benzyl, para-nitrobenzyl, para-methoxybenzyl, triphenylmethyl and the like (substituted)alkyl groups or (substituted)kalkilya group; methoxymethyl, tert-butoxymethyl, tetrahydropyranyl, 2,2,2-trichloroacetyl and such (substituted)ethers; and trimethylsilyl, isopropylimidazole, tert-butyldimethylsilyl, tribenzylamine, tert-butyldiphenylsilyl and such (alkyl and/or aralkyl)substituted silyl group. Compounds having substituents, protected data substituents are especially preferred as intermediates to obtain.

When And1represents the partial structure of the following formula (II)

X2represents a hydrogen atom, amino, a halogen atom, cyano, halogenmethyl, halogenmethyl, alkyl having from 1 to 6 carbon atoms, alkenyl having from 2 to 6 carbon atoms, quinil having from 2 to 6 carbon atoms, or alkoxy having from 1 to 6 carbon atoms, where the amino group may have one or two substituent selected from the group consisting of formyl, alkyl having from 1 to 6 carbon atoms, and acyl having 2 to 5 carbon atoms.

As for the alkyl, it may be straight or branched, having from 1 to 6 carbon atoms, and preferred examples include methyl, ethyl, straight-propyl and isopropyl. Alkenyl may be straight or branched, having from 2 to 6 carbon atoms, and it is preferably vinyl. Quinil may be straight or branched, having from 2 to 6 carbon atoms, it preferably represents ethinyl. The fluorine atom is particularly preferred as the halogen in the halogen-methyl group, and the number can be from 1 to 3. As alkoxyl, he may have from 1 to 6 carbon atoms, it preferably represents methoxy. The fluorine atom is particularly preferred as the halogen in halogenosilanes group, and the number can be from 1 to 3.

Among these substituents, the alkyl or alkoxyl appear before actualname. More preferred are methyl and ethyl. The latter are the preferred substituents, especially when Q represents a partial structure represented by the following formula:

In addition, this X2and above R9can be merged to form a hydrocarbon ring structure (ring size can be from four-membered ring to semichasnoho ring, and it may be saturated or unsaturated) inclusion of the main skeleton (namely the inclusion of the carbon atom to which X2connected and And2), and the thus formed ring may include an oxygen atom, nitrogen atom or sulfur atom as a constituent atom, and the ring may have as a substituent alkyl having from 1 to 6 carbon atoms. Examples of the condensed ring structure formed thereby, can be the following:

Among these condensed ring systems 2,3-dihydro-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid-10-yl, especially its (S)-methyl form in position 3 is preferred.

As for Q, the partial structure of the following formula:

is preferred. Also in this case, it is preferable that the 1was partial structure of formula (II).

When Q represents a partial structure described above, and1is a partial structure of the formula (II), a preferred combination of R11and X2is the case when R11is amino, hydrogen atom, hydroxyl or alkyl having from 1 to 6 carbon atoms, and X2is an alkyl having from 1 to 6 carbon atoms, alkoxyl having from 1 to 6 carbon atoms, halogenation or a hydrogen atom.

The preferred combination is the case when R11is amino, hydrogen atom, hydroxyl or methyl, and X2represents methyl, methoxyl, diformitatii or a hydrogen atom.

The most preferred combination is the case when R11is amino, hydrogen atom, hydroxyl or methyl, and X2represents methyl or methoxyl.

For R11and X2the fluorine atom is preferable as X1.

When the substituents X1and X2represent halogen atoms, a fluorine atom is particularly preferred as the X1and a fluorine atom or a chlorine atom is preferred as X2.

When Q represents a partial structure represented by the following formula:

and1is Nepal the current structure of the formula (II), the preferred combination of R11and X2is the case when R11is amino, hydrogen atom, hydroxyl or alkyl having from 1 to 6 carbon atoms, and X2represents alkyl having from 1 to 6 carbon atoms, alkoxyl having from 1 to 6 carbon atoms, halogenmethyl or a hydrogen atom.

The preferred combination is the case when R11is amino, hydrogen atom, hydroxyl or methyl, and X2represents methyl, methoxyl, diformitatii or a hydrogen atom.

The most preferred combination is the case when R11is amino, hydrogen atom, hydroxyl or methyl, and X2represents methyl or methoxyl.

When the substituents X1and X2represent halogen atoms, a fluorine atom is particularly preferred as the X1and a fluorine atom or a chlorine atom is preferred as X2.

The following describes halogenlampen R9.

As an example, the replacement of the halogen atom can cause a fluorine atom and a chlorine atom, of which a fluorine atom is particularly preferred.

Referring to the steric environment in the group, particularly preferably a halogen atom and a group pyridonecarboxylic acid had a CIS-configuration in tsiklopropanovom ring.

The so-called the e enantiomeric isomers are present only at the expense of one CIS-2-halogencontaining fragment R 9and strong antibacterial activity and high safety was established in both isomers.

The connection according to the invention shows excellent properties due to the presence of pyrrolidinium Deputy patterns below.

B the Deputy of the above four isomers are formed due to the asymmetric carbon atom in the ring pyrrolidine, which is associated with the Deputy-CH(R1)N(R2)-R3and the substituent R4and the asymmetric carbon atom is linked to R1.

On the other hand, Sasi between structure and activity in four optically active compounds due to the spatial configuration of the substituent in position 7 derived from 7-[3-(1-amino-ethyl)pyrrolidin-1-yl]hinolincarbonova acid described in Chemical & Pharmaceutical Bulletin, vol. 42, 1442 R. (1994). Described that 3-(S)-[1-(R)-amino-ethyl]pyrrolidin-1-yl possesses the highest antibacterial activity among the four optically active compounds.

The present inventors believe that

is the most preferred among the four optically active compounds having the structure above.

I.e. the connection according to the invention is characterized in that a derivative of the substituted aromatic group aminol is elparoladon, represented by formula (I), its salts and their hydrates are a wide range and high antibacterial activity against gram-negative and gram-positive bacteria, and exhibits a high antibacterial activity against resistant strains of gram-positive bacteria, including MRSA, PRSP and VRE.

In particular, the compound represented by formula (I), in which the derivative substituted aromatic group aminomethylpyrrolidine having the above structure, introduced in position 10 2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine skeleton or position 7 6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-okahirongo skeleton having excellent safety, its salts and hydrates showed a wide range and high antibacterial activity against both gram-negative and gram-positive bacteria, including resistant to drugs strains that were not supposed to inventions.

When the compound of formula (I) according to the invention has a structure in which there diastereoisomer, and when such a connection according to the invention is administered to a human or an animal, preferably a compound that includes one diastereoisomer. The term includes one diastereoisomer”, used here, means not only the case when it is fully freedoms what about the other diastereoisomer, but the case when it is chemically pure. In other words, it should be understood that other diastereoisomer may be present to such an extent that it does not impact on the physical constants and physiological activity of the connection.

In addition, the term “stereochemical clean”used here means that, when the connection or the like exists in many isomeric forms due to the presence of asymmetric carbon atoms, the compound includes only one of them. The term “pure” in this case should also be considered in the same way as described above.

Derived pyridonecarboxylic acid according to the invention can be used in its free form or in the form of additive salts of the acids or salts of its carboxyl group. Examples of the additive acid salt include hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, phosphate and the like salts of inorganic acids or acetate, methanesulfonate, bansilalpet, toluensulfonate, citrate, maleate, fumarate, lactate and the like organic acid salts.

Salt carboxyl group may be inorganic or organic salt, and its examples include lithium salt, sodium salt, potassium salt and the like alkali metal salts, magnesium salt, calcium salt and the like salts of alkaline-earth metals, ammonium salt or salt of triethylamine, the ol N-methylglucamine, salt of Tris-(hydroxymethyl)aminomethane and the like.

In addition, the data is free form, salt additive acid and a salt of carboxyl group of the compounds according to the invention can be in the form of hydrates.

On the other hand, a quinolone derivative, in which a fragment of the carboxylic acid is a complex ester, useful as intermediate compounds in the synthesis or prodrugs. For example, alkalemia, benzyl, alkoxyalkyl, phenylalkylamine and phenyl esters are useful as intermediates in the synthesis.

In addition, as prodrugs use ester that is easily hydrolyzed in vivo, and forms a free carboxylic acid, and its examples include acetoxymethyl ether, pivaloyloxymethyl ether, ethoxycarbonylethyl ether, kalinovy ether, dimethylaminoethyl ether, 5-indaily ether, caliginosus ether, and 5-alkyl-2-oxo-1,3-dioxol-4-ymetray, 3-acetoxy-2-oxobutanoic and similar oxoalkyl ester.

The connection according to the invention, represented by formula (I)can be obtained in various ways, and in a preferred example, it is possible to obtain, for example, the interaction of a compound represented by the formula (III):

[in which X4represented by the Deputy, to the which acts as a leaving group, such as a fluorine atom, a chlorine atom, a bromine atom, substituted or unsubstituted phenylsulfonyl or substituted or unsubstituted alkylsulfonyl having from 1 to 3 carbon atoms,

Y1is Y having the values defined for formula (I), or a boron-containing group represented by the formula (IV):

-B(Y)11Y12(IV)

(in which Y11and Y1each represents a fluorine atom or alkylcarboxylic having from 2 to 4 carbon atoms), and R9, R10, R11And1and X1have the meanings given for formula (I)]

or compounds represented by formula (V):

[in which X4represented by the Deputy, which functions as a leaving group such as fluorine atom, chlorine atom, bromine atom, substituted or unsubstituted phenylsulfonyl or substituted or unsubstituted alkylsulfonyl having from 1 to 3 carbon atoms, and R9, R10, R11And1X1and Y have the meanings given for formula (I)]

with a compound represented by the following formula (VI)

[in which R222is equal to R2having the values defined for formula (I)], and R1, R3, R4, R5, R6, R7and R8have the meanings given for formula I, or it is additive salt.

The reaction can be carried out with and without the use of solvent. The solvent used in the reaction may be any solvent which is inert under the reaction conditions, and its examples include dimethyl sulfoxide, pyridine, acetonitrile, ethanol, chloroform, dimethylformamide, dimethylacetamide, N-organic, tetrahydrofuran, water and 3-methoxybutanol or mixtures thereof.

It is preferable to conduct the reaction in the presence of an acid receptor, such as an inorganic base or organic base, and examples include a carbonate or bicarbonate of an alkali metal or alkaline-earth metal or triethylamine, pyridine, 1,8-diazabicyclo, N,N-diisopropylethylamine or similar organic primary connection.

The reaction can be conducted generally at a temperature of from room temperature to 200° C, preferably from 25 to 150° C. the Reaction is carried out over a period of time from 30 min to 48 h and finish basically after about 30 min-2 hours

As for aminosidine group, it may be any protective group commonly used in this field, and examples include tert-butoxycarbonyl, 2,2,2-trichloro-etoxycarbonyl and the like (substituted)alkoxycarbonyl group; benzyloxycarbonyl, para-methoxybenzeneboronic, para-nitrobenzyloxy the Nile and the like (substituted) aracelikarsaalyna group; acetyl, methoxyacetyl, TRIFLUOROACETYL, chloroacetyl, pivaloyl, formyl, benzoyl and the like (substituted)acyl groups; tert-butyl, benzyl, para-nitrobenzyl, para-methoxybenzyl, triphenylmethyl and the like (substituted)alkyl groups or (substituted)kalkilya group; methoxymethyl, tert-butoxymethyl, tetrahydropyranyl, 2,2,2-trichloroacetyl and the like (substituted)ethers; and trimethylsilyl, isopropylimidazole, tert-butyldimethylsilyl, tribenzylamine, tert-butyldiphenylsilyl and such (alkyl and/or aralkyl)substituted silyl group.

When each of Y and Y1represents alkyl having from 1 to 6 carbon atoms, alkoxymethyl having from 2 to 7 carbon atoms, or phenylalkyl consisting of alkylene having from 1 to 6 carbon atoms, and phenyl, it can be converted to the corresponding carboxylic acid treatment in an acidic or basic conditions, which are commonly used for hydrolysis of esters of carboxylic acids.

When Y1represents a structure of formula (IV), its transformation into the corresponding carboxylic acid can be performed in the interaction of the compound (III) or compound (V) with compound (VI) and then processed in an acidic or basic conditions.

In addition, when you remove protection, the desired compound represented by the formula (I)can be obtained by removing the protection of the Noah group in terms suitable for the protective group.

The compound of formula (VI) can be obtained in various ways, for example, it can be synthesized by the method presented in reference examples as a preferred example, but not limited to.

The compound of formula (VI) can be obtained by removing Q' of the compounds represented by the following formula

[in which R222is equal to R2having the values defined for formula (I), or is aminosidine group, R1, R3, R4, R5, R6, R7and R8have the meanings given for formula (I),

Q' represents aminosidine group,

where aminosidine group can be selected from the group consisting of (substituted)alkoxycarbonyl, (substituted)orelkinoservisa, (substituted)acyl, (substituted)alkyl, (substituted)aralkyl and substituted silyl groups].

The connection described above, may be in the form of its salt, hydrate, or hydrate of the salt. As examples of the additive salts of acid can lead salt of an inorganic acid and a salt of organic acid. Their illustrative examples include the hydrochloride, sulfate, hydrobromide, hydroiodide, phosphate and the like salts of inorganic acids or methanesulfonate, bansilalpet, tawassul eat (salt sulfonic acid), acetate, citrate, maleate, fumarate, lactate (salts of carboxylic acids) and the like organic acid salts.

When R222and Q' represent aminosidine group, they may be the same or different, but are eligible to obtain the compound (I), so that each was removed under different reaction conditions,

We can cite the following examples for R222and Q' as aminosidine groups. I.e. they are (substituted)alkoxycarbonyl, (substituted)Uralelectromed, (substituted)acyl, (substituted)alkyl, (substituted)aralkyl and substituted silyl groups.

Their illustrative examples include tert-butoxycarbonyl, 1,2,2-trichlorocyanuric and the like (substituted)alkoxycarbonyl group; benzyloxycarbonyl, para-methoxybenzeneboronic, para-nitrobenzenesulfonyl and the like (substituted)aracelikarsaalyna group; acetyl, methoxyacetyl, TRIFLUOROACETYL, chloroacetyl, pivaloyl, formyl, benzoyl and the like (substituted)acyl groups; tert-butyl, benzyl, para-nitrobenzyl, para-methoxybenzyl, triphenylmethyl and the like (substituted)alkyl groups or (substituted)kalkilya group; methoxymethyl, tert-butoxymethyl, tetrahydropyranyl, 2,2,2-trichloroacetyl and such (substituted)ethers; trimethylsilyl, isopropylimidazole, tert-butyldimethylsilyl, tribenzylamine, tre is-butyldiphenylsilyl and such substituted silyl group.

When the compound (I) receive, using the above compound with Q' as a protective group, it is necessary to carry out the reaction of removing the protective group Q'. In this case, its interaction with the compound (III) or (V) can be performed basically in the same reactor or the interaction can be performed immediately after the separation of the compound (VI) removing the protective group.

CIS-2-ferricopiapite consisting of a single isomer, which is preferred for the synthesis of compounds of formula (I)consisting of a single isomer can be synthesized, for example, a method described in JP-A-2-231475 (the term “JP-A”used here means “not passed the examination published a patent application in Japan). The synthesis of compounds of formula (I)consisting of a single isomer, with an optically active derivative of CIS-2-versicolorin thus obtained as a starting compound, can be carried out by a method described, for example in JP-A-2-231475.

Because the connection according to the invention has a high antibacterial effect, it can be useful as a drug for use in humans, animals and fish, or as preservatives, agricultural chemicals and food,

When the connection according to the invention is used as a medicine among the STV for people it dose ranges from 50 mg to 1 g, preferably from 100 mg to 500 mg per day for an adult.

In addition, its dosage for use in animals varies depending on the purpose of his assignment (treatment or prevention), the type and size of each animal undergoing treatment, and the type and amount of each infectious pathogenic bacteria, but generally is in the range from 1 to 200 mg, preferably from 5 to 100 mg per 1 kg of body weight of each animal as a daily dose.

The daily dose is administered once daily or divided into 2 to 4 doses per day. If circumstances so require, the daily dose may be higher than the specified limit.

Because the connection according to the invention is active against wide range of microorganisms that cause various infectious diseases it can treat, prevent or reduce diseases caused by these pathogens.

As examples of bacteria or bacteriorhodopsin microorganisms, in respect of which the effective compound according to the invention, it is possible to lead the genus Staphylococcus, Streptococcus pyogens, hemolytic streptococci, enterococci, pneumococci, genus Peptostreptococcus, Neisseria gonorrhoeae, Escherichia coli, the genus Citrobacter, genus Shigelia, Klebsiella pneumoniae, the genus Enterobacter, the genus Serratia, the genus Proteus, Pseudomonas aeruginosa, Haemophilus influenzae, genus Acinetobacter, the genus Campylobacter, Chlamydia trachomatis, and the like.

To the ome, as examples of the diseases caused by these pathogens can cause folliculitis, furuncle, carbuncle, a face, a phlegmon, lymphangitis, felon, subcutaneous abscess, hydradenitis, nodular acne, infectious atheroma, kolorektalnyy abscess, mastitis, superficial secondary infections after trauma, burn injury, surgical wound, and the like, pharyngitis, acute bronchitis, tonsillitis, chronic bronchitis, bronchiectasis, diffuse bronchiolitis, secondary infection of chronic respiratory disease, pneumonia, pyelonephritis, cystitis, prostatitis, epididymitis, gonococcal urethritis, non-specific urethritis, cholecystitis, cholangitis, bacillary dysentery, enteritis, inflammation of the uterus, intrauterine infection, we have to stop spreading, blepharitis, hordeolum, dacryocystitis, Cartagena, ulcers of the cornea, inflammation of the middle ear (octitis media, sinusitis, periodontic, pericolonic, infection of the jaw, peritonitis, endocarditis, sepsis, meningitis, skin infections, and the like.

It is also effective against various microorganisms that cause infectious disease in animals, such as the genus Escherichia, genus Salmonella, genus Pasteurella, genus Haemophilus, genus Bordetella, genus Staphylococcus, genus Mycoplasma, and the like.

Illustrative examples of such diseases include colibacteriosis, pullers, paratyphoid birds, cholera birds, contagious catarrh of the upper on the respiratory tract, Staphylococcus, infection caused by Mycoplasma, and the like in the case of birds, colibacteriosis, salmonellas, pasteurellosis, the infection caused by the bacteria Haemophilus, atrophic rhinitis, exudative epidemic, infection caused by Mycoplasma, and the like in the case of pigs, colibacteriosis, salmonellas, hemorrhagic septicemia, an infection caused by Mycoplasma, bovine pleuropneumonia, mastitis in cows, and the like in the case of cattle, alisasis, salmonellas, hemorrhagic septicemia, empyema of the uterus, cystitis and the like in the case of dogs and exudative pleurisy, cystitis, chronic rhinitis, infection caused by the bacteria Haemophilus, diarrhea in kittens, the infection caused by Mycoplasma, and the like in the case of cats.

Antibacterial composition, which comprises the compound according to the invention can be obtained by selecting an appropriate composition depending on the method of introducing and using the commonly used methods of obtaining. As for the dosage forms antibacterial composition, which uses the connection according to the invention as her acting start as examples for oral administration include tablets, powders, granules, capsules, solutions, syrups, elixirs, oily or aqueous suspensions, and the like. H what about the concerns of injection, in this composition you can use a stabilizing agent, an antiseptic and solubilizers agent or solution may contain the specified auxiliary agents which may be present in the container and be turned into a solid composition is freeze-drying or similar, which before use to dissolve again. In addition, the unit dose may be in a separate container or in the same container can be repeated doses.

In addition, as an example of the composition for external use can lead to solutions, suspensions, emulsions, ointments, gels, creams, lotions, sprays and the like.

Solid compositions may contain pharmaceutically acceptable additives together with the active compound, and they can be prepared, for example, by mixing the compounds with additives, optionally selected from fillers, diluents, binders, disintegrators that enhance the solubilization agents, moisturizing, lubricating agents and the like.

As examples of liquid compositions can lead to solutions, suspensions, emulsions and the like, which may include as additives suspendisse agent, emulsifier and the like.

Examples of the method of administration of the compounds according to the invention the animals include the way in which it century the completed oral directly or by mixing with feed, the way in which it is prepared from the solution and then administered orally either directly or by mixing with water to drink or food, and the way in which it is administered by injection. With regard to pharmaceutical compositions for administration of the compounds according to the invention to animals, it can not necessarily be included in powders, fine particles, soluble powders, syrups, solutions, injectable solutions using methods commonly used in this field.

Examples of pharmaceutical compositions are given in table 1

Table 1
Example compositions 1 (capsules):
Connection example according to the invention 2100,0
Corn starch23,0
SMS calcium22,5
Hydroxymethylcellulose3,0
Magnesium stearate1,5
In General150,0
Example composition 2 (solutions):
Connection example according to the invention 21-10 g
Acetic acid or sodium hydroxide0.5-2 g
Ethyl-para-oxybenzoic0.1 g
Purified water 88,9-98,4 g
In General100 g

Example of composition 3 (powders for mixing with food):
Connection example according to the invention 21-10 g
Corn starch98,5-89,5 g
Light silicic anhydride0.5 g
In General100 g

The best way of carrying out the invention

The subsequent describes the invention based on examples according to the invention and reference examples, although the invention is not limited to them.

[Reference example 1]

N-Methyl-N-methoxy-1-[1-(R)-phenylethyl]-5-oxopyrrolidin-3-(R)-carboxamide

Under ice cooling was added oxalicacid (6,54 ml, 0.075 ml) and dimethylformamide (3 drops) to a solution of 1-[1-(R)-phenylethyl]-5-oxopyrrolidin-3-(R)-carboxylic acid (11,66 g, 0.05 mol) in dichloromethane (200 ml) and was stirred over night at room temperature. After removal of the solvent under reduced pressure was added toluene (100 ml) and the solvent again drove away under reduced pressure. The residue was mixed with dichloromethane (200 ml) and the hydrochloride of N,O-methylhydroxylamine (vs. 5.47 g, by 0.055 mol), to the mixture was added dropwise a solution of triethylamine (17,4 ml, 0.125 mol) in dichloromethane (50 ml) and the mixture peremeshivaniya ice cooling for 15 minutes The latter was stirred with ice cooling for 30 min and then stirred at room temperature for 3 hours the Reaction solution was washed with 10% aqueous citric acid solution (100 ml), water (100 ml) and saturated aqueous sodium bicarbonate (100 ml) in this order and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the obtained residue was subjected to column chromatography on silica gel. By elution with a mixture of chloroform: methanol (50:1) to (20:1) received 11,32 g (82%) indicated in the title compound as a brown oil.

