Cycloalkyl-substituted derivatives of aminomethylpyrrolidine and antibacterial agent based on thereof

FIELD: organic chemistry.

SUBSTANCE: invention relates to new antibacterial agents. Invention describes cycloalkyl-substituted derivatives of aminomethylpyrrolidine represented by the general formula (I): wherein each among R1 and R2 represents hydrogen atom; n represents a whole number from 1 to 4; Q represents structural moiety represented by the following formula (Ia): wherein R3 represents cyclic alkyl group comprising from 3 to 6 carbon atoms that can be substituted; R4 represents hydrogen atom; R5 represents hydrogen atom or amino-group; X1 represents halogen or hydrogen atom; A1 represents nitrogen atom or structural moiety represented by the formula (II): wherein X2 represents hydrogen, halogen atom or alkyl group comprising from 1 to 6 carbon atoms, or alkoxyl group comprising from 1 to 6 carbon atoms; X2 and R3 can form a ring structure in common with part of the parent skeleton optionally comprising oxygen, nitrogen or sulfur atom as a ring-forming atoms and optionally comprising alkyl group comprising from 1 to 6 carbon atoms as a substitute; Y represents hydrogen atom. Also, invention describes an antibacterial an agent containing compound by cl. 1. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable properties of compounds and agent.

15 cl, 1 tbl, 10 ex

 

The technical field

This invention relates to a synthetic quinolone antibacterial agent, useful as a drug for humans, animals, or fish, or as an antibacterial preservative.

This invention also relates to synthetic quinolone antibacterial agent, in which the structure of the substituent in the 7-position of 1,4-dihydro-4-okahirongo skeleton or 10-position of 2,3-dihydro-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazine skeleton plays an important role in the manifestation of pharmacological properties such as antibacterial activity, pharmacokinetics and safety with 3-[1-amino-1-cycloalkyl]methyl-pyrrolidin-1-ilen group, which can provide an excellent antibacterial activity, pharmacokinetics and safety as a substituent in the 7 - or 10-position, and also having excellent antibacterial activity, the desired pharmacokinetics and high security, namely the derivative of 6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid or a derivative of 2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazine-6-carboxylic acid and antibacterial agent and antibacterial agent, which contains the connection.

Background of the invention

Since opening but is floxacin (Norfloxacin) antibacterial activity and pharmacokinetics of synthetic quinolone antibacterial agents has been improved and currently in the clinical field as chemotherapeutic agents have been used for many compounds that are effective in almost systemic infectious diseases.

In recent years in the clinical field has increased the number of generations of bacteria with low sensitivity to synthetic quinolone antibacterial agents. For example, as in the case of Staphylococcus Staphylococcus aureus (MRSA) and pneumococcus (PRSP), which are insensitive to β -lactam antibiotics, and Enterococcus (VRE), which are not sensitive to aminoglycoside antibacterial agents has increased the number of cases in which gram-positive bacteria, initially resistant to drugs, different from synthetic quinolone antibacterial agents, purchase low sensitivity to synthetic quinolone antibacterial agents. Consequently, in the clinical field was necessary to develop medicines, additionally with high efficiency. On the other hand, it was found that synthetic quinolone antibacterial agents while using together with non-steroidal anti-inflammatory drugs have a side effect that causes convulsions and other side de is affected, such as phototoxicity, thus, in this area also needed a new synthetic quinolone antibacterial agent with advanced high security.

It is known that patterns of substituents in the 7-position and 1-position of great influence on antibacterial activity, pharmacokinetics and safety of synthetic quinolone antibacterial agents. It is already known that quinolone derivatives having as substituent 3-aminomethylpyrrolidine showed strong antibacterial activity against gram-negative and gram-positive bacteria. For example, a derivative of 7-(3-aminomethylpyrrolidine-1-yl)hinolincarbonova acid described in Journal of Medicinal Chemistry, vol.29, p.445 (1986)derived 7-[3-(1-amino-1-methylethyl)pyrrolidin-1-yl)hinolincarbonova acid described in Journal of Medicinal Chemistry, vol.37, p.733 (1994), and derivative of 7-[3-(1-aminoalkyl)pyrrolidin-1-yl]hinolincarbonova acid described in Chemical & Pharmaceutical Bulletin, vol.42, p.1442 (1994). However, compounds having 3-(1-amino-1-cycloalkyl)-methylpyridin-1-ilen group in 7-position is unknown and also belong to the present invention.