1H-NMR (400 MHz, Dl3)δ : and 1.54 (3H, d, J=6,84 Hz), 2,65 (1H, DD, J=9,77, to 7.09 Hz), 2,77 (1H, DD, J=8,79, to 7.09 Hz), 3,12-3,18 (1H, m), 3,20 (3H, s), 3,37-of 3.48 (1H, m), 3,55-of 3.64 (1H, m), the 3.65 (3H, s), of 5.50 (1H, kb, J=6,84 Hz), 7,28-7,37 (5H, m).

[Referential example 2]

4-(R)-Phenylcarbamoyl-1-[1-(R)-phenylethyl]-2-pyrrolidone

In the atmosphere of nitrogen phenylmagnesium (3 mol/l solution in diethyl ether, 15 ml) was added dropwise to a solution of N-methyl-N-methoxy-1-[1-(R)-phenylethyl]-5-oxopyrrolidin-3-(R)-carboxamide (2,49 g, 9.0 mmol) in tetrahydrofuran (50 ml) and the mixture was stirred at room temperature for 30 minutes the Reaction solution was mixed with 1 mol/l hydrochloric acid (50 ml) under cooling with ice and then extracted with ethyl acetate (8 ml × 2). The organic layer was washed with saturated salt solution (100 ml) and ZAT the m was dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the obtained residue was subjected to column chromatography on silica gel. By elution with a mixture of n-hexane:ethyl acetate (1:1) received at 2.36 g (89%) indicated in the title compounds as a light yellow oil.

1H-NMR (400 MHz, Dl3)δ : of 1.55 (3H, d, J=6,83 Hz), and 2.79 (1H, DD, J=17,09, 9,77, Hz)of 2.81 (1H, DD, J=17,09, 7,81 Hz), 3,23 (1H, DD, J=9,76, 8,79 Hz), 3,71 (1H, DD, J=9,76, 6,35 Hz), 3,97-of 4.05 (1H, m)5,54 (1H, kb, J=6,83 Hz), 7,27-7,38 (5H, m), 7,42-to 7.50 (2H, m), 7,55-to 7.61 (1H, m), 7,88-of 7.90 (2H, m).

[Referential example 3]

4-(R)-[1-Hydroxy-1-phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1], [F2]

Under ice cooling sodium borohydride (280 mg) was added to a solution of 4-(R)-phenylcarbamoyl-1-[1-(R)-phenylethyl]-2-pyrrolidone (2.17 g, 7.40 mmol) in anhydrous ethanol (40 ml) and the mixture was stirred at the same temperature for 1 h the Reaction solution was mixed with 10% citric acid (50 ml) under cooling with ice and the ethanol is then drove away under reduced pressure. The residue was extracted with chloroform (80 ml× 2), the organic layer was washed with saturated salt solution (100 ml) and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the obtained residue was subjected to column chromatography on silica gel. By elution with a mixture of n-hexane:ethyl acetate (1:3) to ethyl acetate (100%) received respectively 892 mg (41%) specified in the header joint is low polarity [F1] and then 1,163 g (53%) indicated in the title compounds with high polarity [F2] in the form of a light yellow oil.

[F1];

1H-NMR (400 MHz, Dl3)δ : of 1.46 (3H, d, J=6,84 Hz), 2,03 with 2.14 (2H, m), 2,44-of 2.54 (1H, m), 3,05-to 3.09 (1H, m), 3,36 is 3.40 (1H, m), 3,47 (1H, USS), of 4.45 (1H, d, J=7,81 Hz), 5,38 (1H, kb, J=6,84 Hz), 7,22-7,31 (10H, m).

[F2];

1H-NMR (400 MHz, CDCl3)δ : 1,37 (ZN, d, J=to 7.32 Hz), 2.26 and of-2.32 (1H, m), 2.40 a is 2.55 (2H, m), 2,73-2,77 (1H, m), 3.00 and totaling 3.04 (1H, m), 4,32 (1H, USS), 4,42 (1H, d, J=6.8 Hz), 5,33 (1H, kb, J=to 7.32 Hz), 7,15-7,27 (10H, m).

[Reference example 4]

4-(R)-[1-Azido-1-phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1], [F2]

Under ice cooling, the triethylamine (0,46 ml) and methanesulfonamide (217 μl, 2,80 mmol) was added to a solution of 4-(R)-[1-hydroxy-1-phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1] (738 mg, of 2.50 mmol) in dichloromethane (10 ml) and the mixture was stirred at the same temperature for 1 h the Reaction solution was mixed with 10% citric acid (20 ml) under cooling with ice and was extracted with chloroform (30 ml × 2). The organic layer was washed with saturated salt solution (100 ml) and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, the obtained residue was dissolved in N,N-dimethylformamide (10 ml)was mixed with sodium azide (488 mg, 7,50 mmol) and then heated at 60° within 1.5 hours After spontaneous cooling, the reaction solution was mixed with water (50 ml) and was extracted with ethyl acetate (70 ml × 3), the organic layer was washed with saturated salt solution (150 ml) and then dried over svodnyy sodium sulfate. The solvent is kept under reduced pressure and the obtained residue was subjected to column chromatography on silica gel. By elution with a mixture of n-hexane: ethyl acetate (3:2) received 701 mg (87%) indicated in the title compounds as colorless oils.

A similar reaction was carried out on the basis of 4-(R)-[1-hydroxy-1-phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F2] (77%).

[F1];

1H-NMR (400 MHz, Dl3)δ : of 1.46 (3H, d, J=to 7.32 Hz), 2,53-of 2.66 (3H, m), 2,82 (1H, DD, J=9,76, 7,81 Hz)to 2.94 (1H, DD, J=9,76, 5,86 Hz), 4,37 (1H, d, J=7,81 Hz), vs. 5.47 (1H, kb, J=to 7.32 Hz), 7,21-7,42 (10H, m).

[F2];

1H-NMR (400 MHz, Dl3)δ : and 1.54 (3H, d, J=7,33 Hz), and 2.14 (1H, DD, J=17,09, 7,81 Hz), and 2.26 (1H, DD, J=17,09, 8,78 Hz), 2,55-to 2.65 (1H, m), 3,14 (1H, DD, J=10,26, 7,81 Hz), 3,32 (1H, DD, J=10,26, 6,34 Hz), 4,36 (1H, d, J=9.28 are Hz), 5,49 (1H, kb, J=7,33 Hz), 7,26-the 7.43 (10H, m).

[Reference example 5]

4-(R)-[1-Tert-butoxycarbonylamino-1-phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1], [F2]

A solution of 4-(R)- [1-azido-1-phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1] (641 mg, 2.0 mmol) in ethanol (30 ml) was mixed with catalyst 10% palladium on coal (moisture 53,8%, 600 mg) and spent catalytic hydrogenation at room temperature for 6 h under normal pressure. The reaction solution was filtered and the solvent is kept at reduced pressure. The residue was dissolved in dichloromethane (20 ml), was mixed with di-tert-BUTYLCARBAMATE (655 mg) and triethylamine (560 μl) and then displaced ivali at room temperature for 13 hours To the reaction solution was added chloroform (50 ml), washed with 10% citric acid (8 ml) and water (8 ml) and the resulting organic layer was dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the obtained residue was subjected to column chromatography on silica gel. By elution with a mixture of n-hexane: ethyl acetate (1:1) up (2:3) has obtained 629 mg (80%) indicated in the title compounds as colorless oils.

A similar reaction was carried out on the basis of 4-(R)-[1-azido-1-phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F2] (76%).

[F1];

1H-NMR (400 MHz, Dl3)δ : 1,41 (N, C)of 1.46 (3H, d, J=to 7.32 Hz), 2,47 was 2.76 (3H, m), was 2.76-2,89 (1H, m), 2.95 and-is 3.08 (1H, m), 4,62-to 4.73 (1H, m), 4,99-5,11 (1H, m), vs. 5.47 (1H, kb, J=to 7.32 Hz), 7,20-7,34 (10H, m).

[F2];

1H-NMR (400 MHz, Dl3)δ : 1,37 (N,) and 1.51 (3H, d, J=to 7.32 Hz), 2,08-of 2.26 (2H, m), 2,52-to 2.65 (1H, m), 3,06-3,18 (1H, m), 3,24-of 3.32 (1H, m), to 4.52-of 4.66 (1H, m), 5,01-5,11 (1H, m), vs. 5.47 (1H, kb, J=to 7.32 Hz), 7,19-to 7.35 (10H, m).

[Reference example 6]

3-(R)-[1-Tert-butoxycarbonylamino-1-phenylmethyl]-1-[1-(R)-phenylethyl]pyrrolidin [F1]

In nitrogen atmosphere 1M complex of borane-tetrahydrofuran (4.6 ml) was added dropwise to a solution of 4-(R)-[1-tert-butoxycarbonylamino-1-phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1] (600 mg, of 1.52 mmol) in tetrahydrofuran (10 ml) under ice cooling and then the mixture was stirred at room temperature for 13 hours After removal of the solvent in ponie nom pressure, the obtained residue was mixed with 80% aqueous ethanol (15 ml) and triethylamine (3 ml) and boiled under reflux for 5 hours After spontaneous cooling, the solvent is kept under reduced pressure and the obtained residue was added chloroform (30 ml). The latter was washed with water (10 ml) and saturated salt solution (10 ml) and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the obtained residue was subjected to column chromatography on silica gel. By elution with a mixture of chloroform:methanol (20:1) received 510 mg (88%) indicated in the title compounds as colorless crystals.

A similar reaction was carried out on the basis of 4-(R)-[1-tert-butoxycarbonylamino-1-phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F2] (86%).

[F1];

1H-NMR (400 MHz, Dl3)δ : of 1.34 (3H, d, J=6,35 Hz), 1,47 (N, s), 1.60-to of 1.78 (2H, m), 2,18-2,39 (3H, m), 2,42-of 2.54 (1H, m), 2,83-2,95 (1H, m), 3,11 (1H, kb, J=6,35 Hz), 4,47-of 4.57 (1H, m), 6,06-6,18 (1H, m), 7,16-7,33 (10H, m).

[F2];

1H-NMR (400 MHz, Dl3)δ : of 1.41 (3H, d, J=6,35 Hz), 1,46 (N, C), 1,67-of 1.78 (1H, m), 1,89-2,02 (1H, m), 2,04-2,17 (1H, m), 2,17-of 2.28 (1H, m), 2,37-of 2.50 (2H, m), 3,01-3,19 (2H, m), 4,48-4,58 (1H, m), 6,62-of 6.73 (1H, m), 7,07-7,34 (10H, m).

[Referential example 7]

3-(R)-[1-Tert-butoxycarbonylamino-1-phenylmethyl]pyrrolidine [F1]

A solution of 3-(R)-[1-tert-butoxycarbonylamino-1-phenylmethyl]-1-[1-(R)-phenylethyl]pyrrolidine [F1] (495 mg, of 1.30 mmol) in ethanol (20 ml) was mixed with catalyst 10% palladium on coal (moisture 53,8%, 500 mg) and spent catalytic hydrogenation under normal pressure the AI for 4 hours while heating at a temperature of 50° C. Filtration of the reaction solution and distillation of the solvent was received 359 mg (quantitative) of the crude indicated in the title compounds as colorless crystals. Last used in the next stage without purification.

A similar reaction was carried out on the basis of 3-(R)-[1-tert-butoxycarbonylamino-1-phenylmethyl]-1-[1-(R)-phenylethyl]pyrrolidine [F2] (quantitatively).

[Example according to the invention 1]

5-Amino-7-[3-(R)-(1-amino-1-phenylmethyl)-1-pyrrolidinyl]-6,8-debtor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid [F1]

3-(R)-[1-Tert-butoxycarbonylamino-1-phenylmethyl] pyrrolidine [F1] (332 mg, 1.2 mmol) was added to a suspension of 5-amino-6,1,8-Cryptor-1-[2-(S)-fluoro-1-(S)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid (316 mg, 1.0 mmol) in acetonitrile (15 ml) and the mixture is boiled under reflux for 14 h in the presence of triethylamine (2 ml). After spontaneous cooling, the solvent is kept under reduced pressure and the obtained residue was dissolved in chloroform (50 ml). The latter was washed with 10% citric acid (30 ml × 2) and saturated salt solution (20 ml) and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, the obtained residue was mixed with concentrated hydrochloric acid (15 ml) and stirred at room temperature for 10 minutes This hydrochloric Rast is the PR was washed with chloroform (20 ml × 3), brought to an alkaline reaction by adding 30% aqueous solution of sodium hydroxide under ice cooling and then stirred at room temperature for 1 h the suspension was brought to pH to 7.6 by the addition of concentrated hydrochloric acid and 1 mol/l hydrochloric acid and then was extracted with chloroform (100 ml × 3). The obtained organic layer was dried over anhydrous sodium sulfate and the solvent is kept at reduced pressure. The latter was purified by recrystallization from a mixture of ethanol-diethyl ether to obtain 241 mg (51%) indicated in the title compound as bright yellow crystals.

1H-NMR (400 MHz, 0,1 mol/l NaOD)δ : 1,28 was 1.43 (2H, m), 1,53-of 1.66 (1H, m), 2,16-of 2.28 (1H, m), 2,31-to 2.42 (1H, m), 2,86-2,96 (1H, m), 3,09-3,20 (1H, m), 3,39-3,50 (2H, m), to 3.58-3,70 (2H, m), with 4.64-4,71 (0,5H, m), 4,78-4,96 (0,5H, m), 7,27-7,40 (5H, m), 8,10 (1H, s).

Melting point: 111,8-114,3° C (decomposition).

Elemental analysis: for C24H23F3N4O3·0,25N2O

Calculated: C, 60,44; N, Equal To 4.97; N, 11,75.

Found: C, 60,31; N, To 4.92; N, 11,74.

[Example according to the invention 2]

5-Amino-7-[3-(R)-(1-amino-1-phenylmethyl)-1-pyrrolidinyl]-6,8-debtor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid [F2]

3-(R)-[1-Tert-butoxycarbonylamino-1-phenylmethyl]pyrrolidine [F2] (332 mg, 1.2 mmol) was added to a suspension of 5-amino-6,7,8-Cryptor-1-[2-(S)-fluoro-1-(S)-cyclopropyl]-1,4-dihyd is about-4-oxoindole-3-carboxylic acid (316 mg, 1.0 mmol) in acetonitrile (15 ml) and the mixture is boiled under reflux for 14 h in the presence of triethylamine (2 ml). After spontaneous cooling, the solvent is kept under reduced pressure and the obtained residue was dissolved in chloroform (50 ml). Obtained was washed with 10% citric acid (30 ml× 2) and saturated salt solution (20 ml) and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, the obtained residue was mixed with concentrated hydrochloric acid (15 ml) and stirred at room temperature for 10 minutes This hydrochloric acid solution was washed with chloroform (20 ml × 3), brought to an alkaline reaction by adding 30% aqueous solution of sodium hydroxide under ice cooling and then stirred at room temperature for 1 h the suspension was brought to pH to 7.6 by the addition of concentrated hydrochloric acid and 1 mol/l hydrochloric acid and then was extracted with chloroform (100 ml × 3). The obtained organic layer was dried over anhydrous sodium sulfate and the solvent is kept at reduced pressure. The latter was purified by recrystallization from a mixture of ethanol-diethyl ether to obtain 388 mg (82%) indicated in the title compound as bright yellow crystals.

1H-NMR (400 MHz, 0,1 mol/l NaOD)δ : 1,19 is 1.58 (5H, m), 2,27 is 2.43 (1H, m), 3.27 to to 3.41 (1H, m), 3,463,74 (4H, m), 4,71-5,12 (1H, m), 7,21-7,41 (5H, m), 8,18 (1H, s).

Melting point: 202,3-205,1° C (decomposition).

Elemental analysis: for C24H23F3N4O3·0,25H2O

Calculated: C, 60,44; N, Equal To 4.97; N, 11,75.

Found: C, 60,31; N, 4,89; N, 11,84.

[Example according to the invention 3]

7-[3-(R)-(1-Amino-1-phenylmethyl)-1-pyrrolidinyl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoindole-3-carboxylic acid [F2]

3-(R)-[1-Tert-butoxycarbonylamino-1-phenylmethyl]pyrrolidine [F2] (304 mg, 1.1 mmol) and triethylamine (0,42 ml) was added to a solution of BF2chelate 6,7-debtor-1-[2-(3-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoindole-3-carboxylic acid (325 mg, 0.9 mmol) in dimethyl sulfoxide (3 ml) and the mixture was stirred at 30° C for 19 hours, the Solvent is kept under reduced pressure, the obtained residue was mixed with 80% aqueous ethanol (10 ml) and triethylamine (2 ml) and boiled under reflux for 3 hours After spontaneous cooling, the solvent drove away, the resulting residue was mixed with chloroform (50 ml), washed with 10% citric acid (40 ml × 2) and water (50 ml), dried over anhydrous sodium sulfate and the solvent is then drove away. The obtained residue was mixed with concentrated hydrochloric acid (10 ml) and stirred at room temperature for 10 min and then the resulting aqueous layer was washed chloroform is m (20 ml × 3) and podslushivaet the addition of 30% aqueous sodium hydroxide solution while cooling with ice. Last brought up to a pH of 7.6 by the addition of concentrated hydrochloric acid and 1 mol/l hydrochloric acid and then was extracted with chloroform (80 ml × 3). The obtained organic layer was dried over anhydrous sodium sulfate and the solvent is kept at reduced pressure. The latter was purified by recrystallization from ethanol to obtain 294 mg (70%) indicated in the title compound as bright yellow crystals.

1H-NMR (400 MHz, 0,1 mol/l NaOD)δ : 1,23-to 1.61 (5H, m), 2,42-to 2.57 (1H, m), 3,32-3,44 (1H, m), 3,51 (3H, s), 3,54-of 3.64 (1H, m), 3,69-with 3.79 (2H, m), 3,93-a 4.03 (1H, m), 4,85-4,93 (0,5H, m), 4,99-5,09 (0,5H, m), 7,26-7,44 (5H, m), the 7.65 (1H, d, J=14,16 Hz), 8,40 (1H, s).

Melting point: 141,8-144,2° C (decomposition).

Elemental analysis: for C25H25F2N3O4·0,5H2O

Calculated: C, 62,75; N, Of 5.48; N, 8,78.

Found: C, 63,00; N, To 5.35; N, 8,78.

[Example according to the invention 4]

10-[3-(R)-(1-Amino-1-phenylmethyl)-1-pyrrolidinyl]-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid [F2]

3-(R)-[1-Tert-butoxycarbonylamino-1-phenylmethyl] pyrrolidine [F2] (304 mg, 1.1 mmol) and triethylamine (0,42 ml) was added to a solution of BF2chelate 9,10-debtor-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (296 mg, 0.9 mmol) in dimethyl sulfoxide (3 is l) and the mixture was stirred at 30° C for 19 hours, the Solvent is kept under reduced pressure and the obtained residue was mixed with 80% aqueous ethanol (10 ml) and triethylamine (2 ml) and boiled under reflux for 3 hours After spontaneous cooling, the solvent drove away, the resulting residue was mixed with chloroform (50 ml), washed with 10% citric acid (40 ml × 2) and water (50 ml), dried over anhydrous sodium sulfate and the solvent is then drove away. The obtained residue was mixed with concentrated hydrochloric acid (10 ml) and stirred at room temperature for 10 min, and then the resulting aqueous layer was washed with chloroform (20 ml × 3) and podslushivaet the addition of 30% aqueous sodium hydroxide solution while cooling with ice, the Latter is brought to a pH of 7.6 by the addition of concentrated hydrochloric acid and 1 mol/l hydrochloric acid and then was extracted with chloroform (80 ml × 3). The obtained organic layer was dried over anhydrous sodium sulfate and the solvent is kept at reduced pressure. The latter was purified by recrystallization from ethanol to obtain 158 mg (40%) indicated in the title compound as bright yellow crystals,

1H-NMR (400 MHz, 0,1 mol/l NaOD)δ : 1,35-to 1.61 (5H, m), 2,48-2,61 (1H, m), 3,29-to 3.38 (1H, m), 3,53-of 3.77 (4H, m), 4,21-the 4.29 (1H, m), to 4.41-4,48 (1H, m), to 4.52-br4.61 (1H, m), 7,28-7,42 (5H, m), 7,51 (1H, d, J=of 13.18 Hz), 8,32 (1H, s).

Melting point: 169,3-17,0° C (with decomposition).

Elemental analysis: for C24H24FN3O4·0,25N2About

Calculated: C, 65.22 Per; N, 5,59; N, 9,51.

Found: C, 65,50; N, 5,50; N, 9,52.

[Example according to the invention 5]

5-Amino-7-[3-(R)-(1-amino-1-phenylmethyl)-1-pyrrolidinyl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoindole-3-carboxylic acid [F2]

3-(R)-[1-Tert-butoxycarbonylamino-1-phenylmethyl] pyrrolidine [F2] (414 mg, 1.5 mmol) and triethylamine (2 ml) was added to a solution of 5-amino-6,7-debtor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-6-methyl-4-oxoindole-3-carboxylic acid (312 mg, 1.0 mmol) in dimethyl sulfoxide (3 ml) and the mixture was stirred at 130° C for 5 days under nitrogen atmosphere. The solvent is kept off and the obtained residue was mixed with chloroform (60 ml), washed with 10% citric acid (40 ml × 2), dried over anhydrous sodium sulfate and the solvent is then drove away. The obtained residue was mixed with concentrated hydrochloric acid (10 ml) and stirred at room temperature for 10 min, and then the resulting aqueous layer was washed with chloroform (30 ml × 3) and podslushivaet the addition of 30% aqueous sodium hydroxide solution while cooling with ice. Last brought up to a pH of 7.6 by the addition of concentrated hydrochloric acid and 1 mol/l hydrochloric acid and then was extracted with chloroform (80 ml × 3). The obtained organic leisurely over sodium sulfate, the solvent drove away and then the obtained residue was subjected to preparative TLC. The latter was subjected to separation and purification by development in the lower layer of a mixture of chloroform:methanol:water=7:3:1, thus having 148 mg (32%) crude specified in the connection header. The latter was purified by recrystallization from a mixture of ethanol-hexane to obtain 79 mg (17%) indicated in the title compound as bright yellow crystals.

1H-NMR (400 MHz, 0,1 mol/l NaOD)δ : 0,90-of 1.09 (2H, m), 1,22-is 1.51 (3H, m)of 2.16 (3H, s), 2,34-2,49 (1H, m), 2,99-to 3.09 (1H, m), 3,35-of 3.46 (1H, m), 3,42-3,62 (1H, m), 3,62-to 3.73 (1H, m), 3,78-to 3.89 (1H, m), 4,79-4,88 (0,5H, m), 4,94-5,04 (0,5H, m), 7,22-7,41 (5H, m), compared to 8.26 (1H, s).

Melting point: 179,4-183,6° C (decomposition).

Elemental analysis: for C25H26F2N4O3

Calculated: C, 64,09; N, 5,59; N, 11,96.

Found: C, 63,91; N, Of 5.40; N, 11,96.

[Example according to the invention 6]

7-[3-(R)-(1-Amino-1-phenylmethyl)-1-pyrrolidinyl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoindole-3-carboxylic acid [F2]

3-(R)-[1-Tert-butoxycarbonylamino-1-phenylmethyl]pyrrolidine [F2] (304 mg, 1.1 mmol) and triethylamine (1 ml) was added to a solution of 7-fluoro-1-[2-(8-fluoro-1-(R)-cyclopropyl] -1,4-dihydro-8-methoxy-4-oxoindole-3-carboxylic acid (266 mg, 0.9 mmol) in dimethyl sulfoxide (5 ml) and the mixture was stirred at 100° in for 14 hours, the Solvent is kept under reduced pressure, the obtained residue was mixed the chloroform (50 ml), washed with 10% citric acid (40 ml × 2) and water (50 ml), dried over sodium sulfate and the solvent is then drove away. The obtained residue was mixed with concentrated hydrochloric acid (10 ml) and stirred at room temperature for 10 min, and then the resulting aqueous layer was washed with chloroform (20 ml × 3) and podslushivaet the addition of 30% aqueous sodium hydroxide solution while cooling with ice. Last brought up to a pH of 7.2 by the addition of concentrated hydrochloric acid and 1 mol/l hydrochloric acid and then was extracted with chloroform (80 ml × 3). The obtained organic layer was dried over anhydrous sodium sulfate and the solvent is kept at reduced pressure. The latter was purified by recrystallization from a mixture of ethanol-hexane to obtain 274 mg (67%) indicated in the title compound as light yellow crystals.

1H-NMR (400 MHz, 0,1 mol/l NaOD)δ : 1,25-to 1.67 (4H, m), 2,48-2,61 (1H, m), 3,30-to 3.49 (3H, m), 3,49 (3H, s), 3,61-3,71 (1H, m), 3,71-with 3.79 (2H, m), 3,94-was 4.02 (IH, m),- 4,88-4,94 (0,5H, m), 5,03-5,10 (0,5H, m), of 7.00 (1H, d, J=9.28 are Hz), 7,31-the 7.43 (5H, m), 7,92 (1H, d, J=9.28 are Hz), 8,39 (1H, s).

Melting point: 116,8-120,4° C (decomposition).

Elemental analysis: for C25H26FN3O4·0,25N2O

Calculated: C, 65,85; N, 5,86; N, Of 9.21.

Found: C, 66,14; N, 5,80; N, 9,18.

[Referential example 8]

4-(R)-(2-Methoxy)phenylcarbamoyl-1-[1-(R)-phenylethyl]-2-pyrrolidone

the nitrogen atmosphere of 1 mol/l 2-methoxyphenylacetamide (38 ml), obtained from 2-bromoanisole, was added dropwise to a solution of N-methyl-N-methoxy-1-[1-(R)-phenylethyl]-5-oxopyrrolidin-3-carboxamide (6.20 g, of 22.4 mmol) in tetrahydrofuran (50 ml) and the mixture was stirred at room temperature for 5 minutes the Reaction solution was mixed with 1 mol/l hydrochloric acid (40 ml) under cooling with ice and then extracted with ethyl acetate (80 ml × 2). The organic layer was washed with saturated salt solution (100 ml) and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the obtained residue was subjected to column chromatography on silica gel. By elution with a mixture of n-hexane: ethyl acetate (1:2) to (1:3) was received of 2.45 g (33%) indicated in the title compounds as a light yellow oil,

1H-NMR (400 MHz, Dl3)δ : and 1.54 (3H, d, J=6,84 Hz), 2,73 (2H, d, J=8,30 Hz), 3,18 (1H, DD, J=8,79, 9,77 Hz); 3,66 (1H, DD, J=6,34, 9,77 Hz), 3,82 (ZN, C), Android 4.04 (1H, DD, J=6,34, 8,79 Hz), the 5.51 (1H, kb, J=6,84 Hz)6,94 (1H, d, J=8,30Hz), 7,00? 7.04 baby mortality (1H, m), 7,27-7,38 (5H, m), 7,47-7,51 (1H, m), 7.68 per-of 7.70 (1H, m).

[Referential example 9]

4-(R)-[1-Azido-1-(2-methoxy)phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1], [F2]

Under ice cooling sodium borohydride (150 mg) was added to a solution of 4-(R)-(2-methoxy)phenylcarbamoyl-1-[1-(R)-phenylethyl]-2-pyrrolidone (2,45 g, EUR 7.57 mmol) in ethanol (30 ml) and the mixture was stirred at the same temperature for 20 minutes the Reaction solution was mixed with water (30 ml), paramesh the Wali at room temperature for 30 min and then was extracted with chloroform (80 ml× 3). The organic layer was washed with saturated salt solution (100 ml) and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the obtained residue was subjected to column chromatography on silica gel. By elution with a mixture of 2% methanol-chloroform was received of 1.97 g (6.05 mmol) of the intermediate 4-(R)-[1-(2-methoxy)phenyl-1-hydroxymethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone as a colorless oil (mixture of isomers 1:1). Last tolerated in dichloromethane (35 ml), was mixed with methanesulfonanilide (900 mg, 7.87 mmol) and triethylamine (1.8 ml) and then stirred at room temperature for 50 hours, the Reaction solution was washed with water (30 ml) and saturated salt solution (50 ml), the organic layer was dried over anhydrous sodium sulfate and the solvent is then drove away under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (40 ml)was mixed with sodium azide (2,11 g) and then heated at 80° C for 13 hours After spontaneous cooling, the reaction solution was mixed with water (50 ml) and was extracted with ethyl acetate (70 ml × 3)obtained organic layer was washed with saturated salt solution (150 ml) and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the obtained residue was subjected to column chromatography on silica gel. The elution mixture is n-hexane: ethyl acetate (2:1) consistently received 621 mg (29%) indicated in the title compounds with low polarity [F1] and 1.0 (47%) indicated in the title compounds with high polarity [F2] each in the form of a colourless oil.

[F1];

1H-NMR (400 MHz, Dl3)δ : of 1.47 (3H, d, J=6,83 Hz), 2.49 USD is 2.55 (2H, m), 2,66-by 2.73 (1H, m), 2,85-to 2.94 (1H, m), 2,97 was 3.05 (1H, m), 3,83 (3H, s), of 4.95 (1H, d, J=7,81 Hz), 5,49 (1H, kb, J=6,83 Hz), 6,92 (1H, d, J=8,30 Hz), 6,97-7,01 (1H,m), 7.23 percent-7,34 (7H, m).

[F2];

1H-NMR (400 MHz, Dl3)δ : of 1.55 (3H, d, J=6,84 Hz), 2,18-of 2.34 (2H, m), 2,63-to 2.74 (1H, m), 3,10 (1H, DD, J= 8,30, of 10.25 Hz), 3,30 (1H, DD, J=6,84, of 10.25 Hz), of 3.84 (3H, s), 4,94 (1H, d, J=9.28 are Hz), 5,49 (1H, kb, J - 6,84 Hz), 6,92 (1H, d, J= 8,30 Hz), 6,98-7,01 (1H,m), 7,25 was 7.36 (7H, m).

[Referential example 10]

4-(R)-[1-Tert-butoxycarbonylamino-1-(2-methoxy)phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1], [F2]

A solution of 4-(R) -[1-azido-1-(2-methoxy)phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1] (621 mg, 1.77 mmol) in ethanol (40 ml) was mixed with catalyst 10% palladium on coal (moisture 53,8%, 700 mg) for carrying out catalytic hydrogenation at room temperature for 1 h under normal pressure. The reaction solution was filtered and the filtrate was evaporated under reduced pressure. The obtained residue was dissolved in dichloromethane (40 ml)was mixed with di-tert-BUTYLCARBAMATE (600 mg) and triethylamine (1 ml) and then stirred at room temperature for 15 hours, the Reaction solution was evaporated under reduced pressure, the obtained residue was mixed with chloroform (20 ml), washed with water (10 ml) and then the organic layer was dried over anhydrous sodium sulfate. Dissolve the al drove under reduced pressure and the obtained residue was subjected to column chromatography on silica gel (silica gel, 20 g). By elution with a mixture of n-hexane:ethyl acetate (1:2) received 589 mg (78%) indicated in the title compounds as a colorless amorphous substance.

A similar reaction was carried out on the basis of 4-(R)-[1-azido-1-(2-methoxy)phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F2] (80%).

[F1];

1H-NMR (400 MHz, Dl3)δ : 1,42 (N, C)of 1.47 (3H, d, J=6,84 Hz), 2,50-of 2.54 (2H, m), 2,70-of 2.86 (2H, m), 2,92-a 3.01 (1H, m), 3,82 (3H, s), 4,73-4,80 (1H, m), the 5.45 to 5.56 (2H, m), 6,85-6,93 (2H, m), 7,12-7,30 (7H, m).

[F2];

1H-NMR (400 MHz, Dl3)δ : 1,41 (N, C), and 1.54 (3H, d, J=7,33 Hz), 2,03-of 2.15 (2H, m), 2,68-of 2.81 (1H, m), 3.00 and-3,13 (1H, m), 3,22-to 3.35 (1H, m), of 3.84 (3H, s), 4,60-4,72 (1H, m), 5,39-to 5.56 (2H, m), 6,79-of 6.96 (2H, m), 7,05-7,38 (7H, m).

[Reference example 11]

3-(R)-[1-Tert-butoxycarbonylamino-1-(2-methoxy)phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidin [F1], [F2]

In nitrogen atmosphere 1M complex of borane-tetrahydrofuran (5.5 ml) was added dropwise to a solution of 4-(R)-[1-tert-butoxycarbonylamino-1-(2-methoxy)phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1] (589 mg, of 1.39 mmol) in tetrahydrofuran (20 ml) under ice cooling and then the mixture was stirred at room temperature for 17 hours After addition of methanol (10 ml) under ice cooling and subsequent stirring at room temperature for 20 min the solvent drove away under reduced pressure. The obtained residue was dissolved in 80% aqueous ethanol (40 ml) and boiled under reflux for 30 m is h in the presence of triethylamine (3 ml). After spontaneous cooling, the reaction solution, the solvent is kept under reduced pressure, the obtained residue was added chloroform (30 ml), the organic layer was washed with water (10 ml) and saturated salt solution (10 ml) and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the obtained residue was subjected to column chromatography on silica gel. By elution with a mixture of 3% methanol-chloroform, received 488 mg (86%) indicated in the title compounds as colorless oils.

A similar reaction was carried out on the basis of 4-(R)-[1-tert-butoxycarbonylamino-1-(2-methoxy)phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F2] (99%).

[F1];

1H-NMR (400 MHz, Dl3)δ : of 1.32 (3H, d, J=6,34 Hz), 1,45 (N, C), 1,66-of 1.74 (2H, m), 2,18-2,31 (3H, m), 2,70-to 2.85 (2H, m), 3,11 (1H, q, J=6,34 Hz), with 3.79 (3H, s), 4,70 (1H, t, J=to 7.32 Hz), 6,17 (1H, OSD, J=6,35 Hz), 6,80-6,91 (2N, m), 7,17-7,33 (7H, m).

[F2];

1H-NMR (400 MHz, Dl3)δ : of 1.40 (3H, d, J=6,83 Hz), 1,45 (N, C), 1,80-of 1.92 (1H, m), 2,17-of 2.30 (3H, m), 2,32-to 2.42 (1H, m), 2,53-2,61 (1H, m), 2,75-2,82 (1H, m), 2,89 are 2.98 (1H, m), 3,10-3,18 (1H, m), with 3.79 (3H, s), 4,74 (1H, t, J=6,83 Hz), 6,78 (1H, d, J=7,81 Hz), 6,97-to 7.35 (8H, m).

[Reference example 12]

3-(R)-[1-Tert-butoxycarbonylamino-1-(2-methoxy)phenylmethyl] pyrrolidine [F1], [ F2 ]

A solution of 3-(R)-[1-tert-butoxycarbonylamino-1-(2-methoxy) phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1] (488 mg, 1,19 mmol) in ethanol (30 ml) was mixed the catalyst 10% palladium on coal (moisture 53,8%, 500 mg) and subjected to 3-hour catalytic hydrogenation under normal pressure while heating at 50° C. the Reaction solution was filtered and the filtrate was evaporated under reduced pressure to obtain 353 mg (97%) of crude specified in the title compounds as colorless crystals. Last used in subsequent reactions without purification.

A similar reaction was carried out on the basis of 3-(R)-[1-tert-butoxycarbonylamino-1-(2-methoxy)phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F2] (97%).

[Example according to the invention 7]

5-Amino-7-[3-(R)-(1-amino-1-(2-methoxy)phenylmethyl}-1-pyrrolidinyl]-6,8-debtor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid [F1]

3-(R)-[1-Tert-butoxycarbonylamino-1-(2-methoxy)phenylmethyl]pyrrolidine [F1] (353 mg, 1.15 mmol) was added to a suspension of 5-amino-6,7,8-Cryptor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-di-hydro-2-oxoindole-3-carboxylic acid (316 mg, 1.0 mmol) in acetonitrile (15 ml) and the mixture is boiled under reflux for 11 h in the presence of triethylamine (3 ml). After spontaneous cooling, the solvent of the reaction solution is kept under reduced pressure and the obtained residue was dissolved in chloroform (50 ml). The latter was washed with 10% citric acid (30 ml × 2) and saturated salt solution (20 ml) and dried over anhydrous sodium sulfate. The solvent is kept at igenom pressure, the obtained residue was mixed with concentrated hydrochloric acid (3 ml) and stirred at room temperature for 5 minutes This hydrochloric acid solution was washed with chloroform (20 ml × 3), brought to an alkaline reaction by adding 30% aqueous solution of sodium hydroxide under ice cooling and then stirred at room temperature for 1 h the suspension was brought to pH 7.4 by the addition of concentrated hydrochloric acid and 1 mol/l hydrochloric acid and then was extracted with chloroform (80 ml × 3). The obtained organic layer was dried over anhydrous sodium sulfate and the solvent drove under reduced pressure to obtain 482 mg of crude specified in the connection header. The latter was purified by recrystallization from methanol-ethanol to obtain 213 mg specified in the connection header.

1H-NMR (400 MHz, 0,1 mol/l NaOD)δ : 1,18-to 1.38 (2H, m), 1.41 to 1.55V (1H, m), 2.05 is-to 2.18 (1H, m), 2,28-to 2.40 (1H, m), 2.77-to is 2.88 (1H, m), 3,02-and 3.16 (1H, m), 3,15-to 3.33 (2H, m), 3.43 points-to 3.52 (1H, m)to 3.64 (3H, s), 3,78-3,85 (1H, m), 4,48-4,55 (0,5H, m), 4,65-4,73 (0,5H, m), 6,84-to 6.88 (2H, m), 7,12-7,20 (2H, m), 8,08 (1H, s).

Melting point: 114,8-126,6° C.

Elemental analysis: for C25H25F3N4O4·1,25H2O

Calculated: C, 57,19; N, 5,28; N, 10,67.

Found: C, 57,18; N, 5,12; N, 10,61.

[Example according to the invention 8]

5-Amino-7-[3-(R)-(1-amino-1-(2-methoxy)phenylmethyl)-1-pyrrolidinyl]-6,8-dif is the PR-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid [F2]

3-(R)-[1-Tert-butoxycarbonylamino-1-(2-methoxy)phenylmethyl]pyrrolidine [F2] (353 mg, 1.15 mmol) was added to a suspension of 5-amino-6,7,8-Cryptor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid (316 mg, 1.0 mmol) in acetonitrile (15 ml) and the mixture is boiled under reflux for 11 h in the presence of triethylamine (3 ml). After spontaneous cooling, the solvent of the reaction solution is kept under reduced pressure and the obtained residue was dissolved in chloroform (50 ml). Obtained was washed with 10% citric acid (30 ml × 2) and saturated salt solution (20 ml) and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, the obtained residue was mixed with concentrated hydrochloric acid (3 ml) and stirred at room temperature for 5 minutes This hydrochloric acid solution was washed with chloroform (20 ml × 3), brought to an alkaline reaction by adding 30% aqueous solution of sodium hydroxide under ice cooling and then stirred at room temperature for 1 h the suspension was brought to pH 7.4 by the addition of concentrated hydrochloric acid and 1 mol/l hydrochloric acid and then was extracted with chloroform (80 ml × 3). The obtained organic layer was dried over anhydrous sodium sulfate and the solvent drove under reduced pressure to obtain 468 mg is Iroha specified in the connection header. The latter was purified by recrystallization from methanol-ethanol to obtain 226 mg specified in the connection header.

1H-NMR (400 MHz, 0,1 mol/l NaOD)δ : of 1.05 to 1.48 (4H, m), 2,19-of 2.38 (1H, m), 3,05-to 3.58 (5H, m), 3,52 (3H, s), 3.72 points-of 3.80 (1H, m), to 4.52-4,60 (0,5H, m), 4,70-4,79 (0,5H, m), 6,65-to 6.80 (2H, m), 6,94-7,10 (2H, m), to 8.12 (1H, s).

Melting point: 251,1-253,2° C.

Elemental analysis: for C25H25F3N4O4.

Calculated: C, 59,76; N, Free 5.01; N, Of 11.15.

Found: C, 59,89; N, Of 5.05; N, 11,12.

[Reference example 13]

4-(R)-(2,4-Debtor)phenylcarbamoyl-1-[1-(R)-phenylethyl]-2-pyrrolidone

In a nitrogen atmosphere of 1 mol/l 2,4-differentialalgebraic (54,3 ml)obtained from 2,4-diversamente, was added dropwise to a solution of N-methyl-N-methoxy-1-[1-(R)-phenylethyl]-5-oxopyrrolidin-3-carboxamide (5.50 g, to 19.9 mmol) in tetrahydrofuran (110 ml) and the mixture was stirred at 50° C for 4 h the Reaction solution was mixed with 1 mol/l hydrochloric acid (150 ml) under cooling with ice and extracted with ethyl acetate (150 ml × 2), then the organic layer was washed with saturated salt solution (100 ml) and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the obtained residue was subjected to column chromatography on silica gel. By elution with a mixture of n-hexane: ethyl acetate (2:1) to (1:1) was obtained from 2.00 g (29%) indicated in the title compounds as colorless light yellow is about oil.

1H-NMR (400 MHz, Dl3)δ : of 1.55 (3H, d, J=6,83 Hz), 2,70-to 2.85 (2H, m), 3,21 (1H, t, J=9.28 are Hz), 3,71 of 3.75 (1H, m), 3,85-are 3.90 (1H, m), 5,52 (1H, kb, J=6,83 Hz), 6,85-6,91 (1H, m), 6,98-7,03 (1H, m), 7,26-a 7.92 (5H, m), 7,94-7,97 (1H, m).

[Referential example 14]

4-(R)-[1-Azido-1-(2,4-debtor)phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1], [F2]

Under ice cooling sodium borohydride (332 mg, 8,77 mmol) was added to a solution of 4-(R)-(2,4-debtor)phenylcarbamoyl-1-[1-(R)-phenylethyl]-2-pyrrolidone (2,89 g, 8/78 mmol) in methanol (60 ml) and the mixture was stirred at the same temperature for 30 minutes the Reaction solution was mixed with saturated aqueous ammonium chloride (3 ml) and stirred at room temperature for 30 minutes, the Reaction mixture was extracted with ethyl acetate (80 ml × 3), the organic layer was washed with saturated salt solution (100 ml) and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the obtained residue was subjected to column chromatography on silica gel. By elution with a mixture of n-hexane: ethyl acetate (2:1) to (1:2) received 2,09 g (72%) of intermediate compound 4-(R)-[1-(2,4-debtor)phenyl-1-hydroxymethyl]-[1-(R)-phenylethyl]-2-pyrrolidone as a colorless oil (mixture of isomers 1:1). 1,76 g (and 5.30 mmol) of This compound was dissolved in dichloromethane (35 ml), the solution was mixed with triethylamine (1.04 million ml, 7,46 mmol) and methanesulfonamide (492 μl, 6,36 mmol) under ice cooling is m and then stirred at the same temperature for 30 minutes The reaction solution was washed with a saturated aqueous solution of ammonium chloride (30 ml) and saturated salt solution (50 ml), the organic layer was dried over anhydrous sodium sulfate and the solvent is then drove away under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (17 ml)was mixed with sodium azide (862 mg, 13.3 mmol) and then heated at 50° C for 14 hours After spontaneous cooling, the reaction solution was mixed with water (50 ml), extracted with ethyl acetate (70 ml × 2)obtained organic layer was washed with water (50 ml × 3) and saturated salt solution (150 ml) and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the obtained residue was subjected to column chromatography on silica gel. By elution with a mixture of n-hexane:ethyl acetate (2:1) consistently received 913 mg (40%) specified in the header compounds with low polarity [F1] and 894 mg (39%) specified in the header compounds with high polarity [F2], each in the form of a colourless oil.