On the other hand, quinolone derivatives having as substituent 3-aminomethylpyrrolidine, are compounds exhibiting strong antibacterial active is th but since most of these compounds has a low selective toxicity, they are not only bacteria, but also at cell eukaryotes, making it difficult to use as medicines or medicines for animals.

It is also known that quinolone derivatives having derived 3-aminopyrrolidine in the 7-position and 2-(S)-fluoro-1-(R)-cyclopropyl group in 1-position of the quinoline skeleton, have weaker microkernel inducing toxicity than the corresponding derivatives of 1-cyclopropylidene. Their examples are described in Journal of Medicinal Chemistry, vol.37, p.3344 (1994).

On the other hand, derivatives hinolincarbonova acid with 3-[1-amino-1-cycloalkyl]methylpyrrolidine-1-ilen group as a substituent, which relate to the present invention, is illustrated, for example, in JP-W-3-502452 (the term “JP-W”as used in this description means “not passed the examination of published Japanese application for international patent”), and it describes the connection represented below by formula (a) or (b). However, the substituent in the 5-position data illustrative of quinolones is limited to linear, branched or cyclic lower alkyl having from 1 to 3 carbon atoms, and in JP-W-3-502452 not described compounds having 1-[2-(S)-fluoro-1-(R)-cyclopropyl]Hina the new skeleton or 3-(S)-methyl-7H-pyrido[1,2,3-de][1.4]benzoxazine skeleton, related to the present invention. In addition, in JP-W-3-502452 not disclosed illustrative examples of 3-[1-amino-1-cycloalkyl]methylpyrrolidine-1-ilen group. Formula (a)

[In the above formula, R7represents 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, NH2or HE, R8represents a linear, branched or cyclic lower alkyl having from 1 to 3 carbon atoms, and X3is CH, CF, CCl, CBr, N, CCF3, CNH2CNO2, CR or COR' (in these formulas, R represents lower alkyl, and R' represents hydrogen or lower alkyl). Definitions of the substituents of the compounds of formula (a) are independent of the definitions of the substituents of the compounds of the present invention].

In the above formula, Z is a group represented by the following formula (b).

Formula (b)

(In this formula, m represents an integer from 0 to 4, and the substituents R9and R10each independently represent a hydrogen atom, lower alkyl or cycloalkyl. Definitions of the substituents of the compounds of formula (b) independent from the definition of the substituents of the compounds of the present invention).

In addition, PCT application WO 96/39407 described compounds, represented by the following formula (C), but they are limited to derivatives of 2-pyridone, such as having 4H-4-oxopentanoic skeleton, and in PCT application WO 96/39407 not described compounds having 1,4-dihydro-4-oxopentanoic skeleton or 2,3-dihydro-3-(S)-ethyl-7-oxo-7H-pyrido[1,2,3-de] [1.4]benzoxazine skeleton related to the present invention. Also in PCT application WO 96/39407 not disclosed illustrative examples of the optically active 3-[1-amino-1-cyclopropyl]methylpyrrolidine-1-ilen group.

In addition, in PCT application WO 96/39407 no mention of security compounds of the formula (C).

Formula (C)

Description of the invention

Based on the above, the authors of the present invention conducted intensive studies with the aim to offer in the clinical field compound which has excellent antibacterial activity, high efficiency and excellent safety. As a result of intensive study, it was unexpectedly found that cycloalkylation derived aminomethylpyrrolidine represented by the formula (I)described below, its salts and hydrates may exhibit strong antibacterial activity against wide range of gram-negative and gram-positive bacteria, can demonstrate particularly strong antibacterial activity of Rotel resistant strains of gram-positive bacteria, including MRSA, PRSA and VRE, and also have excellent security and good pharmacokinetics, thus leading to the Commission of the present invention.