[F1];

1H-NMR (400 MHz, Dl3)δ : for 1.49 (3H, d, J=to 7.32 Hz), 2,-53-2,-65 (3H, m), 2,86-only 2.91 (1H, m),2,96-to 2.99 (1H, m), of 4.77 (1H, d, J=8,30 Hz), 5,49 (1H, q, J=to 7.32 Hz), 6,85-of 6.90 (1H, m), 6,93-6,97 (1H, m), 7.23 percent and 7.36 (6N, m).

[F2];

1H-NMR (400 MHz, Dl3)δ : of 1.55 (3H, d, J= to 7.32 Hz), 2,17 (1H, DD, J=8,06, 16,85 Hz), 2,31 (1H, DD, J=9,04, 16,85 Hz), 2,61-to 2.67 (1H, m), of 3.13 (1H, DD, J=8,06, of 10.25 Hz), 3,9 (1H, DD, J=6.35mm, of 10.25 Hz), and 4.75 (1H, d, J=9.28 are Hz), 5,49 (1H, kb, J=to 7.32 Hz), 6,65-6,91 (1H,m), 6,93-6,97 (1H, m), 7,26 and 7.36 (6N, m).

[Referential example 15]

4-(R)-[1-Tert-butoxycarbonylamino-1-(2,4-debtor)phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1], [F2]

A solution of 4-(R)-[1-azido-1-(2,4-debtor)phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1] (913 mg/ 2.56 mmol) in ethanol (20 ml) was mixed with catalyst 10% palladium on coal (moisture 53,8%, 900 mg) for carrying out catalytic hydrogenation at room temperature for 1 h under normal pressure. The reaction solution was filtered and the solvent of the filtrate is kept under reduced pressure. The obtained residue was dissolved in dichloromethane (20 ml), was mixed with di-tert-BUTYLCARBAMATE (647 μl, of 2.81 mmol) and triethylamine (464 μl, of 3.33 mmol) and then stirred at room temperature for 24 hours the Reaction solution was evaporated under reduced pressure and the obtained residue was subjected to column chromatography on silica gel. By elution with a mixture of n-hexane:ethyl acetate (1:1) received 567 mg (52%) specified in the connection header [F1] in the form of a colorless amorphous substance.

A similar reaction was carried out on the basis of 4-(R)-[1-azido-1-(2,4-debtor)phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F2] (84%).

[F1];

1H-NMR (400 MHz, Dl3)δ : 1,41 (N, C)to 1.48 (3H, d, J=6,84 Hz), 2,44-2,95 (5H, m), 4,78-4,80 (1H, m), 5,04 is 5.07 (1H, m), 5,49 (1H, kb, J=6,84 Hz), is 6.78-6.87 in (2H, m), 7.18 in-7,32 (M, m).

[F2];

1H-NMR (400 MHz, Dl3)δ : 1,40 (N,) and 1.5 (3H, d, J=7,33 Hz), 2,08 (1H, DD, J=8,06, 17,09 Hz), 2,22 (1H, DD, J=8,79, 17,09 Hz), 2,65-to 2.67 (5H, m), 3,10-3,14 (1H, m), 3.25 to be 3.29 (1H, m), 4,70-4,72 (1H, m), 4,99-free 5.01 (1H, m), 5,49 (1H, kb, J=7,33 Hz), 6,79-6,89 (2H, m), 7,26-7,37 (6N, m).

[Referential example 16]

3-(R)-[1-Tert-butoxycarbonylamino-1-(2,4-debtor)phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidin [F1], [F2]

In nitrogen atmosphere 1M complex of borane-tetrahydrofuran (9,60 ml) was added dropwise to a solution of 4-(R)-[1-tert-butoxycarbonylamino-1-(2,4-debtor)phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1] (560 mg, of 1.30 mmol) in tetrahydrofuran (12 ml) under ice cooling and then the mixture was stirred at room temperature for 17 hours After removal of the solvent under reduced pressure the resulting residue was dissolved in 80% aqueous ethanol (10 ml) and heated under reflux for 1 h in the presence of triethylamine (1 ml). After spontaneous cooling, the reaction solution, the solvent is kept under reduced pressure, the obtained residue was added chloroform (30 ml), then the obtained organic layer was washed with a saturated solution of ammonium chloride (10 ml) and saturated salt solution (10 ml) and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the obtained residue was subjected to column chromatography on silica gel. By elution with a mixture of n-hexane:tracecut (1:1) received 485 mg (90%) indicated in the title compounds as colorless oils.

A similar reaction was carried out on the basis of 4-(R)-[1-tert-butoxycarbonylamino-1-(2,4-debtor)phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F2] (82%).

[F1];

1H-NMR (400 MHz, Dl3)δ : of 1.37 (3H, d, J=6,84 Hz), 1,48 (N, C), 1,67-1,69 1(1H, m), 2,20-of 2.24 (1H, m), a 2.36-2,39 (1H, m), 2.57 m) at 2.59 (1H, m), 3,01 is 3.15 (1H, m), 4,67-4,72 (1H, m), 6,35-to 6.39 (1H, m), of 6.71-6,83 (2H, m), 7,22-of 7.36 (6N, m).

[F2];

1H-NMR (400 MHz, Dl3)δ : of 1.41 (3H, d, J=6,84 Hz), 1,48 (N, C)of 1.74 to 1.76 (1H, m), 2,01-2,04 (2H, m), 2,19-of 2.23 (1H, m), 2,35 is 2.44 (1H, m), 3,14-3,17 (2H, m), 4,71-to 4.73 (1H, m), 6,68-6,70 (1H, m), 6.89 in-6,95 (2H, m), 7,26-7,34 (6N, m).

[Reference example 17]

3-(R)-[1-Tert-butoxycarbonylamino-1-(2,4-debtor)phenylmethyl]pyrrolidine [F1], [F2]

A solution of 3-(R)-[1-tert-butoxycarbonylamino-1-(2,4-debtor) phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1] (243 mg, of 0.58 mmol) in ethanol (10 ml) was mixed with catalyst 10% palladium on coal (moisture 53,8%, 245 mg) and subjected to catalytic hydrogenation for 2 hours at normal pressure while heating at 50° C. the Reaction solution was filtered and the solvent of the filtrate kept at reduced pressure to obtain 200 mg of the crude indicated in the title compounds as colorless crystals. Last used in subsequent reactions without purification.

A similar reaction was carried out on the basis of 3-(R)-[1-tert-butoxycarbonylamino-1-(2,4-debtor)phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F2].

[Example p the invention 9]

5-Amino-7-[3-(R)-(1-amino-1-(2,4-debtor)phenylmethyl)-1-pyrrolidinyl]-6,8-debtor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid [F1]

3-(R)-[1-Tert-butoxycarbonylamino-1-(2,4-debtor)phenylmethyl]pyrrolidine [F1] (of 0.58 mmol) was added to a suspension of 5-amino-6,7,8-Cryptor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid (183 mg, of 0.58 mmol) in acetonitrile (10 ml) and the mixture is boiled under reflux for 15 h in the presence of triethylamine (0.5 to ml). After spontaneous cooling, the solvent of the reaction solution is kept under reduced pressure. The obtained residue was dissolved in chloroform (50 ml), washed with 10% citric acid (30 ml) and saturated salt solution (20 ml), dried over anhydrous sodium sulfate and the solvent is then drove away under reduced pressure. The obtained residue was mixed with concentrated hydrochloric acid (5 ml) under cooling with ice, then mixed with 1 mol/l aqueous solution of hydrochloric acid (5 ml) at room temperature and then washed with chloroform (50 ml × 3) and the insoluble substance was removed by filtration. This hydrochloric acid solution was brought to alkaline by adding 10 mol/l aqueous solution of sodium hydroxide under ice cooling and then stirred at room temperature for 1 h the suspension was brought to pH 7.4 added on the m of concentrated hydrochloric acid and 1 mol/l hydrochloric acid and then was extracted with chloroform (80 ml × 3). The obtained organic layer was dried over anhydrous sodium sulfate and the solvent drove under reduced pressure to get crude specified in the title compound as bright yellow crystals. The latter was purified by recrystallization from ethanol to obtain 125 mg (42%) specified in the connection header.

1H-NMR (400 MHz, Dl3)δ : 1,40-is 1.51 (2H, m), 1,84-1,89 (1H, m), 2,28-to 2.29 (1H, m), 2.57 m) at 2.59 (1H, m), 3,35-3,90 (5H, m), 4,13 (1H, d, J=9.28 are Hz), 4,79 (1H, OSD, J=62,50 Hz), 6,38 (1H, s), 6,79-6,91 (2H, m), 7,37-7,41 (1H, m), 8,51 (1H, s).

Melting point: 182-183° C.

Elemental analysis: for C24H21F5N4O3·0,25H2O

Calculated: C, 56,20; N, 4,22; N, 10,92.

Found: C, 56,30; N, 4,39; N, 10,77.

[Example of the invention 10]

5-Amino-7-[3-(R)-(1-amino-1-(2,4-debtor)phenylmethyl)-1-pyrrolidinyl]-6,8-debtor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid [F2]

3-(R)-[1-Tert-butoxycarbonylamino-1-(2,4-debtor)phenylmethyl]pyrrolidine [F2] (0.50 mmol) was added to a suspension of 5-amino-6,7,8-Cryptor-1-[2-(3-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid (158 mg, 0.50 mmol) in acetonitrile (7 ml) and the mixture is boiled under reflux for 15 h in the presence of triethylamine (0.5 to ml). After spontaneous cooling, the solvent of the reaction solution is kept under reduced pressure. The obtained residue Rast is oral in chloroform (50 ml), washed with 10% citric acid (30 ml) and saturated salt solution (20 ml), dried over anhydrous sodium sulfate and the solvent is then drove away under reduced pressure. The obtained residue was mixed with concentrated hydrochloric acid (5 ml) under cooling with ice, then mixed with 1 mol/l aqueous solution of hydrochloric acid (5 ml) at room temperature, then washed with chloroform (50 ml) and the insoluble substance was removed by filtration. This hydrochloric acid solution was brought to alkaline by adding 10 mol/l aqueous solution of sodium hydroxide under ice cooling and then stirred at room temperature for 1 h the suspension was brought to pH 7.4 by the addition of concentrated hydrochloric acid and 1 mol/l hydrochloric acid and then was extracted with chloroform (80 ml × 3). The obtained organic layer was dried over anhydrous sodium sulfate and the solvent drove under reduced pressure to get crude specified in the title compound as bright yellow crystals. The latter was purified by recrystallization from ethanol to obtain 165 mg (65%) specified in the connection header.

1H-NMR (400 MHz, Dl3)δ : 1,53-to 1.60 (3H, m), 1,69-1,71 (1H, m), 2,52-of 2.58 (1H, m), 3,66-3,91 (5H, m), 4,08 (1H, d, J=9,76 Hz), a 4.83 (1H, OSD, J=62,75 Hz), 6.42 per (1H, s), 6,80-6,93 (2H, m), 7,34-7,40 (1H, m), 8,54 (1H, s).

Melting point: 218-220° With (with what Ozanam).

Elemental analysis: for C24H21F5N4O3

Calculated: C, 56,69; N, 4,16; N, 11,02.

Found: C, 56,20; N, 4,22; N, 10,92.

[Referential example 18]

4-(R)-(2-Furyl)carbonyl-1-[1-(R)-phenylethyl]-2-pyrrolidone

In the atmosphere of nitrogen 0.5 mol/l 2-fullpagename (180 ml), obtained from furan was added dropwise to a solution of N-methyl-N-methoxy-1-[1-(R)-phenylethyl]-5-oxopyrrolidin-3-carboxamide (8,30 g, 30.0 mmol) in tetrahydrofuran (160 ml) and the mixture was stirred for 30 minutes the Reaction solution was mixed with 1 mol/l hydrochloric acid (200 ml) under cooling with ice, extracted with ethyl acetate (200 ml × 2)then the organic layer was washed with saturated salt solution (100 ml) and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the obtained residue was subjected to column chromatography on silica gel. By elution with a mixture of n-hexane:ethyl acetate (1:1) to (1:2) received 3.94 g (46%) indicated in the title compounds as a light yellow oil,

1H-NMR (400 MHz, CDCl3)δ : of 1.55 (3H, d, J=6,84 Hz), 2,72-2,87 (2H, m), 3,20-of 3.25 (1H, m)to 3.67 (1H, DD, J=6,83, 9,77 Hz), 3,80-389 (1H, m), of 5.53 (1H, kb, J=6,84 Hz), to 6.57 (1H, DD, J=1,46, 3.42 Hz), 7.18 in-7,38 (6N, m), 7,60 (1H, d, J=0,98 Hz).

[Reference example 19]

4-(R)-[1-Amino-1-(2-furyl)methyl]-1-[1- (R)-phenylethyl]-2-pyrrolidone [F1], [F2]

Under ice cooling sodium borohydride (522 mg, of 13.8 mmol) was added to a solution of 4-(R)-(2-Furi is)carbonyl-1-[1-(R)-phenylethyl]-2-pyrrolidone (3,90 g, of 13.8 mmol) in methanol (80 ml) and the mixture was stirred at the same temperature for 30 minutes the Reaction solution was mixed with saturated aqueous ammonium chloride (50 ml)was stirred at room temperature for 30 min and then was extracted with chloroform (100 ml × 3). The organic layer was washed with saturated salt solution (100 ml) and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the obtained residue was subjected to column chromatography on silica gel. By elution with a mixture of toluene: ethyl acetate (1:2) was received of 3.64 g (12.7 mmol) of the intermediate 4-(R)-[1-(2-furyl)-1-hydroxymethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone as a colorless oil (mixture of isomers 1:1). Last translated in dichloromethane (90 ml)was mixed with triethylamine (5,97 ml, 42.8 mmol) and methanesulfonamide and 2.83 ml of 36.7 mmol) under cooling with ice and stirred at room temperature for 24 hours the Reaction solution was washed with a saturated aqueous solution of ammonium chloride (100 ml) and saturated salt solution (100 ml), the organic layer was dried over anhydrous sodium sulfate and the solvent is then drove away under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (45 ml)was mixed with sodium azide (equal to 4.97 g, 76,45 mmol) and then heated at 50° C for 3 hours After cooling with ice, the reaction R is the target was mixed with water (100 ml), were extracted with ethyl acetate (100 ml × 2)obtained organic layer was washed with water (80 ml × 3) and saturated salt solution (100 ml) and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the obtained residue was subjected to column chromatography on silica gel. By elution with a mixture of n-hexane:ethyl acetate (2:1) to (1:1) was obtained as 4.02 g (12.7 mmol) of the intermediate 4-(R)-[1-azido-1-(2-furyl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone as a colorless oil (mixture of isomers 1:1). Last translated in ethanol (100 ml) and mixed with catalyst 10% palladium on coal (moisture 53,8%, 4,80 mg) and then spent catalytic hydrogenation at room temperature for 2 hours under normal pressure. The reaction solution was filtered and the solvent from the resulting filtrate drove away under reduced pressure. The obtained residue was subjected to column chromatography on silica gel. By elution with a mixture of chloroform:methanol (98:2) to (95:5) consistently received 1.42 g (39%) specified in the header compounds with low polarity [F2] and 1.75 g (49%) indicated in the title compounds with high polarity [F1], each in the form of a colourless oil.

[F1];

1H-NMR (400 MHz, Dl3)δ : of 1.46 (3H, d, J=6,84 Hz), 2,47-to 2.65 (3H, m), 2.93 which is only 2.91 (1H, m), of 3.13 (1H, DD, J=5,86, 9,76 Hz), a 3.87 (1H, d, J=6,84 Hz), 5,46 (1H, kb, J=6,84 Hz), 6,14 (1H, d, J=2,93 Hz), 6,29-631 (1H, m), 7,26-7,34 (6N, m).

[F2];

1H-NMR (400 MHz, CDCl3)δ : of 1.50 (3H, d, J=to 7.32 Hz), 2,28 (1H, DD, J=7,81, 17,09 Hz)to 2.41 (1H, DD, J=8,79, 17,09 Hz), 2,54 at 2.59 (1H, m), 3,17 (1H, DD, J=8,30, 10,01 Hz), 3,32 (1H, DD, J=6.35mm, 10,01 Hz), with 3.79 (1H, d, J=8,30 Hz), of 5.48 (1H, kb, J=to 7.32 Hz), 6,13 (1H, d, J=2,93 Hz), 6,30 (1H, DD, J=1,96, with 2.93 Hz), 7,26 and 7.36 (6N, m).

[Referential example 20]

4-(R)-[1-Tert-butoxycarbonylamino-1-(2-furyl)methyl]-1-[1-(R) -phenylethyl]-2-pyrrolidone [F1], [F2]

A solution of 4-(R)-[1-amino-1-(2-furyl)methyl]1-[1-(R)-phenylethyl]-2-pyrrolidone [F1] (2.00 g, 7.03 mmol) in dichloromethane (40 ml) was mixed with di-tert-BUTYLCARBAMATE (1,95 ml, 8,44 mmol) and triethylamine (1,38 ml, 9,84 mmol) and stirred at room temperature for 8 hours the Reaction solution was concentrated under reduced pressure and the obtained residue was subjected to column chromatography silica gel. By elution with a mixture of n-hexane:ethyl acetate (1:1) received 2,32 g (86%) specified in the connection header [F1] in the form of a colorless amorphous substance.

A similar reaction was carried out on the basis of 4-(R)-[1-amino-1-(2-furyl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F2] (78%).

[F1];

1H-NMR (400 MHz, Dl3)δ : of 1.44 (1H, s)of 1.47 (3H, d, J=to 7.32 Hz), 2,43 (1H, DD, J=7,08, 17.3 Hz), of 2.56 (1H, DD, J=9,04, 17,33 Hz), 2,44-2,77 (1H, m), 2,97-2,99 (1H, m), 3,12-3,14 (1H, m), 4,82 to 4.92 (2H, m), vs. 5.47 (1H, d, J=7,32 Hz), 6,18 (1H, d, J=3,41 Hz), 6,29 of 6.31 (1H, m), 7,26-7,33 (6N, m).

[F2];

1H-Mr (400 MHz, Dl3)δ : 1,43 (N, C)1,49 (ZN, d, J=6,84 Hz), and 2.27 (1H, DD, J=7,32, 17,09 Hz), 2,41 1H, DD, J=8,79, 17,09 Hz), 2,67-2,69 (1H, m), 3,05-of 3.06 (1H, m), 3,23 (1H, DD, J=5,86, of 10.25 Hz), 4.75 V-4,84 (2H, m), vs. 5.47 (1H, d, J=6,84 Hz), 6,21 (1H, s), of 6.31 (1H, DD, J=1,95, with 2.93 Hz), 7,26 and 7.36 (6N, m).

[Referential example 21]

3-(R)-[1-Tert-butoxycarbonylamino-1-(2-furyl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidin [F1], [F2]

In nitrogen atmosphere 1M complex of borane-tetrahydrofuran (14,8 ml) was added dropwise to a solution of 4-(R)-[1-tert-butoxy-carbylamine-1-(2-furyl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1] (2,03 g, 5,28 mmol) in tetrahydrofuran (40 ml) under ice cooling and then the mixture was stirred at room temperature for 17 hours After removal of the solvent under reduced pressure the resulting residue was dissolved in 80% aqueous ethanol (40 ml) and boiled under reflux for 1 h in the presence of triethylamine (1 ml). After spontaneous cooling, the reaction solution, the solvent is kept under reduced pressure, the obtained residue was added chloroform (100 ml), then the obtained organic layer was washed with a saturated aqueous solution of ammonium chloride (80 ml) and saturated salt solution (80 ml) and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the obtained residue was subjected to column chromatography on silica gel. By elution with chloroform to the mixture of chloroform:methanol (97:3) was obtained 1.54 g (79%) indicated in the title compound in the form of a white crystal of the century

A similar reaction was carried out on the basis of 4-(R)-[1-tert-butoxycarbonylamino-1-(2-furyl)methyl]-1-[1-(R)-phenylethyl]-2-pirrolidone [F2] (63%).

[F1];

1H-NMR (400 MHz, Dl3)δ : of 1.35 (3H, d, J=6,84 Hz), 1,47 (N, C), 1,67-of 1.73 (1H, m), 1,83-of 1.85 (1H, m), 2,25-2,31 (3H, m), 2,45-2,47 (1H, m), 2,60-2,62 (1H, m), was 2.76-2,78 (1H, m), 3,13 is 3.15 (1H, m), 4,60-to 4.62 (1H, m), 5,64-5,66 (1H, m), 6,13 (1H, s), 6,27 (1H, DD, J=1,965, with 2.93 Hz), 7,22-7,31 (6N, m).

[F2];

1H-NMR (400 MHz, Dl3)δ : to 1.38 (3H, d, J=6,34 Hz), 1,46 (N, C), 1,63-of 1.65 (1H, m), 1,90 of 1.99 (1H, m), 2,30 at 2.59 (4H, m), 2,85-2,87 (1H, m), 3,16-3,18 (1H, m), 4,60-to 4.62 (1H, m), 6,01 (1H, s), from 6.22 (1H, DD, J=1,95, with 2.93 Hz), of 7.23-7,32 (6N, m).

[Referential example 22]

3-(R)-[1-Tert-butoxycarbonylamino-1-(2-furyl)methyl]-1-benzyloxycarbonylamino [F1], [F2]

In the atmosphere of nitrogen benzylchloride (761 μl, 5,31 mmol) was added dropwise to a solution of 3-(R)-[1-tert-butoxycarbonylamino-1-(2-furyl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1] (658 mg, 1.77 mmol) in dichloroethane (15 ml) under ice cooling and the mixture is then boiled under reflux for 30 hours After removal of the solvent under reduced pressure the residue was subjected to column chromatography on silica gel. By elution with chloroform to the mixture of chloroform: methanol (97:3) received 526 mg (74%) indicated in the title compound as white crystals.

A similar reaction was carried out on the basis of 3-(R)-[1-tert-butoxycarbonylamino-1-(2-furyl)methyl]-1-[1-(R)-phenylethyl] pyrrolidine [F2 (quantitatively).

[F1];

1H-NMR (400 MHz, Dl3)δ : 1,43 (N, C), 1,76-to 1.87 (1H, m), 2,03-2,05 (1H, m), 2,55-to 2.65 (1H, m), 3,05-3,13 (1H, m), 3,32-3,59 (1H, m), 4,70-4,72 (1H, m), 4.92 in-4,94 (1H, m), 5,11 (2H, s), 6,18 (1H, s), of 6.31 (1H, s), 7,26-7,38 (6N, m).