In particular, it was found that the compound represented by the following formula (I), in which cycloalkylation derived aminomethylpyrrolidine injected into the 7-position of 1-[2-(S)-fluoro-1-(R)-cyclopropyl]quinoline skeleton, its salts and hydrates show a wide and excellent antibacterial activity against any of the gram-negative and gram-positive bacteria, including strains that are resistant to medicines, has excellent security with sharply weakened micro-inducing activity and also has excellent pharmacokinetics.

Accordingly, the present invention relates to a compound represented by the following formula (I), its salts and hydrates:

where R1and R2each independently represents a hydrogen atom or alkyl group having from 1 to 6 carbon atoms, where the alkyl group may have one or more substituents selected from the group consisting of hydroxyl group, halogen atom, ancilliary having from 1 to 6 carbon atoms, and alkyloxy; n represents an integer from 1 to 4 and Q represents the structural part, presents the th following formula (Ia):

where R3represents an alkyl group having from 1 to 6 carbon atoms, alkenylphenol group having from 2 to 6 carbon atoms, halogenation group having from 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms, which may have a Deputy, aryl group which may have a Deputy, a heteroaryl group which may have a Deputy, CNS group having from 1 to 6 carbon atoms, or alkylamino having from 1 to 6 carbon atoms;

R4represents a hydrogen atom or allylthiourea having from 1 to 6 carbon atoms;

R4and above R3may form, together with part of the original skeletal ring structure, optionally containing a sulfur atom as forming a ring atom and optionally having an alkyl group containing from 1 to 6 carbon atoms as a substituent;

R5represents a hydrogen atom, amino group, hydroxyl group, Tilney group, halogenmethyl group, alkyl group having from 1 to 6 carbon atoms, alkenylphenol group having from 2 to 6 carbon atoms, alkylamino group having from 2 to 6 carbon atoms, or CNS group having from 1 to 6 carbon atoms, where the amino group may have one or several mandated the residents, selected from the group consisting of formyl group, an alkyl group having from 1 to 6 carbon atoms, and acyl groups having from 2 to 5 carbon atoms;

X1represents a halogen atom or a hydrogen atom,

And1represents a nitrogen atom or a structural unit represented by formula (II):

where X2represents a hydrogen atom, amino group, halogen atom, cyano, halogenmethyl group, halogenmethyl group, alkyl group having from 1 to 6 carbon atoms, alkenylphenol group having from 2 to 6 carbon atoms, alkylamino group having from 2 to 6 carbon atoms, or CNS group having from 1 to 6 carbon atoms, where the amino group may have one or more substituents selected from the group consisting of formyl group, an alkyl group having from 1 to 6 carbon atoms, and acyl groups having from 2 to 5 carbon atoms; and

X2and above R3may form, together with part of the original skeletal ring structure, optionally containing oxygen atom, nitrogen atom or sulfur atom as a forming ring atoms and optionally having an alkyl group containing from 1 to 6 carbon atoms as a substituent; and

Y represents a hydrogen atom, phenyl group, acetoxymethyl group is, pivaloyloxymethyl group, ethoxycarbonyl group, Kalinovo group, dimethylaminoethyl group, 5-indenolol group, phthalidyl group, 5-alkyl-2-oxo-1,3-dioxol-4-ylmethylene group, 3-acetoxy-2-oxobutyl group, alkyl group having from 1 to 6 carbon atoms, alkoxymethyl group having 2 to 7 carbon atoms, or phenylalkyl the group consisting of alkalinous group having from 1 to 6 carbon atoms, and phenyl groups.

The present invention also relates to each of the following items.

Connection, its salts and 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-strong group;

the above compound, its salts and hydrates, where

the compound of formula (I) is the stereochemical net connection;

the above compound, its salts and hydrates, where R3in the formula (I) is halogencontaining group;

the above compound, its salts and hydrates, where halogencyclopropanes group in the formula (I) is 1,2-CIS-halogencontaining group;

the above compound, its salts and hydrates, where halogencyclopropanes group in the formula (I) is pure stereochemical Deputy;

the above compound, its salts and hydrates, where halogencyclopropanes gr is the PAP in the formula (I) is (1R,2S)-2-halogencontaining group;

the above compound, its salts and hydrates, where the halogen atom in halogencontaining group in the formula (I) represents a fluorine atom;

the above compound, its salts and hydrates, where the compound of formula (I) is the stereochemical net connection;

the above compound, its salts and hydrates, where n in the formula (I) is equal to 1;

the above compound, its salts and hydrates, where the compound of formula (I) is the stereochemical net connection;

7-[3-[1-(S)-amino-1-cyclopropyl]methylpyrrolidine-1-yl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoindole-3-carboxylic acid, its salts and hydrates;

5-amino-7-[3-[1-(S)-amino-1-cyclopropyl]methylpyrrolidine-1-yl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoindole-3-carboxylic acid, its salts and hydrates;

5-amino-7-[3-[1-(S)-amino-1-cyclopropyl]methylpyrrolidine-1-yl]-6,8-debtor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid, its salts and hydrates;

the above compound, its salts and hydrates, where Y represents the hydrogen atom;

drug containing as an active ingredient the above-mentioned compound, its salts and hydrates and

antibacterial agent containing as an active ingredient the above-mentioned compound, its salts and hydrates.

Ways of carrying out the invention

Each is Deputy compounds of the present invention, represented by formula (I):

(where R1, R2, n and Q are such as defined above) will be explained next.

The substituents R1and R2each independently represent a hydrogen atom or alkyl group having from 1 to 6 carbon atoms, where the alkyl group can contain one or more substituents selected from the group consisting of hydroxyl group, halogen atom, ancilliary having from 1 to 6 carbon atoms, and alkyloxy.

The alkyl group may be either linear or branched group containing from 1 to 6 carbon atoms, and preferred examples include methyl, ethyl, normal, sawn and isopropyl group.

When the alkyl group contains as a substituent a hydroxyl group, an alkyl group may be either linear or branched and contains from 1 to 6 carbon atoms, and a hydroxyl group may preferably be a Deputy at the end of the carbon atom alkyl groups. Preferred examples of the alkyl group containing a hydroxyl group include those which have from 1 to 3 carbon atoms, such as, for example, hydroxymethylene group, 2-hydroxyethylene group, 2-hydroxiproline group and 3-hydroxiproline group.

When the alkyl group contains the as Deputy halogen atom, the alkyl group may be either linear or branched and contains from 1 to 6 carbon atoms, and a fluorine atom is a desirable halogen atom. In terms of the number of fluorine atoms, this may be from a single atom in the case of monotomidae to perversione. Examples include monitoramento, deformational, triptorelin, 2-foretelling, 2,2-defloration and 2,2,2-triptorelin group. Among such groups mooftormetilnoy group and 2-florachilena group are more preferred.

When the alkyl group has as Deputy allylthiourea, the alkyl group may be either linear or branched and contains from 1 to 6 carbon atoms, and allylthiourea can also be either linear or branched and contains from 1 to 6 carbon atoms. Alkylthiomethyl group, alkylthiomethyl group and alkylthiophene group is desirable as the alkyl group having allylthiourea, and allylthiourea preferably may contain from 1 to 3 carbon atoms. More preferred examples are methylthiomethyl group, ethylthiomethyl group and methylthioethyl group.

When the alkyl group has as Deputy CNS group, the alkyl group may be either linear or branched what Ruppel, containing from 1 to 6 carbon atoms, and CNS group may be either linear or branched and contains from 1 to 6 carbon atoms. As alkyl groups having CNS group, are desirable alkoxymethyl group, alkoxyethyl group and alkoxyphenyl group and CNS group preferably can contain up to 3 carbon atoms. Preferred examples of such groups are methoxymethyl group, ethoxymethylene group and methoxyaniline group.