[F2];

1H-NMR (400 MHz, Dl3)δ : 1,43 (N, C), 1,58-to 1.61 (1H, m), 1,84 is 1.86 (1H, m), 2.26 and-to 2.29 (1H, m), 3,24-to 3.34 (2H, m), 3,52-of 3.64 (2H, m), 4,76-4,78 (1H, m), 4,89-4,91 (1H, m)to 5.13 (2H, s), to 6.19 (1H, s), 6,30 (1H, s), 7,26 was 7.36 (6N, m).

[Reference example 23]

3-(R)-[1-Tert-butoxycarbonylamino-1-(2-furyl)methyl]pyrrolidin [F1], [F2]

A solution of 3-(R)-[1-tert-butoxycarbonylamino-1-(2-furyl) methyl]-1-benzyloxycarbonylamino [F1] (507 mg, 1.37 mmol) in ethanol (10 ml) was mixed with catalyst 10% palladium on coal (moisture 53,8%, 500 mg) and spent catalytic hydrogenation at room temperature for 4 h under normal pressure. The reaction solution was filtered and the solvent of the filtrate drove under reduced pressure to obtain 358 mg of crude specified in the title compounds as colorless crystals. Last used at a later stage without purification.

A similar reaction was carried out on the basis of 3-(R)-[1-tert-butoxycarbonylamino-1-(2-furyl)methyl]-1-benzyloxycarbonylamino [F2].

[Example according to the invention 11]

5-Amino-7-{3-(R)-[1-amino-1-(2-furyl)methyl]-1-pyrrolidinyl}-6,8-debtor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid [F1]

3-(R)-[1-Tert-bout is ccarbonate-1-(2-furyl)methyl] pyrrolidin [F1] (of 1.30 mmol) was added to a suspension of 5-amino-6,7,8-Cryptor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid (316 mg, 1.00 mmol) in acetonitrile (10 ml) and the mixture is boiled under reflux for 19 h in the presence of triethylamine (0.5 ml). After cooling, the solvent of the reaction solution is kept under reduced pressure. The obtained residue was dissolved in chloroform (150 ml), washed with 10% citric acid (80 ml) and saturated salt solution (80 ml), dried over anhydrous sodium sulfate and the solvent is then drove away under reduced pressure. The obtained residue was mixed with concentrated hydrochloric acid (10 ml) under cooling with ice, then mixed with 1 mol/l aqueous solution of hydrochloric acid (5 ml) at room temperature and then washed with chloroform (50 ml × 4) and the insoluble substance was removed by filtration. This hydrochloric acid aqueous solution was brought to alkaline by adding 10 mol/l aqueous solution of sodium hydroxide under ice cooling and then stirred at room temperature for 1 h the suspension was brought to pH 7.4 by the addition of concentrated hydrochloric acid and 1 mol/l hydrochloric acid and then was extracted with chloroform (150 ml × 3). The obtained organic layer was dried over anhydrous sodium sulfate and the solvent drove under reduced pressure to get crude specified in the title compound as bright yellow crystals. The latter was purified, precrystallization is from ethanol to obtain 294 mg (64%) specified in the connection header.

1H-NMR (400 MHz, 0,1 mol/l NaOD)δ : 1,34-of 1.56 (3H, m), 2,35-2,39 (1H, m), 2.06 to of 2.08 (1H, m), 3,18-3,20 (2H, m), 3,40-of 3.42 (1H, m), 3,48-3,50 (1H, m), to 3.58-of 3.60 (1H, m), of 3.69 (1H, D, J=9.28 are Hz), was 4.76 (1H, OSD, J=62,50 Hz), 6,18 (1H, d, J=3.42 Hz), 6,34 (1H, s), 7,37 (1H, s), 8,07 (1H, s).

Melting point: 188-189° C.

Elemental analysis: for C22H21F3N4O4

Calculated: C, 57,14; N, 4,58; N, 12,12.

Found: C, 57,14; N, 4,78; N, 12,07.

[Example according to the invention 12]

5-Amino-7-{3-(R)-[1-amino-1-(2-furyl)methyl]-1-pyrrolidinyl]-6,8-debtor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid [F2]

3-(R)-[1-Tert-butoxycarbonylamino-1-(2-furyl)methyl]pyrrolidin [F2] (0,749 mmol) was added to a suspension of 5-amino-6,7,8-Cryptor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid (215 mg, 0,681 mmol) in acetonitrile (10 ml) and the mixture is boiled under reflux for 19 h in the presence of triethylamine (0.5 to ml). After cooling, the solvent of the reaction solution is kept under reduced pressure. The obtained residue was dissolved in chloroform (150 ml), washed with 10% citric acid (80 ml) and saturated salt solution (80 ml), dried over anhydrous sodium sulfate and the solvent is then drove away under reduced pressure. The obtained residue was mixed with concentrated hydrochloric acid (10 ml) under cooling with ice, then mixed with 1 mol/l aqueous solution of hydrochloric acid (5 ml) is room temperature, then washed with chloroform (50 ml × 4) and the insoluble substance was removed by filtration. This hydrochloric acid aqueous solution was brought to alkaline by adding 10 mol/l aqueous solution of sodium hydroxide under ice cooling and then stirred at room temperature for 1 h the suspension was brought to pH 7.4 by the addition of concentrated hydrochloric acid and 1 mol/l hydrochloric acid and then was extracted with chloroform (150 ml × 3). The obtained organic layer was dried over anhydrous sodium sulfate and the solvent drove under reduced pressure to get crude specified in the title compound as bright yellow crystals. The latter was purified by recrystallization from ethanol to obtain 120 mg (38%) specified in the connection header.

1H-NMR (400 MHz, 0,1 mol/l NaOD)δ : 1,24 was 1.43 (3H, m), 1,57-to 1.59 (1H, m), 2,27-to 2.29 (1H, m), 3.27 to be 3.29 (1H, m), 3,35-3,37 (1H, m), 3,51 of 3.56 (3H, m), 3,63 (1H, d, J=8,79 Hz), 4,79 (1H, OSD, J=62,99 Hz), 6,13 (1H, d, J=2,93 Hz), of 6.31 (1H, s), 7,34 (1H, s), of 8.09 (1H, s).

Melting point: 187-188° C.

Elemental analysis: for C22H21F3N4O4·0,5H2O

Calculated: C, 56,05; N, 4,70; N, 11,88.

Found: C, 56,06; N, 4,89; N, Are 11.62.

[Reference example 24]

4-(R)-(Thiazole-2-yl)carbonyl-1-[1-(R)-phenylethyl]-2-pyrrolidone

In the atmosphere of nitrogen and at -78°With n-utility (20.4 ml, 30.0 mmol, 1,47M solution in hexane is) was added dropwise to a solution of 2-bromothiazole (4,92 g, 30.0 mmol) in tetrahydrofuran (200 ml) for 10 min and the mixture was stirred at the same temperature for 1 h To this was added dropwise a solution of N-methyl-N-methoxy-1-[1-(R)-phenylethyl]-5-oxopyrrolidin-3-carboxamide (6,91 g 25,0 mmol) in tetrahydrofuran (50 ml) for 10 min, the mixture was stirred at -78° C for 30 min and then under ice cooling for 1 h the Reaction solution was mixed with 1 mol/l hydrochloric acid (150 ml) under cooling with ice and extracted with ethyl acetate (100 ml × 2)obtained organic layer was washed with saturated salt solution (300 ml) and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the residue was subjected to column chromatography on silica gel. By elution with a mixture of n-hexane: ethyl acetate (1:1) received 2.70 g (36%) indicated in the title compounds as a light yellow oil,

1H-NMR (400 MHz, Dl3)δ : of 1.55 (3H, d, J=to 7.32 Hz), 2,04 of 2.92 (2H, m), 3.33 and-to 3.38 (1H, m), 3,63-3,68 (1H, m), 4.26 deaths is 4.35 (1H, m), of 5.53 (1H, D, J=to 7.32 Hz), 7,27-7,38 (5H, m), 7,73 (1H, d, J=2,93 Hz), 8,00 (1H, d, J=2,93 Hz).

[Reference example 25]

4-(R)-[1-Hydroxy-1-(thiazol-2-yl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1], [F2]

Under ice cooling sodium borohydride (409 mg) was added to a solution of 4-(R)-(thiazole-2-yl)carbonyl-1-[1-(R)-phenylethyl]-2-pyrrolidone (3,24 g, 10,80 mmol) in ethanol (50 ml) and the mixture was stirred at the same temperature for 30 mi is. The reaction solution was mixed with 10% citric acid (50 ml) under ice cooling, ethanol drove under reduced pressure and then the resulting residue was extracted with chloroform (80 ml× 2). The organic layer was washed with saturated salt solution (100 ml) and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the obtained residue was subjected to column chromatography on silica gel. By elution with ethyl acetate successively received 1.28 g (39%) specified in the header compounds with low polarity [F1] and 1.38 g (42%) indicated in the title compounds with high polarity [F2], respectively, in the form of bright yellow crystals and light yellow oil,

[F1];

1H-NMR (400 MHz, Dl3)δ : of 1.47 (3H, d, J=to 7.32 Hz), 2,46 (1H, DD, J=9,77, to 7.09 Hz), 2,61 (1H, DD, J=7,32, to 7.09 Hz), 2,73-and 2.83 (1H, m), 3,06 (1H, DD, J=10,26, 8,30 Hz), 3,40 (1H, DD, J=10,26, 6,34 Hz), 3,55 (1H, d, J=lower than the 5.37 Hz), to 4.98 (1H, t, J=lower than the 5.37 Hz), 5,46 (1H, kb, J=to 7.32 Hz), 7,26-7,35 (6N, m), 7,73 (1H, d, J=2,23 Hz).

[F2];

1H-NMR (400 MHz, Dl3)δ : to 1.48 (3H, d, J=6,84 Hz), 2.49 USD (2H, d, J=8,30 Hz), 2,79-is 2.88 (1H, m), 2,96-a 3.01 (1H, m)to 3.38 (1H, DD, J=9,77, 5,86 Hz), equal to 4.97 (1H, DD, J=lower than the 5.37, 4,96 Hz), 5,27 (1H, Ushs), 5,43 (1H, kb, J=6,84 Hz), 7.23 percent-7,32 (6N, m), 7,66 (1H, d, J=3.42 Hz).

[Referential example 26]

4-(R)-[1-Azido-1-(thiazol-2-yl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1], [F2]

Under ice cooling, the triethylamine (725 μl) and methanesulfonamide (341 μl, 4.40 mmol) was added to rest the ru 4-(R)-[1-hydroxy-1-(thiazol-2-yl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1] (1,21 g, 4.00 mmol) in dichloromethane (20 ml) and the mixture was stirred at the same temperature for 1 h the Reaction solution was mixed with 10% citric acid (30 ml) under cooling with ice, extracted with chloroform (30 ml × 2), the organic layer was washed with saturated salt solution (100 ml) and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, the obtained residue was dissolved in N,N-dimethylformamide (30 ml)was mixed with sodium azide (780 mg, 12,0 mmol) and then heated at 60° C for 15 hours After spontaneous cooling, the reaction solution was mixed with water (70 ml), was extracted with ethyl acetate (80 ml × 3), the organic layer was washed with saturated salt solution (200 ml) and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the obtained residue was subjected to column chromatography on silica gel. By elution with a mixture of n-hexane:ethyl acetate (1:2) to (1:3) received 1,263 g (96%) indicated in the title compounds as a light yellow oil.

A similar reaction was carried out on the basis of 4-(R)-[1-hydroxy-1-(thiazol-2-yl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F2] (85%).

[F1];

1H-NMR (400 MHz, Dl3)δ : of 1.52 (3H, d, J=to 7.32 Hz), is 2.37 (1H, DD, J=7,32, to 7.09 Hz), 2,52 (1H, DD, J=8,79, to 7.09 Hz), 2,84-2,96 (1H, m), of 3.13 (1H, DD, J=of 10.25, 8,30 Hz)to 3.36 (1H, DD, J=of 10.25, 6,35 Hz), to 4.81 (1H, d, J=7,81 Hz), of 5.48 (1H, kb, J=to 7.32 Hz), 7,26-737 (5H, m), 7,39 (1H, d, J=3.42 Hz), 7,81 (1H, d, J=3.42 Hz).

[F2];

1H-NMR (400 MHz, Dl3)δ : to 1.48 (3H, d, J=to 7.32 Hz), 2,60 (2H, d, J=7,81 Hz), 2,82-only 2.91 (1H, m), 3,05 (1H, DD, J=of 10.25, 8,30 Hz), up 3.22 (1H, DD, J=of 10.25, 5,86 Hz), to 4.81 (1H, d, J=7,81 Hz), of 5.48 (1H, kb, J=to 7.32 Hz), 7,25-7,34 (5H, m), 7,38 (1H, d, J=3,41 Hz), 7,80 (1H, d, J=3,41 Hz).

[Referential example 27]

4-(R)-[1-Tert-butoxycarbonylamino-1-(thiazol-2-yl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1], [F2]

A solution of 4-(R)-[1-azido-1-(thiazol-2-yl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1] (1.18 g, of 3.60 mmol) in ethanol (50 ml) was mixed with catalyst 10% palladium on coal (moisture 53,8%, 1.20 g) and spent catalytic hydrogenation at room temperature for 3 h under normal pressure. The reaction solution was filtered and the solvent is kept at reduced pressure. The residue was dissolved in dichloromethane (30 ml)was mixed with di-tert-BUTYLCARBAMATE (1,179 g) and triethylamine (1 ml) and then stirred at room temperature for 14 hours To the reaction solution was added chloroform (50 ml), washed with 10% citric acid (80 ml) and water (80 ml) and the resulting organic layer was dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the obtained residue was subjected to column chromatography on silica gel. By elution with a mixture of n-hexane:ethyl acetate (1:3) received 1,205 g (83%) indicated in the title compounds as colorless amorphous substances is STV.

A similar reaction was carried out on the basis of 4-(R)-[1-azido-1-(thiazol-2-yl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F2] (75%).

[F1];

1H-NMR (400 MHz, Dl3)δ : 1,44 (N,) and 1.51 (3H, d, J=6,84 Hz), of 2.38 (1H, DD, J=17,09, of 7.82 Hz), 2.49 USD (1H, DD, J=17,09, 9.28 are Hz), 2,83-2,95 (1H, m), is 3.08 (1H, DD, J=9,77, 8,30 Hz), or 3.28 (1H, DD, J=9,77, at 6.84 Hz), 5,01-5,09 (1H, m), 5,19-of 5.26 (1H, m), of 5.48 (1H, kb, J=6,84 Hz), 7,26-7,35 (6N, m), 7,73 (1H, d, J=2,93 Hz)

[F2];

1H-NMR (400 MHz, Dl3)δ : of 1.44 (3H, d, J=7,33 Hz), 1,45 (N, C), 2,42 (1H, DD, J=17,09, at 6.84 Hz), of 2.56 (1H, DD, J=17,09, 9.28 are Hz), 2,90-of 3.00 (1H, m)to 3.09 (1H, DD, J=9,76, 8,79 Hz), or 3.28 (1H, DD, J=9,76, to 5.85 Hz), 5,07-5,13 (1H, m), 5,38-5,46 (1H, m), the 5.45 (1H, kb, J=7,33 Hz), 7,25-7,34 (6N, m), 7,71 (1H, d, J=2,92 Hz)

[Reference example 28]

3-(R)-[1-Tert-butoxycarbonylamino-1-(thiazol-2-yl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidin [F1], [F2]

In nitrogen atmosphere 1M complex of borane-tetrahydrofuran (8.1 ml) was added dropwise to a solution of 4-(R)-[1-tert-butoxy-carbylamine-1-(thiazol-2-yl)phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1] (1,084 g, 2,70 mmol) in tetrahydrofuran (20 ml) under ice cooling and then the mixture was stirred at room temperature for 14 hours After removal of the solvent under reduced pressure the resulting residue was mixed with 80% aqueous ethanol (20 ml) and triethylamine (4 ml) and boiled under reflux for 4 hours After spontaneous cooling, the solvent drove away under reduced pressure, the obtained residue was added chlorof the RM (30 ml), then washed with water (10 ml) and saturated salt solution (10 ml) and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the obtained residue was subjected to column chromatography on silica gel. By elution with a mixture of chloroform:methanol (20:1) received 984 g (94%) indicated in the title compounds as colorless oils.

A similar reaction was carried out on the basis of 4-(R)-[1-tert-butoxycarbonylamino-1-(thiazol-2-yl)phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F2] (85%).

[F1];

1H-NMR (400 MHz, CDCl3)δ : of 1.40 (3H, d, J=6,35 Hz)and 1.51 (N, C), 1,58-1,71 (1H, m), 1,76-1,89 (1H, m), 2,02-of 2.30 (2H, m), 2.40 a-2,50 (1H, m), 2,74-to 2.85 (1H, m), is 3.08 is 3.23 (1H, m), 40,82-of 4.90 (1H, m), to 7.09 (1H, d, J=3.42 Hz), 7,20-to 7.32 (5H, m), 7,63 (1H, d, J=3.42 Hz).

[F2];

1H-NMR (400 MHz, Dl3)δ : to 1.38 (3H, d, J=6,35 Hz), 1,52 (N, C), 1,68-to 1.82 (2H, m), 2,11-of 2.23 (1H, m), 2,23-of 2.34 (1H, m), 2,45 is 2.55 (1H, m), 2,79 of 2.92 (1H, m), 3,03-is 3.21 (2H, m), a 4.83-4,91 (1H, m), 6,64-of 6.73 (1H, m), 7,20 (1H, d, J=3,41 Hz), 7,22-to 7.32 (5H, m), of 7.70 (1H, d, J=3,41 Hz).

[Referential example 29]

3-(R)-[1-Tert-butoxycarbonylamino-1-(thiazol-2-yl)methyl]-1-benzyloxycarbonylamino [F1], [F2]

In the atmosphere of nitrogen benzylchloride (628 μl, 4.40 mmol) was added dropwise to a solution of 3-(R)-[1-tert-butoxycarbonylamino-1-(thiazol-2-yl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1] (852 mg, of 2.20 mmol) in dichloroethane (15 ml) under ice cooling and the mixture is then boiled under reflux for 16 hours On the Le spontaneous cooling, the reaction solution was mixed with chloroform (50 ml), washed with saturated aqueous sodium bicarbonate (5 ml) and then the organic layer was dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the obtained residue was subjected to column chromatography on silica gel. By elution with a mixture of n-hexane:ethyl acetate (1:1) received 646 mg (70%) indicated in the title compounds as colorless oils.

A similar reaction was carried out on the basis of 3-(R)-[1-tert-butoxycarbonylamino-1-(thiazol-2-yl)methyl]-1-[1-(R)-phenyl-ethyl]-2-pyrrolidone [F2] (83%).

[F1];

1H-NMR (400 MHz, Dl3)δ : 1,43 (N, C), 1,65-of 1.84 (1H, m), 1,84 is 2.00 (1H, m), 2,75-only 2.91 (1H, m), 3,22-3,39 (2H, m), 3,47-3,68 (2H, m), 4,98-5,12 (1H, m), 5,12 (2H, s), of 5.53-5,62 (1H, m), 7.24 to 7,35 (6N, m), 7,71 (1H, d, J=3.42 Hz).

[F2];

1H-NMR (400 MHz, Dl3)δ : 1,43 (N, C), 1,74 is 1.91 (1H, m), 1,95-of 2.09 (1H, m), was 2.76-2,89 (1H, m), 3,14-3,2 (1H, m), 3,29-3,39 (2H, m), 3,49-of 3.64 (2H, m), equal to 4.97-5,09 (1H, m), 5,11 (2H, s), 5,38-vs. 5.47 (1H, m), 7,25-7,35 (6N, m), 7,71 (1H, d, J=3.42 Hz).

[Reference example 30]

Di-triptorelin 3-(R)-[1-amino-1-(thiazol-2-yl)methyl]-1-pyrrolidine [F1], [F2]

3-(R)-[1-Tert-butoxycarbonylamino-1-(thiazol-2-yl)methyl]-1-benzyloxycarbonylamino [F1] (480 mg, 1.15 mmol) was mixed with triperoxonane acid (10 ml), the mixture was stirred at room temperature for 1 h and then boiled under reflux for 17 hours After spontaneous cooling, the solvent drove with onigen the m pressure and the obtained residue was mixed with toluene (10 ml). Again when the distillation of the solvent under reduced pressure received 473 mg (quantitative) of the crude indicated in the title compounds as colorless oils. Last used in subsequent reactions without purification.

A similar reaction was carried out on the basis of 3-(R)-[1-tert-butoxycarbonylamino-1-(thiazol-2-yl)methyl]-1-benzyloxycarbonylamino [F2].

[Example according to the invention 13]

5-Amino-7-[3-(R)-(1-amino-1-(thiazol-2-yl)methyl)-1-pyrrolidinyl]-6,8-debtor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid [F1]

Di-triptorelin 3-(R)-[1-amino-1-(thiazol-2-yl)methyl] pyrrolidine [F1] (473 mg, 1.15 mmol) was added to a suspension of 5-amino-6,7,8-Cryptor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid (253 mg, 0.8 mmol) in acetonitrile (10 ml) and the mixture is boiled under reflux for 18 h in the presence of triethylamine (3 ml). After spontaneous cooling, the solvent of the reaction solution is kept under reduced pressure, the obtained residue was mixed with concentrated hydrochloric acid (15 ml) and stirred at room temperature for 5 minutes This hydrochloric acid aqueous solution was washed with chloroform (20 ml × 3) and then brought to alkaline by the addition of 30% aqueous sodium hydroxide solution while cooling with ice. This suspension was brought to pH of 7.6 by adding the concentration of the new hydrochloric acid and 1 mol/l hydrochloric acid and then was extracted with chloroform (100 ml × 3). The organic layer was dried over anhydrous sodium sulfate and the solvent is kept at reduced pressure. The latter was purified by double recrystallization from ethanol to obtain 73 mg (19%) indicated in the title compound as bright yellow crystals.