The symbol n represents an integer from 1 to 4, preferably 1 or 2 and more preferably 1.

Q represents a structural unit represented by the following formula (Ia):

In the above formula (Ia) R3represents an alkyl group having from 1 to 6 carbon atoms, alkenylphenol group having from 2 to 6 carbon atoms, halogenation group having from 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms, which may have a Deputy, aryl group which may have a Deputy, a heteroaryl group which may have a Deputy, CNS group having from 1 to 6 carbon atoms, or alkylamino having from 1 to 6 carbon atoms.

In this case, the ethyl group is the OS is especially desirable as alkyl groups, having from 1 to 6 carbon atoms. As alkenylphenol group having from 2 to 6 carbon atoms, it is desirable vinyl group or 1-isopropylene group. As halogenoalkanes group having from 1 to 6 carbon atoms, it is desirable 2-florachilena group. Cyclopropyl group is particularly desirable as a cyclic alkyl group and a halogen atom, especially a fluorine atom is preferable as the substituent of the cyclic alkyl group.

Examples of the aryl group which may have a Deputy, is a phenyl group which may have 1 to 3 substituents selected from the group including, for example, fluorine, chlorine, bromine or similar halogen atom, hydroxyl group, amino group, the nitro-group, alkyl group having from 1 to 6 carbon atoms, and CNS group having from 1 to 6 carbon atoms, and preferred illustrative examples are phenyl group, 2-Fortunella group, 4-Fortunella group, 2,4-diferencia group, 2-fluoro-4-hydroxyproline group, 3-amino-4,6-diferencia group and 4.6-debtor-3-methylenedianiline group.

Heteroaryl group is a compound derived from a five - or six-membered aromatic heterocyclic compound that contains one or more of Goethe is oetomo, selected from nitrogen atom, oxygen atom and sulfur atom. Examples are Peregrina group and piramidalnaya group. As Deputy data rings are desirable alkyl group, halogen atom and the like. Particularly preferred is 5-amino-2,4-diferencijalna group.

As CNS group having from 1 to 6 carbon atoms, it is desirable metaxalona group. As alkylamino having from 1 to 6 carbon atoms, it is desirable methylaminopropyl.

As Deputy R3it is desirable cyclic alkyl group or halogennitroalkane group. Among these groups are particularly desirable cyclopropyl group or 2-halogencyclopropanes group. As the halogen atom, the desired fluorine atom.

Deputy R4represents a hydrogen atom or allylthiourea containing from 1 to 6 carbon atoms, or R3and R4may together form a ring structure through the introduction of the source skeleton (namely, by introducing the nitrogen atom is linked to R3and the carbon atom is linked to R4). Thus formed ring may contain as a constituent of its atom, a sulfur atom, and the ring may optionally contain an alkyl group having from 1 to 6 atoms in the of Lerida, as Deputy. The size of the educated in such a case, the ring can be from four-membered ring to a six-membered ring and the ring may be saturated or unsaturated.

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

Deputy R5represents a hydrogen atom, amino group, hydroxyl group, Tilney group, halogenmethyl group, alkyl group having from 1 to 6 carbon atoms, alkenylphenol group having from 2 to 6 carbon atoms, alkylamino group having from 2 to 6 carbon atoms, or CNS group having from 1 to 6 carbon atoms, where the amino group may have one or two substituent selected from the group consisting of formyl group, an alkyl group having from 1 to 6 carbon atoms, and acyl groups having from 2 to 6 carbon atoms.

An alkyl group can represent either a linear or branched group containing from 1 to 6 carbon atoms, and preferred examples are methyl group, ethyl group, normal through the group and isopropyl group. Alchemilla group can represent either a linear or branched group containing the Yu from 2 to 6 carbon atoms, and is preferably vinyl group. Alchemilla group can represent either a linear or branched group containing from 2 to 6 carbon atoms, and preferably represents etinilnoy group. The fluorine atom is particularly desirable as a halogen in halogenmethyl group, and the number of such atoms can be from 1 to 3. CNS group may contain from 1 to 6 carbon atoms, and preferably represents metaxylene group.

Deputy R5preferably represents a hydrogen atom, alkyl group, or amino group, among which methyl group or an unsubstituted amino group are more preferable.

When the substituent R5represents an amino group, a hydroxyl group or Tilney group, these groups may be protected by commonly used protective groups.

Examples of such protective groups include tert-butoxycarbonyl, 2,2,2-trichlorocarbanilide and the like alkoxycarbonyl group, benzyloxycarbonyloxy, para-methoxybenzylideneamino, para-nitrobenzisoxazole and the like aracelikarsaalyna group, acetyl, methoxyacetyl, trifluoracetyl, chloroacetyl, pivaloyl, formyl, benzoyloxy and the like acyl group, tert-boutelou, benzyl, p is RA-nitrobenzyloxy, pair-methoxybenzyloxy, triphenylmethyl and the like alkyl or kalkilya group, methoxymethyl, tert-butoxymethyl, tetrahydropyranyl, 2,2,2-trichloroacetyl and the like ether group and trimethylsilyloxy, isopropylideneglycerol, tert-butyldimethylsilyloxy, tribenzylamine, tert-butyldiphenylsilyl and the like substituted silyl group. Compounds, the substituents of which are protected by protective groups, are particularly useful as intermediates receipt.

When And1is a partial structure represented by formula (II):

X2represents a hydrogen atom, amino group, halogen atom, cyano, halogenmethyl group, halogenmethyl group, alkyl group having from 1 to 6 carbon atoms, alkenylphenol group having from 2 to 6 carbon atoms, alkylamino group having from 2 to 6 carbon atoms, or CNS group having from 1 to 6 carbon atoms, where the amino group may have one or two substituent selected from the group comprising formyl group, an alkyl group having from 1 to 6 carbon atoms, and acyl group having from 2 to 5 atoms of carbon.

An alkyl group can represent either a linear or branched group containing up to 6 carbon atoms, and its preferred examples are methyl group, ethyl group, normal through the group and isopropyl group. Alchemilla group may be either linear or branched group containing from 2 to 6 carbon atoms, and preferably represents a vinyl group. Alchemilla group can represent either a linear or branched group containing from 2 to 6 carbon atoms, and preferably represents etinilnoy group. The fluorine atom is particularly desirable as a halogen in halogenmethyl group, and the number of such atoms can be from 1 to 3. CNS group may contain from 1 to 6 carbon atoms, and preferably represents metaxylene group. The fluorine atom is particularly desirable as a halogen in halogenosilanes group, and the number of such atoms can be from 1 to 3.

Among these substituents are desired halogen atom, an alkyl group or CNS group, and a fluorine atom, a methyl group or metaxylene group is the most desirable. These substituents is particularly desirable in the case where Q represents a structural unit represented by formula (Ia).

In addition, X2and above R3may together form a hydrocarbon ring structure (ring size can be from chetyrekh the military ring to semichasnoho ring, and the ring may be saturated or unsaturated) due to the inclusion of the source skeleton (namely, due to the inclusion of the carbon atom is linked to X2and the nitrogen atom is linked to R3), and the thus formed ring may contain oxygen atom, nitrogen atom or sulfur atom as a constituent atoms, and the ring may have as a substituent alkyl group having from 1 to 6 carbon atoms.

The structural part represented by the above formula (Ia), desirable as Q. In this case, it is desirable that A1represented a structural unit represented by formula (II).

When Q represents a structural unit of the formula (Ia) and1is the structural portion of formula (II), a preferred combination of R5and X2is the case where R5represents an amino group, a hydrogen atom, hydroxyl group or alkyl group having from 1 to 6 carbon atoms, and X2represents a halogen atom, an alkyl group having from 1 to 6 carbon atoms, CNS group having from 1 to 6 carbon atoms, halogenmethyl group or a hydrogen atom.