1H-NMR (400 MHz, 0,1 mol/l NaOD)δ : 1,46-of 1.62 (2H, m), 1,74 is 1.86 (1H, m), 1,89 is 2.00 (1H, m), 2.71 to 2,84 (1H, m), 3,51-3,88 (5H, m), is 4.85-4.92 in (0,5H, m), 5,01-5,08 (0,5H, m), of 5.15 (1H, d, J=3.42 Hz), 7,50 (1H, d, J=3.42 Hz), 7,72 (1H, d, J=3.42 Hz), 8,19 (1H, s).

Melting point: 237, 2-241, 6° C (decomposition).

Elemental analysis: for C21H20F3N5O3S· 1,25H2O

Calculated: C, 50,25; N, To 4.52; N, 13,95.

Found: C, 50,10; N, To 4.52; N, 14,09.

[Example according to the invention 14]

5-Amino-7-[3-(R)-(1-amino-1-(thiazol-2-yl)methyl)-1-pyrrolidinyl]-6,8-debtor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid [F2]

Di-triptorelin 3-(R)-[1-Amino-1-(thiazol-2-yl)methyl] pyrrolidine [F2] (473 mg, 1.15 mmol) was added to a suspension of 5-amino-6,7,8-Cryptor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid (253 mg, 0.8 mmol) in acetonitrile (10 ml) and the mixture is boiled under reflux for 18 h in the presence of triethylamine (3 ml). After spontaneous cooling, the solvent of the reaction solution is kept under reduced pressure, the obtained residue was mixed with concentrated hydrochloric acid (15ml) and stirred at room temperature for 5 minutes This hydrochloric acid solution was washed with chloroform (20 ml × 3) and then brought to alkaline by the addition of 30% aqueous sodium hydroxide solution while cooling with ice. This suspension was brought to pH to 7.6 by the addition of concentrated hydrochloric acid and 1 mol/l hydrochloric acid and then was extracted with chloroform (100 ml × 3). The organic layer was dried over anhydrous sodium sulfate and the solvent is kept at reduced pressure. The latter was purified by double recrystallization from ethanol to obtain 113 mg (29%) indicated in the title compound as bright yellow crystals.

1H-NMR (400 MHz, 0,1 mol/l NaOD)δ : 1,46-of 1.62 (2H, m), 1,74 is 1.86 (1H, m), 1,90-2,00 (1H, m), 2,73-to 2.85 (1H, m), to 3.58-3,88 (5H, m), 4,84 to 4.92 (0,5H, m), 5,01-,08 (0,5H, m), of 5.15 (1H, d, J=9,27 Hz), 7,50 (1H, d, J=3.42 Hz), 7,72 (1H, d, J=3.42 Hz), 8,19 (1H, s).

Melting point: 236,4-239,8° C (decomposition).

Elemental analysis: for C21H20F3N5O3S· 1.0 h2About

Calculated: C, 50,70; N, To 4.46; N, 14,08.

Found: C, 50,90; H, Was 4.42; N, 14,16.

[Reference example 31]

1-[1-(R)-Phenylethyl]-4-(R)-[(2-pyridyl)carbonyl]-2-pyrrolidone

In the atmosphere of nitrogen and at -78° With n-utility (1.5 mol/l solution in tetrahydrofuran; 13,2 ml, to 19.9 mmol) was added dropwise to a solution of 2-bromopyridine (1,94 ml, to 19.9 mmol) in tetrahydrofuran (40 ml) and then the mixture was stirred for 10 minutes Then to last at -78° C was added dropwise a solution of N-methyl-N-methoxy-1-[1-(R)-phenylethyl]-5-oxopyrrolidin-3-(R)-carboxamide (3,66 g, 13,2 mmol) in tetrahydrofuran (20 ml) and the mixture was stirred for 30 minutes the Reaction solution was mixed with 1 mol/l hydrochloric acid (200 ml), warmed to room temperature and then was extracted with diethyl ether (200 ml × 2). The obtained organic layer was washed with saturated salt solution (100 ml) and dried over anhydrous magnesium sulfate. The solvent is kept under reduced pressure and the residue was subjected to column chromatography on silica gel (silica gel, 100 g). By elution with a mixture of n-hexane:ethyl acetate (3:1) to (1:1) was received of 1.97 g (52%) indicated in the title compounds as a light yellow oil.

1H-NMR (400 MHz, Dl3)δ : and 1.54 (3H, d, J=7,08 Hz), 2,80-and 2.83 (2H, m)to 3.35 (1H, t, J=9,37 Hz), 3,61 (1H, DD, J=6.35mm, 9,37 Hz), 4,49-of 4.54 (1H, m)5,54 (1H, kb, J - 7,08 Hz), 7,25-7,38 (5H, m), 7,47-7,50 (1H, m), 7,86 (1H, dt, J=1,71, 7,81 Hz), 8,08 (2H, d, J=7,81 Hz), 8,64-8,65 (1H, m).

[Referential example 32]

4-(R)-[1-Azido-1-(2-pyridyl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1], [F2]

Under ice cooling sodium borohydride (233 mg, 6,15 mmol) was added to a solution of 1-[1-(R)-phenylethyl]-4-(R)-[(2-pyridyl)carbonyl]-2-pyrrolidone (1,81 g, x 6.15 mmol) in methanol (40 ml) and the mixture was stirred at the same temperature for 30 minutes the Reaction solution was mixed with saturated aqueous ammonium chloride (5 ml), was stirred at room temperature for 30 min and then was extracted with chloroform (100 ml × 3). The organic layer was washed with saturated salt solution (50 ml) and dried over anhydrous sodium sulfate. The solvent is kept at reduced pressure obtaining of 2.23 g (quantitative) of 4-(R)-[1-hydroxy-1-(2-pyridyl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone as a colorless oil (mixture of isomers 1:1). Last translated in dichloromethane (40 ml)was mixed with triethylamine (1.20 ml, 8,61 mmol) and methanesulfonamide (0,571 ml, 7,38 mmol) under cooling with ice and stirred at room temperature for 30 minutes the Reaction solution was washed with a saturated aqueous solution of ammonium chloride (50 ml) and saturated salt solution (50 ml), the organic layer was dried over anhydrous sodium sulfate and the solvent is then drove away under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (15 ml)was mixed with sodium azide (1,00 g of 15.4 mmol) and then heated at 50° C for 15 hours, After cooling with ice, the reaction solution was mixed with water (50 ml) and was extracted with ethyl acetate (50 ml × 2)obtained organic layer was washed with water (40 ml × 3) and saturated salt solution (40 ml) and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the obtained residue was subjected to column x is matography on silica gel (silica gel, 100 g). By elution with a mixture of n-hexane: ethyl acetate (1:1) to (1:3) consistently received 754 mg (38%) indicated in the title compounds with low polarity [F1] 651 mg (33%) specified in the header compounds with high polarity [F2], each in the form of a colourless oil.

[F1];

1H-NMR (400 MHz, Dl3)δ : to 1.48 (3H, d, J=7,20 Hz), 2,52 is 2.55 (2H, m), 2,86-2,95 (2H, m), of 3.13 (1H, DD, J=5,62, 9.28 are Hz), 4,50 (1H, d, J=to 7.32 Hz), vs. 5.47 (1H, kb, J=7,20 Hz), 7.23 percent-7,34 (7H, m), of 7.75 (1H, dt, J=1,71, of 7.69 Hz), 8,58 at 8.60 (1H, m).

[F2];

1H-NMR (400 MHz, Dl3)δ : of 1.53 (3H, d, J=7,21 Hz), of 2.23 (1H, DD, J=7,81, 17,09 Hz), 2,34 (1H, DD, J=9,03, 17,09 Hz), 2,86-2,96 (1H, m), of 3.13 (1H, DD, J=8,06, 10,13 Hz)to 3.36 (1H, DD, J=6.35mm, 10,13 Hz), of 4.45 (1H, d, J=8,55 Hz), of 5.48 (1H, kb, J=7,21 Hz), 7,26 and 7.36 (7H, m), of 7.75 (1H, dt, J=1,71, of 7.69 Hz), to 8.62 (1H, d, J=3,91 Hz).

[Referential example 33]

4-(R)-[1-Tert-butoxycarbonylamino-1-(2-pyridyl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1], [F2]

A solution of 4-(R)-[1-azido-1-(2-pyridyl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1] (619 mg, of 1.93 mmol) in ethanol (30 ml) was mixed with catalyst 10% palladium on coal (moisture 53,8%, 620 mg) and spent catalytic hydrogenation at room temperature for 20 min under normal pressure. The reaction solution was filtered and the solvent of the filtrate is kept under reduced pressure. A solution of the obtained residue in dichloromethane (20 ml) was mixed with di-tert-BUTYLCARBAMATE (463 mg, 2,12 mmol) and triethylamine (350 μl, 2.51 mmol) and p is remedial at room temperature for 17 hours The solvent is kept under reduced pressure and the obtained residue was subjected to column chromatography on silica gel (silica gel, 40 g). By elution with a mixture of n-hexane: ethyl acetate (1:1) to (1:3) received 750 mg (87%) specified in the connection header [F1] in the form of a colorless amorphous substance.

A similar reaction was carried out on the basis of 4-(R)-[1-azido-1-(2-pyridyl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F2] (50%).

[F1];

1H-NMR (400 MHz, Dl3)δ : of 1.39 (3H, d, J=7,20 Hz), 1,44 (N, C), 2,37-to 2.42 (1H, m), 2,48-of 2.54 (1H, m), 2.77-to and 2.79 (1H, m), 2,89-to 2.94 (1H, m), 3.25 to 3.27 to (1H, m), 4,82-4,84 (1H, m), of 5.40 (1H, kb, J=7,20 Hz), of 5.89 (1H, d, J=7,32 Hz), 7,19-to 7.32 (7H, m), the 7.65 (1H, dt, J=1,79, of 7.69 Hz), 8,53 (1H, d, J=4,39 Hz).

[F2];

1H-NMR (400 MHz, Dl3)δ : 1,42 (N, C)of 1.52 (3H, d, J=7,10 Hz), 2,24-of 2.26 (1H, m), 2,66-of 2.72 (1H, m), 3,01 (1H, DD, J=8,33, 10,04 Hz), the 3.35 (1H, DD, J=6,61, 10,04 Hz), 4.72 in (1H, t, J=8,33 Hz), 5,46 (1H, kb, J=7,10 Hz), 5,61 (1H, d, J=8,33 Hz), 7,19-7,34 (7H, m), of 7.64 (1H, dt, J=1,72, 7,72 Hz), charged 8.52-8,54 (1H, m).

[Referential example 34]

3-(R)-[1-Tert-butoxycarbonylamino-1-(2-pyridyl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidin [F1], [F2]

In nitrogen atmosphere 1M complex of borane-tetrahydrofuran (6,76 ml, 6,76 mmol) was added dropwise to a solution of 4-(R)-[1-tert-butoxycarbonylamino-1-(2-pyridyl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1] (668 mg, was 1.69 mmol) in tetrahydrofuran (15 ml) under ice cooling and then the mixture was stirred at room temperature for 16 hours After distillation rastvoritelyami reduced pressure, the obtained residue was mixed with 80% aqueous ethanol (15 ml) and boiled under reflux for 4 h in the presence of triethylamine (1 ml). After spontaneous cooling, the reaction solution, the solvent is kept under reduced pressure, the obtained residue was added chloroform (50 ml) and then the organic layer was washed with water (40 ml) and saturated salt solution (40 ml) and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the obtained residue was subjected to column chromatography on silica gel (silica gel, 20 g). By elution with a mixture of chloroform:methanol (100:0) to (95:5) was obtained 600 mg (93%) indicated in the title compound as white crystals.

A similar reaction was carried out on the basis of 4-(R)-[1-tert-butoxycarbonylamino-1-(2-pyridyl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F2] (87%).

[F1];

1H-NMR (400 MHz, Dl3)δ : of 1.34 (3H, d, J=to 6.43 Hz), 1,47 (N, C), 1,67 is 1.70 (1H, m), 2,23 to 2.35 (4H, m), 2,67-2,69 (1H, m), 2,86-only 2.91 (1H, m), 3,13 (1H, q, J=to 6.43 Hz), to 4.62 (1H, t, J=6,00 Hz), 6.35mm (1H, s), 7,10-7,13 (1H, m), 7,13-7,33 (6N, m), EUR 7.57 to 7.62 (1H, m), and 8.50 (1H, d, J=4,16 Hz).

[F2];

1H-NMR (400 MHz, Dl3)δ : of 1.39 (3H, d, J=6,61 Hz), 1,46 (N, C), 1,71-of 1.74 (1H, m), 1,91-of 1.94 (1H, m), 2,22-of 2.36 (4H, m), 2,66 (1H, s), 2,94-2,95 (1H, m), 3,15-3,17 (1H, m), 4,60-4,63 (1H, m), 6,60-6,69 (1H, m),? 7.04 baby mortality-was 7.08 (1H, m), 7,21-7,32 (6N, m), 7,51 (1H, dt, J=1,71, 7,72 Hz), of 8.47 (1H, D, J=4,16 Hz).

[Referential example 35]

3-(R)-[1-Tert-butoxycarbonylamino-1 -(2-pyridyl)methyl]-1-benzyloxycarbonylamino [F1], [F2]

In the atmosphere of nitrogen benzylchloride (728 μl, 5,09 mmol) was added by ka the NML to a solution of 3-(R)-[1-tert-butoxycarbonylamino-1-(2-pyridyl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1] (648 mg, 1.70 mmol) in dichloroethane (20 ml) under ice cooling and the mixture is then boiled under reflux for 30 hours After removal of the solvent under reduced pressure the residue was subjected to column chromatography on silica gel (silica gel, 40 g). By elution with a mixture of chloroform: methanol (100:0) to (97:3) received 500 mg (72%) indicated in the title compound as white crystals.

A similar reaction was carried out on the basis of 3-(R)-[1-tert-butoxycarbonylamino-1-(2-pyridyl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F2] (61%).

[F1];

1H-NMR (400 MHz, Dl3)δ : 1,40-1,45 (1H, m), 1,42 (9), 1,86-of 1.94 (1H, m), 2,59-2,62 (1H, m), 3.04 from-3,11 (1H, m), 3,22-to 3.33 (2H, m), 3,54-to 3.58 (1H, m), of 4.66-4.72 in (1H, m), 5,09 (2H, s), 5,71-5,73 (1H, m), 7,16-7,34 (7H, m), 7,63 (1H, dt, J=1,71, to 7.59 Hz), 8,53 (1H, d, J=3,92 Hz).

[F2];

1H-NMR (400 MHz, Dl3)δ : 1,42 (9), 1,58-to 1.67 (2H, m), 2,61-to 2.67 (1H, m), 3.27 to 3,55 (4H, m), 4,70-4,80 (1H, m), 5,10 (1H, s), 5,12 (1H, s), 5,71-5,78 (1H, m), 7,17 and 7.36 (7H, m), 7,60-7,63 (1H, m), 8,55 (1H, s).

[Referential example 36]

3-(R)-[1-Tert-butoxycarbonylamino-1-(2-pyridyl)methyl] pyrrolidin [F1], [F2]

A solution of 3-(R)-[1-tert-butoxycarbonylamino-1-(2-pyridyl)-methyl]-1-benzyloxycarbonylamino [F1] (500 mg, 1,22 mmol) in ethanol (20 ml) was mixed with catalyst 10% palladium on coal (moisture 53,8%, 500 mg) and spent catalytic hydrogenation at room temperature for 18 h under normal pressure. The reaction solution was filtered and R is storytell filtrate drove under reduced pressure to get crude specified in the title compounds as colorless crystals. Last used in subsequent reactions without purification.

A similar reaction was carried out on the basis of 3-(R)-[1-tert-butoxycarbonylamino-1-(2-pyridyl)methyl]-1-benzyloxycarbonylamino [F2].

[Example according to the invention 15]

5-Amino-7-{3-(R)-[1-amino-1-(2-pyridyl)methyl]-1-pyrrolidinyl}-6,8-debtor-1-[(1R,2S)-2-forciblepoppy]-1,4-dihydro-4-oxoindole-3-carboxylic acid [F2]

3-(R)-[1-Tert-butoxycarbonylamino-1-(2-pyridyl)methyl]pyrrolidin [F1] (339 mg, 1,22 mmol) was added to a suspension of 5-amino-6,7,8-Cryptor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid (316 mg, 1.00 mmol) in acetonitrile (10 ml) and the mixture is boiled under reflux for 14 h in the presence of triethylamine (0.5 ml). After cooling, the solvent of the reaction solution is kept under reduced pressure. The obtained residue was dissolved in chloroform (150 ml), washed with 10% citric acid (80 ml) and saturated salt solution (80 ml), dried over anhydrous sodium sulfate and the solvent is then drove away under reduced pressure. The obtained residue was mixed with concentrated hydrochloric acid (10 ml) under cooling with ice, then mixed with 1 mol/l aqueous solution of hydrochloric acid (5 ml) at room temperature, and then washed with chloroform (50 ml × 4) and the insoluble substance was removed by filtration. This hydrochloric acid aqueous solution was brought dodelochnyh reaction by adding 10 mol/l aqueous solution of sodium hydroxide. This suspension was brought to pH by the addition of concentrated hydrochloric acid and 1 mol/l hydrochloric acid and then was extracted with chloroform (150 ml × 4). The obtained organic layer was dried over anhydrous sodium sulfate and the solvent drove under reduced pressure to get crude specified in the title compound as bright yellow crystals. The latter was purified by recrystallization from ethanol to obtain 316 mg (67%) specified in the connection header.

1H-NMR (400 MHz, 0,1 mol/l NaOD)δ : of 1.45 to 1.47 (2H, m), a 1.75-1.77 in (1H, m), 2,25-of 2.27 (1H, m), 2,48-of 2.50 (1H, m), 2,97-of 3.00 (1H, m), 3,30-a 3.83 (5H, m), was 4.76 (1H, OSD, J=62,50 Hz), 7,35-7,44 (2H, m), charged 8.52 (1H, t, J=7,81 Hz)to 8.12 (1H, s), 8,46 (1H, d, J=4,39 Hz).

Melting point: 194-196° C.

Elemental analysis: for C23H22F3N5O3·0,5EtOH· 0,5H2O

Calculated; C, 57,03; N, 5,18; N, 13,85.

Found: C, 57,03; N, 5,11; N, 13,85.

[Example according to the invention 16]

5-Amino-7-{3-(R)-[1-amino-1-(2-pyridyl)methyl]-1-pyrrolidinyl}-6,8-debtor-1-[(1R,2S)-2-forciblepoppy]-1,4-dihydro-4-oxoindole-3-carboxylic acid

3-(R)-[1-Tert-butoxycarbonylamino-1-(2-pyridyl)methyl]pyrrolidin [F2] (0,535 mmol) was added to a suspension of 5-amino-6,7,8-Cryptor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid (169 mg, 0,534 mmol) in acetonitrile (5 ml) and the mixture is boiled under reflux for 19 h in proudtobeanechelon (0.5 ml). After cooling, the solvent of the reaction solution is kept under reduced pressure. The obtained residue was dissolved in chloroform (50 ml), washed with 10% citric acid (40 ml) and saturated salt solution (40 ml), dried over anhydrous sodium sulfate and the solvent is then drove away under reduced pressure. The obtained residue was mixed with concentrated hydrochloric acid (5 ml) under ice cooling, optionally mixed with 1 mol/l aqueous solution of hydrochloric acid (5 ml) at room temperature and then washed with chloroform (50 ml × 5). This hydrochloric acid aqueous solution was brought to alkaline by adding 10 mol/l aqueous solution of sodium hydroxide and then stirred at room temperature for 1 h the suspension was brought to pH 7.4 by the addition of concentrated hydrochloric acid and 1 mol/l hydrochloric acid and then was extracted with chloroform (150 ml × 3). The obtained organic layer was dried over anhydrous sodium sulfate and the solvent drove under reduced pressure to get crude specified in the title compound as bright yellow crystals. The latter was purified by recrystallization from ethanol to obtain 136 mg (54%) specified in the connection header.

1H-NMR (400 MHz, 0,1 mol/l NaOD)δ : 1,52-and 1.54 (3H, m), 2.49 USD is 2.51 (2H, m), 3,41-3,86 (6N, m), 4,69-of 4.77 (1H, m), 7,35-7,42 (2H, m), 7,82-7,86 (1H, m, 8,17 (1H, s), 8,46 (1H, s).

Melting point: 178-180° C.

Elemental analysis: for C23H22F3N5O3·0,N2O

Calculated: C, 56,73; N, A 4.86; N, 14,38.

Found: C, 56,50; N, To 4.81; N, 14,29.

[Example according to the invention 17]

5-Amino-7-{3-(R)-[1-amino-1-(2-pyridyl)methyl]-1-pyrrolidinyl}-6-fluoro-1-[(1R,23)-2-forciblepoppy]-1,4-dihydro-8-methyl-4-oxoindole-3-carboxylic acid (F2: D91-5400)

3-(R)-[1-Tert-butoxycarbonylamino-1-(2-pyridyl)methyl]-pyrrolidin [F2] (1.00 mmol) was added to a suspension of 5-amino-6,7,8-Cryptor-1-[2-(8-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid (284 mg, 0,910 mmol) in dimethyl sulfoxide (3 ml) and the mixture was stirred at 80°C for 93 h in the presence of N-methylpiperidine (0,146 ml of 1.09 mmol). After cooling, the solvent of the reaction solution is kept under reduced pressure. The obtained residue was dissolved in chloroform (50 ml), washed with 10% citric acid (50 ml) and saturated salt solution (40 ml), dried over anhydrous sodium sulfate and the solvent is then drove away under reduced pressure. The obtained residue was subjected to column chromatography on silica gel (silica gel, 40 g)was suirable a mixture of chloroform:methanol (100:0) to (98:2) and then the solvent in the eluate drove away under reduced pressure. The obtained residue was mixed with concentrated hydrochloric acid (5 ml) under cooling l is ω, then was mixed with 1 mol/l aqueous solution of hydrochloric acid (5 ml) at room temperature and then washed with chloroform (50 ml × 4). This hydrochloric acid aqueous solution was brought to alkaline by adding 10 mol/l aqueous solution of sodium hydroxide. This suspension was brought to pH 7.4 by the addition of concentrated hydrochloric acid and 1 mol/l hydrochloric acid and then was extracted with chloroform (150 ml × 3). The obtained organic layer was dried over anhydrous sodium sulfate, the solvent is kept under reduced pressure and then the resulting residue was partially purified on TLC paper (Whatman, PLK5F, 150) to obtain the crude specified in the title compound as bright yellow crystals. Obtained was purified by recrystallization from isopropyl alcohol to obtain 70.0 mg (16%) specified in the connection header.