The preferred combination is the case where R5represents an amino group, a hydrogen atom, a hydroxyl group or methyl group, and X2is ATO is fluorine, methyl group, metaxylene group, diplomatically group or a hydrogen atom.

The most preferred combination is the case where R5represents an amino group, a hydrogen atom, a hydroxyl group or methyl group, and X2represents a fluorine atom, methyl group or metaxylene group. For these groups, R5and X2as X1desirable is a fluorine atom.

When the substituents X1and X2are halogen atoms, X1especially preferably represents a fluorine atom, and X2preferably represents a fluorine atom or a chlorine atom.

Next will be explained in relation to halogencontaining group, R3.

As a replacement of the halogen atom can be presented as an example of a fluorine atom and a chlorine atom, among which fluorine atom is particularly preferred.

As for the steric environment of this fragment, particularly preferably a halogen atom and fragment pyridonecarboxylic acid in tsiklopropanovom ring had a CIS-configuration.

The so-called enantiomorphic isomers exist due only CIS-2-halogencyclopropanes fragment R3and significant antibacterial activity and high safety were found for both isomers.

The real connection is th invention shows excellent characteristics due to the presence of the Deputy, represented by the following formula, 10-position of the skeleton 2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazine-6-carboxylic acid or 7-position of the skeleton 6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid:

This Deputy exist in the following four optically isomeric forms due to the asymmetric carbon atom at the 3-position pyrolidine ring and the asymmetric carbon atom at the 1-position cycloalkylation aminomethyl substituent:

Among them the authors of the present invention consider the structure of the following formula as a more desirable:

That is, it was found that when the 10-position of the skeleton 2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazine-6-carboxylic acid or 7-position of the skeleton 6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid is Deputy represented by the above formula, the compound of the present invention exhibits strong antibacterial activity in against gram-negative bacteria and gram-positive bacteria and also has excellent security and good pharmacokinetics, as, for example, negative micro-kernel test (very with the Abaya microkernel inducing toxicity), what was not expected until the present invention.

When the compound of formula (I) of the present invention has a structure allowing the existence of diastereomers, when administered to humans or animals, it is desirable to enter the compound containing pure diastereoisomer. The term “containing pure diastereoisomer,” as it is used herein, means not only the case in which compound does not contain the other diastereoisomer(s), but also a case where it is chemically pure. In other words, it is interpreted as that the other diastereoisomer(s) may be present to such an extent that it does not affect the physical constants and physiological activity of the connection.

Also, the term “stereochemical pure”as used herein, means a compound that represents one of its stereoisomers, when the connection has many isomers due contained in the asymmetric carbon atom. The term “pure” in this case can also be viewed the same way as described above.

The compound of the present invention can be used either in free form or in the form of an acid additive salt, or a salt of carboxylic group. Examples of the acid additive salts include hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, phosphate podobnie salts of inorganic acids or methanesulfonate, bansilalpet, toluensulfonate (sulfonate), acetate, citrate, maleate, fumarate, lactate (carboxylate) and similar salts of organic acids.

Salt carboxyl group can represent either inorganic or organic salt, and illustrative examples include lithium salt, sodium salt, potassium salt and the like alkali metal salts, salt, magnesium salt and calcium salt such alkaline earth metal salt or ammonium salt, triethylamine salt, N-methylglucamine salt of Tris(hydroxymethyl)aminomethane and the like.

Also, this free form, an acid additive salt and salt at the carboxyl group of this compound can exist in the form of hydrates.

When the compound of the present invention is used in antibacterial purposes, it is desirable to use the compound carboxylic acid, in which the group Y represents hydrogen atom, while the quinolone derivative, in which a fragment of the carboxylic acid is a complex ester, useful as an intermediate of synthesis, or procarcinogen funds. For example, alkalemia esters, benzyl esters, alkoxyalkyl esters, phenylalkylamine esters and phenyl esters are used as intermediate products of the synthesis.