1H-NMR (400 MHz, 0,1 mol/l NaOD)δ : 1,02-1,11 (1H, m), 1,46-to 1.59 (2H, m), 2,20-of 2.26 (1H, m), of 2.23 (1H, s), 2,58-2,61 (1H, m), 3,13-3,17 (1H, m), 3.45 points-of 3.64 (3H, m), a 3.87-to 3.92 (2H, m), 4,78 of 4.83 (1H, m), 7,34-7,45 (2H, m), a 7.85-7,87 (1H, m), of 8.27 (1H, s), to 8.45 (1H, s).

Melting point: 127-129° C.

Elemental analysis: for C24H25F2H5O3·1,25H2O

Calculated: C, 58,59; N, 5,63; N, 14,23.

Found: C, 58,69; N, 5,52; N, 14,25.

[Referential example 37]

1-[1-(R)-Phenylethyl]-4-(R)-[(3-pyridyl)carbonyl]-2-pyrrolidone

At at the osphere nitrogen and at -78° With n-utility (1.5 mol/l solution in tetrahydrofuran; 18,1 ml of 27.2 mmol) was added dropwise to a solution of 3-bromopyridine (2,61 ml of 27.2 mmol) in tetrahydrofuran (200 ml) and then the mixture was stirred for 10 minutes Then the last was added dropwise at -78° With a solution of N-methyl-N-methoxy-1-[1-(R)-phenylethyl]-5-oxopyrrolidin-3-carboxamide (of 5.00 g of 18.1 mmol) in tetrahydrofuran (15 ml) and the mixture was stirred for 30 minutes the Reaction solution was mixed with 1 mol/l hydrochloric acid (100 ml), warmed to room temperature, was extracted with chloroform (200 ml × 2), then the obtained organic layer was washed with saturated salt solution (100 ml) and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and the obtained residue was subjected to column chromatography on silica gel (silica gel, 100 g). By elution with a mixture of n-hexane: ethyl acetate (1:4) to (0:100) received 2.16 g (41%) indicated in the title compounds as a light yellow oil.

1H-NMR (400 MHz, Dl3)δ : of 1.56 (3H, d, J=to 7.32 Hz), 2,82 (2H, d, J=to 7.32 Hz), 3,20-of 3.27 (1H, m), 3,70-3,74 (1H, m), 3,97-4,01 (1H, m), 5,51-of 5.55 (1H, m), 7,26-7,47 (6N, m), 8,21 (1H, d, J=8,06 Hz), 8,81 (1H, d, J=4,39 Hz), which is 9.09 (1H, s).

[Reference example 38]

4-(R)-[1-Azido-1-(3-pyridyl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1], [F2]

Under ice cooling sodium borohydride (580 mg, and 15.3 mmol) was added to a solution of 1-[1-(R)-phenylethyl]-4-(R)-[(3-PI is ideal) carbonyl]-2-pyrrolidone (4,51 g, of 15.3 mmol) in methanol (90 ml) and the mixture was stirred at the same temperature for 30 minutes the Reaction solution was mixed with saturated aqueous ammonium chloride (50 ml)was stirred for 30 min and then was extracted with ethyl acetate (100 ml × 3). The organic layer was washed with saturated salt solution (50 ml) and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain 3.88 g (86%) of the intermediate 4-(R)-[1-hydroxy-1-(3-pyridyl) methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone as a colourless oil. Last translated in dichloromethane (100 ml)was mixed with triethylamine (3,10 ml of 22.3 mmol) and methanesulfonamide (1,52 ml of 19.7 mmol) under ice cooling and then stirred at room temperature for 30 minutes the Reaction solution was washed with a saturated aqueous solution of ammonium chloride (100 ml) and saturated salt solution (100 ml), the organic layer was dried over anhydrous sodium sulfate, and the solvent is then drove away under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (30 ml)was mixed with sodium azide (2,49 g is 32.8 mmol) and then heated at 40° C for 14 h, After cooling with ice, the reaction solution was mixed with water (100 ml) and was extracted with ethyl acetate (100 ml × 2)obtained organic layer was washed with water (80 ml × 3) and nasyscennosti salt (80 ml) and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the obtained residue was subjected to column chromatography on silica gel (silica gel, 100 g). By elution with a mixture of n-hexane: ethyl acetate (3:5), ethyl acetate and a mixture of chloroform:methanol (90:10) consistently received 976 mg (23%) specified in the header compounds with low polarity [F1] and 1.73 g (41%) indicated in the title compounds with high polarity [F2], each in the form of a colorless oil.

[F1];

1H-NMR (400 MHz, Dl3)δ : to 1.48 (3H, d, J=7,08 Hz), 2,54-of 2.64 (3H, m), 2,82-of 2.86 (1H, m), 2,96 (1H, DD, J=5,86, 10,01 Hz), of 4.44 (1H, d, J=7,33 Hz), of 5.48 (1H, kb, J=7,08 Hz), 7,21-7,62 (6N, m)to 7.64 (1H, d, J=6,10 Hz), 8,54 (1H, d, J=1,95 Hz), 8,63 (1H, DD, J=1,47, a 4.86 Hz).

[F2];

1H-NMR (400 MHz, Dl3)δ : and 1.54 (3H, d, J=7,08 Hz), 2,11-to 2.18 (1H, m), 2.26 and is 2.33 (1H, m), 2,56 of 2.68 (1H, m), 3,13-3,29 (2H, m), 4,43 (1H, d, J=9.28 are Hz), 5,46-of 5.53 (1H, m), 7.24 to 7,38 (6N, m), 7,63 (1H, dt, J=1,95, 7,81 Hz), to 8.57 (1H, d, J=2.20 Hz), 8,64 (1H, DD, J=1,71, 4,88 Hz).

[Referential example 39]

4-(R)-[1-Tert-butoxycarbonylamino-1-(3-pyridyl)methyl 3-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1], [F2]

A solution of 4-(R)-[1-azido-1-(3-pyridyl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1] (976 mg, totaling 3.04 mmol) in ethanol (30 ml) was mixed with catalyst 10% palladium on coal (moisture 53,8%, and 1.00 g) and spent catalytic hydrogenation at room temperature for 1 h under normal pressure. The reaction solution was filtered and the solvent of the filtrate drove with onigen the m pressure. A solution of the obtained residue in dichloromethane (20 ml) was mixed with tert-BUTYLCARBAMATE (729 mg, to 3.34 mmol) and triethylamine (551 μl, 3.95 mmol) and stirred at room temperature for 16 hours the Solvent is kept under reduced pressure and the obtained residue was subjected to column chromatography on silica gel (silica gel, 20 g). By elution with a mixture of chloroform: methanol (100:0) to (95:5) received 654 mg (54%) specified in the connection header [F1] in the form of a colorless amorphous substance.

A similar reaction was carried out on the basis of 4-(R)-[1-azido-1-(3-pyridyl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F2] (36%).

[F1];

1H-NMR (400 MHz, Dl3)δ : 1,41 (N, C)of 1.47 (3H, d, J=to 7.32 Hz), of 2.44-2.50 (1H, m), 2.57 m-of 2.64 (1H, m), 2,63-to 2.67 (1H, m), 2,83-2,87 (1H, m), 2,97-a 3.01 (1H, m), and 4.68-4.72 in (1H, m), 4,91 to 4.92 (1H, m), of 5.48 (1H, q, J=to 7.32 Hz), 7,21-7,32 (6N, m), 7,55 (1H, d, J=7,81 Hz), charged 8.52-8,55 (1H, m).

[F2];

1H-NMR (400 MHz, Dl3)δ : 1,39 (N, C)of 1.53 (3H, d, J=7,17 Hz), 2,13 (1H, DD, J=8,08 and 16.9 Hz), and 2.27 (1H, DD, J=8,57, and 16.4 Hz), 2,61-to 2.65 (1H/ m), 3,11 -, and 3.16 (1H, m), 3.25 to 3,30 (1H, m), 4,62-of 4.66 (1H, m), 4,77-to 4.81 (1H, m), 5,48 (1H, kb, J=7,17 Hz), 7,26 and 7.36 (6N, m), 7,54 (1H, d, J=7,35 Hz), 8,54 (2H, DD, J=1,71, 4,90 Hz).

[Referential example 40]

3-(R)-[1-Tert-butoxycarbonylamino-1-(3-pyridyl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidin [F1], [F2]

In nitrogen atmosphere 1M complex of borane-tetrahydrofuran (7,74 ml, 7,74 mmol) was added dropwise to a solution of 4-(R)-[1-tert-butoxycarbonylamino-1-(3-pyridyl)methyl]-1-[1-(R)-f is niatel]-2-pyrrolidone [F1] (612 mg, 1.55 mmol) in tetrahydrofuran (12 ml) under ice cooling and then the mixture was stirred at room temperature for 18 hours After removal of the solvent under reduced pressure the resulting residue was dissolved in 80% aqueous ethanol (20 ml) and boiled under reflux for 4 h in the presence of triethylamine (1 ml). After spontaneous cooling, the reaction solution, the solvent is kept under reduced pressure, the obtained residue was added chloroform (40 ml), then the obtained organic layer was washed with water (30 ml) and saturated salt solution (30 ml) and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the obtained residue was subjected to column chromatography on silica gel (silica gel, 10 g). By elution with a mixture of chloroform: methanol (100:0) to (97:3) received 461 mg (78%) indicated in the title compound as white crystals.

A similar reaction was carried out on the basis of 4-(R)-[1-tert-butoxycarbonylamino-1-(3-pyridyl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F2] (71%).

[F1];

1H-NMR (400 MHz, Dl3)δ : of 1.37 (3H, d, J=6,59 Hz), 1,49 (N, C), 2,17 was 2.25 (2H, m), 2,42 at 2.45 (2H, m), 2.95 and-and 3.16 (2H, m), 4.53-in-of 4.57 (1H, m), 6,44-6,48 (1H, m), 7,21-7,35 (6N, m), 7,52-rate of 7.54 (1H, m), 8,46 (1H, DD, J=1,47, 4,88 Hz), and 8.50 (1H, s).

[F2];

1H-NMR (400 MHz, Dl3)δ : of 1.41 (3H, d, J=6,59 Hz), 1,47 (N, s), 2.00 in 2,04 (2H, m), 2,20-of 2.26 (1H, m), a 2.36-to 3.41 (2H, m), 3,14-3,21 (N, m), 4.53-in-4,56 (1H, m), 6,99-7,01 (1H, m), 7,10-7,13 (1H, m), 7,26-7,35 (6N, m), 8,35-8,39 (2H, m).

[Referential example 41]

3-(R)-[1-Tert-butoxycarbonylamino-1-(3-pyridyl)methyl] pyrrolidin [F1], [F2]

A solution of 3-(R)-[1-tert-butoxycarbonylamino-1-(3-pyridyl) methyl]-1-[1-(R)-phenylethyl]pyrrolidin [F1] (105 mg, 0,275 mmol) in ethanol (10 ml) was mixed with the catalyst 10% palladium on coal (moisture 53,8%, 105 mg) and spent catalytic hydrogenation at 40°C for 23 h at normal pressure. The reaction solution was filtered and the solvent of the filtrate drove under reduced pressure to get crude specified in the title compounds as colorless crystals. The latter directly used at a later stage.

A similar reaction was carried out on the basis of 3-(R)-[1-tert-butoxycarbonylamino-1-(3-pyridyl)methyl]-1-[1-(R)-phenylethyl]pyrrolidine [F2].

[Example according to the invention 18]

5-Amino-7-{3-(R)-[1-amino-1-(3-pyridyl)methyl]-1-pyrrolidinyl}-6,8-debtor-1-[(1R,2S)-2-forciblepoppy]-1,4-dihydro-4-oxoindole-3-carboxylic acid

3-(R)-[1-Tert-butoxycarbonylamino-1-(3-pyridyl)methyl]pyrrolidin [F1] (70 mg, 0,252 mmol) was added to a suspension of 5-amino-6,7,8-Cryptor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid (87,0 mg, 0,275 mmol) in acetonitrile (3 ml) and the mixture is boiled under reflux for 19 h in the presence of triethylamine (0.3 ml). After cooling, RA is the maker of the reaction solution is kept under reduced pressure. The obtained residue was dissolved in chloroform (50 ml), washed with 10% citric acid (40 ml) and saturated salt solution (40 ml), dried over anhydrous sodium sulfate and the solvent is then drove away under reduced pressure. The obtained residue was mixed with concentrated hydrochloric acid (2 ml) under cooling with ice, then mixed with 1 mol/l aqueous solution of hydrochloric acid (2 ml) at room temperature, then washed with chloroform (30 ml × 4) and the insoluble substance was removed by filtration. This hydrochloric acid solution was brought to alkaline by adding 10 mol/l aqueous solution of sodium hydroxide. This suspension was brought to pH 7.4 by the addition of concentrated hydrochloric acid and 1 mol/l hydrochloric acid and then was extracted with chloroform (150 ml × 3). The obtained organic layer was dried over anhydrous sodium sulfate and the solvent drove under reduced pressure to get crude specified in the title compound as bright yellow crystals. The latter was purified by recrystallization from a mixture of Ethnology ammonia with the receipt of 65.1 mg (54%) specified in the connection header.

1H-NMR (400 MHz, 0,1 mol/l NaOD)δ : 1,32-to 1.38 (2H, m), 1,54 is 1.58 (1H, m), 2,19-of 2.21 (1H, m), is 2.30 to 2.35 (1H, m), 2,79-of 2.81 (1H, m), is 3.08-3,10 (1H, m), 3,34-3,69 (N, m), 4,77-to 4.81 (1H, DM), the 7.43 (1H, d, J=EUR 7.57 Hz), 7,79 (1H, d, J=EUR 7.57 Hz)to 8.12 (1H, s), 8,43-to 8.45 (2H, m).

Melting point: 263265° C (with decomposition).

Elemental analysis: for C23H22F3N5O3·0,25N2O

Calculated: C, 57,80; N, 4,74; N, 14,65.

Found: C, 57,62; N, To 4.81; N, 14,30.

[Example on finding 19]

5-Amino-7-{3-(R)-[1-amino-1-(3-pyridyl)methyl]-1-pyrrolidinyl}-6,8-debtor-1-[(1R,2S)-2-forciblepoppy]-1,4-dihydro-4-oxoindole-3-carboxylic acid

3-(R)-[1-Tert-butoxycarbonylamino-1-(3-pyridyl)methyl]pyrrolidin [F2] (0,461 mmol) was added to a suspension of 5-amino-6,7,8-Cryptor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-Digi-DRO-4-oxoindole-3-carboxylic acid (156 mg, 0,493 mmol) in acetonitrile (5 ml) and the mixture is boiled under reflux for 19 h in the presence of triethylamine (0.5 ml). After cooling, the solvent of the reaction solution is kept under reduced pressure. The obtained residue was dissolved in chloroform (50 ml), washed with 10% citric acid (40 ml) and saturated salt solution (40 ml), dried over anhydrous sodium sulfate and the solvent is then drove away under reduced pressure. The obtained residue was mixed with concentrated hydrochloric acid (5 ml) under cooling with ice, then mixed with 1 mol/l aqueous solution of hydrochloric acid (5 ml) at room temperature and then washed with chloroform (50 ml × 5). This hydrochloric acid aqueous solution was brought to alkaline by adding 10 mol/l aqueous solution of caustic soda which I then brought to pH 7.4 by the addition of concentrated hydrochloric acid and 1 mol/l hydrochloric acid and then was extracted with chloroform (150 ml × 3). The obtained organic layer was dried over anhydrous sodium sulfate and the solvent drove under reduced pressure to get crude specified in the title compound as bright yellow crystals. Obtained was purified by recrystallization from ethanol to obtain to 71.5 mg (32%) specified in the connection header.

1H-NMR (400 MHz, 0,1 mol/l NaOD)δ : 1,36-to 1.45 (2H, m), 1,53-to 1.59 (2H, m), 2,42-2,47 (1H, m), 3,40-3,81 (6N, m), 4,95-free 5.01 (1H, DM), 7,46 (1H, d, J=6,35 Hz), 7,83 (1H, d, J=EUR 7.57 Hz), 8,18 (1H, s), 8,44-8,48 (2H, m).

Melting point: 123-126° C.

Elemental analysis: for C23H22F3N5O3·1H2O

Calculated: C, 56,21; N, To 4.92; N, 14,25.

Found: C, 56,43; N, To 4.87; N, 14,05.

[Example according to the invention 20]

5-Amino-7-{3-(R)-[1-amino-1-(3-pyridyl)methyl]-1-pyrrolidinyl}-6-fluoro-1-[(1R,2S)-2-forciblepoppy]-1,4-dihydro-4-oxoindole-3-carboxylic acid

3-(R)-[1-Tert-butoxycarbonylamino-1-(3-pyridyl)methyl] pyrrolidin [F2] (1,60 mmol) was added to a suspension of 5-amino-6,7,8-Cryptor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoindole-3-carboxylic acid (427 mg, of 1.33 mmol) in dimethyl sulfoxide (3 ml) and the mixture was stirred at 80° in over 161 h in the presence of N-methylpiperidine (0,356 ml of 2.93 mmol). After the cooling gap is placed the solvent of the reaction solution is kept under reduced pressure. The obtained residue was dissolved in chloroform (100 ml), washed with 10% citric acid (50 ml) and saturated salt solution (40 ml), dried over anhydrous sodium sulfate and the solvent is then drove away under reduced pressure. The obtained residue was mixed with concentrated hydrochloric acid (5 ml) under cooling with ice, then mixed with 1 mol/l aqueous solution of hydrochloric acid (5 ml) at room temperature and then washed with chloroform (30 ml× 4). This hydrochloric acid aqueous solution was brought to alkaline by adding 10 mol/l aqueous solution of sodium hydroxide. This suspension was brought to pH 7.4 by the addition of concentrated hydrochloric acid and 1 mol/l hydrochloric acid and then was extracted with chloroform (150 ml × 3). The obtained organic layer was dried over anhydrous sodium sulfate and the solvent is kept under reduced pressure, and the resulting residue was partially purified on TLC paper (Whatman, PLK5F, 150) to obtain 100 mg of the crude indicated in the title compound as bright yellow crystals. The latter was purified by recrystallization from isopropyl alcohol with getting to 62.2 mg (10%) specified in the connection header.

1H-NMR (400 MHz, 0,1 mol/l NaOD)δ : 1,04 was 1.06 (1H, m), 1,11-of 1.13 (1H, m), 1,45-1,49 (2H, m), 1,58 is 1.60 (1H, m), of 2.23 (3H, s), 2,56 at 2.59 (1H, m), 3,14-and 3.16 (1H, m), 3,49-3,51 (1H, m), 3,59-3,62 (2H, m), 3,85-3,89 2H, m}, 4,88-5,04 (1H, DM), 7,46 (1H, s), 7,86 (1H, d, J=7,34 Hz), of 8.27 (1H, s), to 8.45 (1H, d, J=4,89 Hz), 8,51 (1H, s).

Melting point: 213-215° C.

Elemental analysis: for C24H25F2N5O3·0,5H2O

Calculated: C, 60,24; N, Of 5.48; N, 14,64.

Found: C, 60,46; N, 5,46; N, 14,55.

Antibacterial activity of the compounds according to the invention was determined by the standard method described by Japanese Society of Chemotherapy with the results presented in table 2 in the form of MIC values (μg/ml). In this context also presents the MIC for levofloxacin (LVFX), ciprofloxacin (CPFX) and 5-amino-7-[3-(R)-[1-(S)-amino-ethyl] pyrrolidin-1-yl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl-8-methyl-1,4-dihydro-4-oxoindole-3-carboxylic acid (control drug 1), described in WO 9623782, for comparison with the MIC values of the compounds according to the invention.

0,025tr>
Table 2
Antibacterial activity
Bacteria/connection (No. of example)1234
D. coli NIHJ≤ 0,003≤ 0,003≤ 0,003≤ 0,003
S. flexneri 2A 55030,006≤ 0,003≤ 0,003≤ 0,003
Pr. Vulgaris 086010,10,0250,013
K. pneumoniae TYPE 10,050,0130,0250,025
Ser. Marcescens 101000,10,050,050,025
Ps. Aeruginosa 321040,20,10,10,1
Ps. Aeruginosa 321210,10,0250,050,05
X. maltophilia IID 12750,10,0250,0250,05
S. aureus FDA 209P≤ 0,003≤ 0,003≤ 0,003≤ 0,003
S. epidermidis 56500≤ 0,003≤ 0,003≤ 0,003≤ 0,003
Str. pyrogenes G-360,013≤ 0,003≤ 0,003≤ 0,003
E. faecalis ATCC 194330,050,0060,0130,006
S. aureus 8703070,025≤ 0,003≤ 0,003≤ 0,003
Sfcr. Pneumoniae J240,006≤ 0,003≤ 0,003≤ 0,003
Bacteria/connection (No. of example)56810
E. coli NIHJ≤ 0,0030,006≤ 0,003≤ 0,003
S. flexneri 2A 5503≤ 0,0030,0130,006≤ 0,003
Pr. Vulgaris 086010,0130,10,20,1
K. pneumoniae TYPE 10,0130,050,050,013
Ser. Marcescens 101000,0250,10,20,1
Ps. Aeruginosa 321040,10,20,20,2
Ps. Aeruginosa 321210,0250,10,10,1
X. maltophilia IID 12750,0250,10,20,05
S.aureus FDA 209P≤ 0,003≤ 0,003≤ 0,003≤ 0,003
S. epiclermiclis 56500≤ 0,0030,006≤ 0,003≤ 0,003
Str. pyrogenes G-36≤ 0,003≤ 0,003≤ 0,003≤ 0,003
E. faecalis ATCC 194330,0060,0250,0250,025
S. aureus 870307≤ 0,0030,0130,013 0,006
Str. Pneumoniae J24≤ 0,003≤ 0,003≤ 0,003≤ 0,003

0,2
Bacteria/connection (No. of example)11121617
E. coil NIHJ≤ 0,003≤ 0,003≤ 0,003≤ 0,003
S. flexneri 2A 5503≤ 0,003≤ 0,003≤ 0,0030,006
Pr. Vulgaris 086010,050,0130,0250,05
K. pneumoniae TYPE 10,0250,0250,0250,05
Ser. Marcescens 101000,050,0250,10,1
Ps. Aeruginosa 321040,20,10,20,2
Ps. Aeruginosa 321210,050,050,050,1
X. maltophilia IID 12750,050,050,10,05
S. aureus FDA 209P≤ 0,003≤ 0,003≤ 0,003≤ 0,003
S. epidermidis 56500≤ 0,003≤ 0,003ɤ 0,003≤ 0,003
Str. pyrogenes G-360,013≤ 0,003≤ 0,003≤ 0,003
E. faecalis ATCC 194330,0250,0060,0130,025
S. aureus 8703070,025≤ 0,0030,0060,013
Str. Pneumonias J240,006≤ 0,003≤ 0,003≤ 0,003
Bacteria/connection (No. of example)1920LVFXF
E. coil NIHJ≤ 0,0030,0060,013≤ 0,003
S. flexneri 2A 5503≤ 0,0030,0060,0250,006
Pr. Vulgarls 086010,0250,0250,13≤ 0,003
K. pneumoniae TYPE 10,0250,050,10,025
Ser. Marcescens 101000,10,10,10,025
Ps. Aeruginosa 321040,20,20,20,05
Ps. Aeruginosa 321210,050,050,10,025
X. maltophilia IID 12750,10,390,78
5. aureus FDA 209P≤ 0,003≤ 0,0030,20,1
S. epidermidis 56500≤ 0,003≤ 0,0030,390,2
Str. pyrogenes G-36≤ 0,003≤ 0,0030,21,56
E. faecalis ATCC 194330,0250,0250,780,78
S. aureus 8703070,0250,05≤ 6,253,13
Str. Pneumoniae J24≤ 0,003≤ 0,0030,780,1

Bacteria/ connection (No. of example)Control Medicine 1
E. coli MIHJ0,006
5. flexneri 2A 55030,006
Pr. Vulgarls 086010,013
K. pneumoniae TYPE I0,05
Ser. Marcescens 101000,1
Ps. Aeruginosa 321040,1
Ps. Aeruginosa 321210,05
X. maltophilla IID 12750,2
S. aureus PDA 209P≤ 0,003
S. epidermidis 56500≤ 0,003
Str. pyrogenee G-36 ≤ 0,003
E. faecalis ATCC 194330,025
S. aureus 8703070,025
Str. Bespoke J24≤ 0,003

LVFX - levofloxacin

CPFX - ciprofloxacin

Industrial applicability

Compounds according to the invention are quinolone compound represented by the following formula:

quinolone compound represented by the following formula:

or the following formula:

in which the substituent R1represents an aromatic Deputy, which are useful as antibacterial compounds due to their excellent antibacterial activity against gram-negative bacteria and gram-positive bacteria, and also against various resistant to the drugs strains.

1. Derivatives aminomethylpyrrolidine, represented by the following formula (I), their salts or their hydrates

in which R1represents aryl having 6 to 10 carbon atoms, or heteroaryl where heteroaryl is five-membered ring or six-membered ring and contains from 1 to 2 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom,

where aryl and heteroaryl can who have one or more substituents, selected from the group consisting of a halogen atom or alkoxyl having from 1 to 6 carbon atoms;

R2and R3each independently represents a hydrogen atom;

R4, R5and R6each represents a hydrogen atom;

R7and R8each represents a hydrogen atom;

Q represents a partial structure represented by the following formula:

in which R9is cyclic alkyl having 3 to 6 carbon atoms which may be substituted with halogen;

R10represents a hydrogen atom,

R11represents a hydrogen atom or the amino group:

X1represents a halogen atom,

And1represents a partial structure represented by formula (II)

in which X2represents a hydrogen atom, halogen atom, halogenmethyl, alkyl having from 1 to 6 carbon atoms or alkoxy having from 1 to 6 carbon atoms, and

X2and above R9can be combined with the formation of the ring structure by the inclusion of the main skeleton and thus formed ring include an oxygen atom, nitrogen atom or sulfur atom as a constituent of the ring atoms and the ring may also have the as Deputy alkyl, having from 1 to 6 carbon atoms), and

Y represents a hydrogen atom.

2. The compound according to claim 1, its salt or hydrates, where Q in formula (I) is 6-carboxy-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazine-10-Il.

3. The compound according to claim 1, its salt or hydrates, where Q in formula (I) is 8-amino-6-carboxy-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazine-10-Il.

4. The compound according to claim 1, its salt or hydrates, where Q in formula (I) is 3-carboxy-8-chloro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-7-yl.

5. The compound according to claim 1, its salt or hydrates, where Q in formula (I) is 3-carboxy-6-fluoro-1-[2-(S)-fluoro-6-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoindole-7-yl.

6. The compound according to claim 1, its salt or hydrates, where Q in formula (I) is 3-carboxy-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoindole-7-yl.

7. The compound according to claim 1, its salt or hydrates, where Q in formula (I) is 3-carboxy-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-deformedarse-1,4-dihydro-4-oxoindole-7-yl.

8. The compound according to claim 1, its salt or hydrates, where Q in formula (I) is 3-carboxy-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-deformedarse-1,4-dihydro-4-oxoindole-7-yl.

9. The compound according to claim 1, its salt or hydrates, where Q in formula (I) is 3-carboxy-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-what ihydro-4-oxoindole-7-yl.

10. The compound according to claim 1, its salt or hydrates, where Q in formula (I) is 5-amino-3-carboxy-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoindole-7-yl.

11. The compound according to claim 1, its salt or hydrates, where Q in formula (I) is 5-amino-3-carboxy-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoindole-7-yl.

12. The compound according to claim 1, its salt or hydrates, where Q in formula (I) is 5-amino-3-carboxy-6,8-debtor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-7-yl.

13. The connection according to one of items 1 to 12, its salts or hydrates, where R1in the formula (I) represents aryl having 6 to 10 carbon atoms which may be substituted with halogen or alkoxyl having from 1 to 6 carbon atoms.

14. The connection 13, its salts or hydrates, where R1in the formula (I) represents aryl having 6 to 10 carbon atoms which may have a Deputy, and his aryl group is phenyl or naphthyl.

15. The connection according to one of items 1 to 12, its salts or hydrates, where R1in the formula (I) represents heteroaryl.

16. The connection 15, its salts or hydrates, where R1in the formula (I) represents heteroaryl, which may have a Deputy, and his heteroaryl group represents furyl, thiazolyl or pyridyl.

17. The connection according to one of items 1 to 16, its salts or hydrates, where the connection is their formula (I) represents the stereochemical net connection.

18. Connection to items 1, 13, 14, 15 or 16, its salts or hydrates, where R9is cyclopropyl having a halogen atom as a substituent.

19. Connection p, its salts or hydrates, in which cyclopropyl having a halogen atom as a substituent, represents a 1,2-CIS-halogenlampen.

20. The connection according to claim 19, its salts or hydrates, in which cyclopropyl having a halogen atom as a substituent, is pure stereochemical Deputy.

21. Connection claim 20, its salts or hydrates, in which cyclopropyl having a halogen atom as a substituent, is (1R,2S)-2-halogenlampen.

22. Connection item 21, its salts or hydrates, in which the halogen atom of cyclopropyl having a halogen atom as a substituent is a fluorine atom.

23. Therapeutic agent for the treatment of bacterial infectious diseases, which contains a compound according to one of claims 1 to 22, its salts or hydrates as an active ingredient and pharmaceutical ingredients.

24. A method of obtaining a therapeutic agent for the treatment of bacterial infectious diseases, including the introduction of its connection to one of claims 1 to 22, its salts or hydrates as an active ingredient and pharmaceutical ingredients.



 

Same patents:

The invention relates to new chemical compounds, namely new condensed heterocyclic systems - 2-3-dihydropyrido[1,2,3-de]-1,4-benzoxazine (1)

The invention relates to new, containing in the 3-position of the indole ring is substituted piperazinylcarbonyl the rest of 1.7-bellrowan derivatives of indole and their salts, to the way they are received, as well as containing these compounds, pharmaceutical compositions and the intermediate product to obtain these compounds

The invention relates to antimicrobial compound used as a drug for humans and animals, and fish

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine of the formula (I): , wherein X represents 1) group of the formula (1): , wherein S1 means hydrogen, halogen atom; S2 and S3 mean independently of one another hydrogen atom, (C1-C6)-alkyl, phenyl or benzyl; S4 means two hydrogen atoms, oxo-group; S5 means hydrogen atom (H), (C1-C4)-alkyl; Y means CH2, oxygen atom (O), sulfur atom (S); or 2) group of the formula (2): , wherein S1 has above given values; R means hydrogen atom (H), (C1-C4)-alkyl, (C2-C6)-alkoxyalkyl, (C2-C4)-alkenyl or (C2-C4)-alkynyl; or 3) group of the formula (3): wherein S1 has above given values; Z means CH2, oxygen atom (O), nitrogen atom (N); or 4) group of the formula (4): , wherein S1 has above given values; or 5) group of the formula (5): , wherein S1 has above given values; A means oxygen atom (O), nitrogen atom (N) linked with piperazine ring at position 5 or 8; or 6) group of the formula (6): , wherein S1 has above given values; S6 and S7 mean hydrogen atom or oxo-group; or 7) group of the formula (7): , wherein one of dotted line can represent a double bond; S1 has above given values; P = T = Q mean nitrogen atom or P = T mean nitrogen atom; Q means CH or CH2; or P = Q mean nitrogen atom; T means CH, CH2, CH-CH3, C-CH3; or P means nitrogen atom; T means CH, CH2; Q represents sulfur atom; m = 2-6; n = 0-2; R5 and R6 mean independently of one another hydrogen atom (H), (C1-C3)-alkyl; or R5 + R6 represent group -(CH2)p- wherein p = 3-5; R7 means (C1-C3)-alkyl, (C1-C3)-alkoxy-, halogen atom, cyano-group; or R6 + R7 (R7 at position 7 of indole ring) mean group -(CH2)q wherein q = 2-4, and their salts. Compound of the formula (I) elicit high affinity both to dopamine D2-receptor and to serotonin reuptake site that allows their applying in treatment of the central nervous system diseases.

EFFECT: valuable medicinal properties of compounds.

5 cl, 3 tbl, 4 sch, 8 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of dihydropyrimidine of the general formula (I):

or its isomeric form of the formula (Ia):

that can be used, for example, for treatment and prophylaxis of hepatitis B. In indicated formulas R1 means unsubstituted phenyl or phenyl substituted once or many times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, nitro-, amino-group, hydroxyl and alkyl with 1-6 carbon atoms, or residues of formulas:

, or ; R2 means residue of the formula -XR5 wherein X means a bond or oxygen atom; R5 means alkenyl with 2-4 carbon atoms or alkyl with 1-4 carbon atoms that can be unsubstituted or substituted with phenoxy-group; R3 means amino-group, alkyl with 1-4 carbon atoms or cyclopropyl; R4 means pyridyl that is substituted with up to three times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, alkoxy-group with 1-6 carbon atoms and alkyl with 1-6 carbon atoms, and their salts. Also, invention relates to 3,5-difluoro-2-pyridincarboxyimidamide and 3,5-difluoro-2-pyridincarbonitrile that can be sued as intermediates products for preparing compounds of the formula (I) or (Ia) and to a medicinal gent.

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

10 cl, 2 sch, 4 tbl, 9 ex

The invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the formula

or their pharmaceutically acceptable salts, where R1represents H, COCOR2, COOR3or SO2R3, R2is1-6alkyl, C1-6alkenyl,5-7cycloalkyl, 2-thienyl, 3-thienyl, phenyl or substituted phenyl, R3is phenylalkyl,represents a saturated five-membered nitrogen-containing heterocyclic ring with one nitrogen atom or benzododecinium saturated six-membered nitrogen-containing heterocyclic ring;is oxazol, oxadiazole or thiazole, And is associated with carbon atom of the five-membered heteroaromatic rings and represents COO(CH2)mAr,where R1has the values listed above or is CONR4(CH2)mAr or (CH2)mO(CH2)nAr and R1cannot be COCOR2or SO2R3, R4represents H or<

The invention relates to new N-heterocyclic derivatives of the formula (I):

where: A means-OR1-C(O)N(R1R2or-N(R1R21; each X, Y and Z independently represents N or C(R19); each U represents N or C(R5), provided that U is N only when X represents N, and Z and Y denote CR19; each W represents N or CH; V denotes: (1) N(R4); (2) C(R4)H; or (3) the groupdirectly related to the group -(C(R14R20)n-A,denotes a 5-6-membered N-heterocyclyl, optionally containing 6-membered ring additional heteroatom selected from oxygen, sulfur and NR6where R6denotes hydrogen, optionally substituted phenyl, 6-membered heterocyclyl containing 1-2 nitrogen atom, optionally substituted 5-membered heterocyclyl containing 1-2 nitrogen atom, aminosulfonyl, monoalkylammonium, dialkylaminoalkyl,1-6alkoxycarbonyl, acetyl, etc

The invention relates to organic chemistry, in particular, optionally N-oxidized compounds represented by the formula:

in which R1represents a hydrogen atom, a C1-6alkyl group, phenyl group, optionally substituted by a halogen atom, a C1-6alkylthio or C1-6alkylsulfonyl, or amino group, optionally substituted (i) C1-6alkyl group, or (ii) acyl group(C=O)-R5where R5represents C1-6alkyl group, phenyl or pyridyl; R2is6-14aryl group, optionally substituted by a halogen atom or C1-6alkoxy, or 5 - or 6-membered aromatic heterocyclic group containing one sulfur atom or one nitrogen atom; R3represents a phenyl group, optionally substituted by one or two C1-6alkyl groups or C1-6alkoxy; X represents a sulfur atom; Y represents O, S, SO2or NR4where R4represents a hydrogen atom or a C1-6alkyl group; and Z represents a bond, C1-6alkylenes group, optional zameshannuu oxo or C1-6alkyl group

The invention relates to new nitrogen-containing aromatic 6-membered cyclic compounds of the formula (I) or their pharmaceutically acceptable salts, demonstrating excellent selective PDE V inhibitory activity

The invention relates to the field of chemistry, particularly the proton pump inhibitors

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to substituted 3-oxo-1,2,3,4-tetrahydroxinoxalines of general formula 1 , wherein R1 represents substituted sulfanyl or substituted sulfonyl group, containing as substituent optionally substituted C1-C4-alkyl, optionally substituted C3-C8-cycloalkyl, aryl-(C1-C4)alkyl optionally substituted in aril or alkyl group, heterocyclyl-(C1-C4)alkyl optionally substituted in heterocycle or alkyl group; R2 and R3 independently represent hydrogen, halogen, CN, NO2, optionally substituted hydroxyl, optionally substituted amino group, optionally substituted carboxylic group, optionally substituted carbamoyl group, optionally substituted arylcarbonyl group or optionally substituted heterocyclylcarbonyl group; R4 and R5 independently represent hydrogen or inert substituent. Claimed compounds are high effective kaspase-3 inhibitors and are useful in production of pharmaceutical compositions for treatment of diseases associated with excess apoptosis activation, as well as for experimental investigations of apoptosis in vivo and in vitro. Also disclosed are pharmaceutical composition in form of tablets, capsules or injections in pharmaceutically acceptable package, as well as method for production thereof and therapy method.

EFFECT: pharmaceutical composition for apoptosis treatment and investigation.

6 cl, 3 dwg, 8 ex, 1 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-aminopyridine derivatives of formula I , wherein R1 is cyano, carboxyl or carbamoyl; R2 is hydrogen, hydroxyl, C1-C6-alkoxy or phenyl; R3 and R4 are aromatic hydrocarbon such as phenyl or naphthyl, 5-14-membered 5-14-membered optionally substituted aromatic group, excepted cases, when (1) R1 is cyano, R2 is hydrogen, and R3 and R4 are simultaneously phenyl;(2) R1 is cyano, R2 is hydrogen, R3 is 4-pyridyl, and R4 is 1-pyridyl; (3) R1 is cyano, R2 is 4-methylphenyl, and R3 and R4 are simultaneously phenyl;(4) R1 is cyano, R2, R3 and R4 are simultaneously phenyl, or salts thereof. Derivatives of present invention have adenosine receptor antagonist activity and are useful in medicine for treatment of irritable bowel syndrome, constipation, and defecation stimulation.

EFFECT: 2-aminopyridine derivatives as adenosine receptor antagonists useful in medicine.

34 cl, 2 tbl, 179 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine of the formula (I): , wherein X represents 1) group of the formula (1): , wherein S1 means hydrogen, halogen atom; S2 and S3 mean independently of one another hydrogen atom, (C1-C6)-alkyl, phenyl or benzyl; S4 means two hydrogen atoms, oxo-group; S5 means hydrogen atom (H), (C1-C4)-alkyl; Y means CH2, oxygen atom (O), sulfur atom (S); or 2) group of the formula (2): , wherein S1 has above given values; R means hydrogen atom (H), (C1-C4)-alkyl, (C2-C6)-alkoxyalkyl, (C2-C4)-alkenyl or (C2-C4)-alkynyl; or 3) group of the formula (3): wherein S1 has above given values; Z means CH2, oxygen atom (O), nitrogen atom (N); or 4) group of the formula (4): , wherein S1 has above given values; or 5) group of the formula (5): , wherein S1 has above given values; A means oxygen atom (O), nitrogen atom (N) linked with piperazine ring at position 5 or 8; or 6) group of the formula (6): , wherein S1 has above given values; S6 and S7 mean hydrogen atom or oxo-group; or 7) group of the formula (7): , wherein one of dotted line can represent a double bond; S1 has above given values; P = T = Q mean nitrogen atom or P = T mean nitrogen atom; Q means CH or CH2; or P = Q mean nitrogen atom; T means CH, CH2, CH-CH3, C-CH3; or P means nitrogen atom; T means CH, CH2; Q represents sulfur atom; m = 2-6; n = 0-2; R5 and R6 mean independently of one another hydrogen atom (H), (C1-C3)-alkyl; or R5 + R6 represent group -(CH2)p- wherein p = 3-5; R7 means (C1-C3)-alkyl, (C1-C3)-alkoxy-, halogen atom, cyano-group; or R6 + R7 (R7 at position 7 of indole ring) mean group -(CH2)q wherein q = 2-4, and their salts. Compound of the formula (I) elicit high affinity both to dopamine D2-receptor and to serotonin reuptake site that allows their applying in treatment of the central nervous system diseases.

EFFECT: valuable medicinal properties of compounds.

5 cl, 3 tbl, 4 sch, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indolylpiperidine of the formula (I): wherein A1 means (C1-C7)-alkylene, (C1-C7)-alkyleneoxy-, (C1-C7)-alkylenethio-, (C1-C7)-alkanoyl, hydroxy-(C1-C7)-alkylene; A2 means a single bond, (C1-C7)-alkylene, (C2-C5)-alkenylene; W means a single bond, phenylene, furanylene that is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkoxy- and/or alkyl groups; R1 means hydrogen atom (H), (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C2-C5)-alkoxyalkyl, (C3-C7)-alkenyloxyalkyl, (C3-C7)-alkynyloxyalkyl, (C3-C7)-alkoxyalkoxyalkyl, phenyl-(C1-C7)-alkyl wherein phenyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy- or arylalkoxy- (preferably with phenylalkoxy-) groups, or means (C3-C10)-cycloalkyl-(C1-C7)-alkyl wherein cycloalkyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy-groups; R2 means hydrogen atom (H), halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-; R3 means carboxyl, tetrazolyl, and to their pharmaceutically acceptable salts. Compounds of the formula (I) elicit antihistaminic and anti-allergic activity that allows their using in composition used for treatment of allergic diseases including bronchial asthma, rhinitis, conjunctivitis, dermatitis and nettle rash. Also, invention describes methods for preparing compounds of the formula (I).

EFFECT: valuable medicinal properties of compounds.

15 cl, 2 sch, 3 tbl, 162 ex

The invention relates to benzimidazole derivative of the formula (I)

or its pharmaceutically acceptable salt, where Rrepresents a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents a group of formula-CO2R2where R2is hydroxyalkyl, alkoxyalkyl or toolboxitem, Rrepresents a group of the formula

where o is 0 or 1, n is 0, 1 or 2, X represents N or CH, Y is O, NR11or CHR11where R11represents hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl, or acyl, or a group of the formula -(alkyl)p-CN, -(alkyl)p-aryl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)p"heterocycle", -(alkyl)p-CO2"heterocycle" or -(alkyl-CO2)s-(alkyl)t-COR5and , in these formulas, R, s and t independently of each other 0 or 1, "heterocycle" represents a 5 the n heteroatom, represents a nitrogen, oxygen or sulfur, and which may substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl and oxo, R5represents a hydroxy, alkoxy, hydroxy-C1-8-alkoxy, C1-8-alkoxyalkane, Tiltonsville, aryl, or aralkyl, or a group of the formula-NR6R7or-O-alkyl-NR6R7and , in these formulas, R6and R7independently of one another represent hydrogen or alkyl, and R14and R15independently of one another represent hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl or acyl; or where R' is a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents fornillo group; and Rrepresents -(alkyl)m-CO2R8where m is 0 or 1, R8represents a group of formula -(alkyl)p-NR9R10where R is 0 or 1, and R9and R10together with the nitrogen atom to which they are attached, form a piperazinilnom group, possibly substituted by acyl

The invention relates to new N-heterocyclic derivatives of the formula (I):

where: A means-OR1-C(O)N(R1R2or-N(R1R21; each X, Y and Z independently represents N or C(R19); each U represents N or C(R5), provided that U is N only when X represents N, and Z and Y denote CR19; each W represents N or CH; V denotes: (1) N(R4); (2) C(R4)H; or (3) the groupdirectly related to the group -(C(R14R20)n-A,denotes a 5-6-membered N-heterocyclyl, optionally containing 6-membered ring additional heteroatom selected from oxygen, sulfur and NR6where R6denotes hydrogen, optionally substituted phenyl, 6-membered heterocyclyl containing 1-2 nitrogen atom, optionally substituted 5-membered heterocyclyl containing 1-2 nitrogen atom, aminosulfonyl, monoalkylammonium, dialkylaminoalkyl,1-6alkoxycarbonyl, acetyl, etc

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