Also ester for use as prosecuting the funds is an ester, capable of cleavage in vivo with the formation of free carboxylic acids, illustrative examples of ester include acetoxymethyl ester, pivaloyloxymethyl ester, ethoxycarbonyl ester, kalinovy ester, dimethylaminoethyl ester, 5-indaily ester, caliginosus ester, 5-alkyl-2-oxo-1,3-dioxol-4-ymetray ester and oxoalkyl ester, such as 3-acetoxy-2-oxobutyl ester.

The compound of the present invention represented by the formula (I)can be obtained in a variety of ways and in a preferred example of such methods, it can be obtained, for example, by the interaction of the compounds represented by formula (III):

where X3represented by the Deputy, which functions as a leaving group such as fluorine atom, chlorine atom, bromine atom, substituted or unsubstituted phenylsulfonyl group or a substituted or unsubstituted alkylsulfonyl group having from 1 to 3 carbon atoms,

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

-B(Y11)Y12(IV)

where each of the Y11and Y12represents a fluorine atom or alkylcarboxylic having from 2 to 4 atoms in the of Lerida, a R3, R4, R5And1and X1defined as indicated for formula (I),

with the compound represented by formula (V):

where R11and R21each independently represents a hydrogen atom, alkyl group having from 1 to 6 carbon atoms, or a protective group of amino group, where the alkyl group may have a Deputy selected from the group consisting of hydroxyl group, halogen atom, ancilliary having from 1 to 6 carbon atoms, and CNS group having from 1 to 6 carbon atoms, and n is as defined for formula (I)] or its acid salt additive (examples of the acid additive salts include hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide phosphate and the like salts of inorganic acids or methanesulfonate, bansilalpet, toluensulfonate (sulfonate), acetate, citrate, maleate, fumarate, lactate (carboxylate) and similar salts of organic acids.

The reaction can be performed with or without using a solvent. The solvent for use in the reaction may be any solvent which is inert to the reaction conditions, and its illustrative examples include dimethyl sulfoxide, pyridine, acetonitrile, ethanol, chloroform, dimethylformamide, dimethylacetamide, N-Meile religon, tetrahydrofuran, water and 3-methoxybutanol or their mixture.

Preferably the reaction may be carried out in the presence of an acid acceptor, such as an inorganic base (for example, carbonate or bicarbonate of an alkali metal or alkaline earth metal or an organic base (e.g. triethylamine, pyridine, 1,8-diazabicyclo).

The reaction can be conducted at a temperature from room temperature to 200° C, preferably from 25 to 150° C. the Reaction is carried out for from 30 minutes to 48 hours, and it usually ends after about 30 minutes to 2 hours.

When a protected amino group, examples of protective groups for amino group include those usually used in this field, such as tert-butoxycarbonyl, 2,2,2-trichlorocarbanilide and the like alkoxycarbonyl group, benzyloxycarbonyl, para-methoxybenzylideneamino, para-nitrobenzisoxazole and the like aracelikarsaalyna group, acetyl, methoxyacetyl, trifluoracetyl, chlorocichla, bialoleka, formyl, benzoline and the like acyl group, tert-bucilina, benzyl, para-nitrobenzyl, para-methoxybenzyl, triphenylmethyl and the like alkyl or kalkilya group, methoxymethyl, tert-butoxymethyl, tetrahydropyranyl is, 2,2,2-trichloroethylene and the like ether group and trimethylsilyl, isopropylideneuridine, tert-butyldimethylsilyl, tribenzylamine, tert-butyldiphenylsilyl and the like substituted silyl group.

When Y and Y1represent an alkyl group having from 1 to 6 carbon atoms, alkoxymethyl group having 2 to 7 carbon atoms, or phenylalkyl the group consisting of alkalinous group having from 1 to 6 carbon atoms, and phenyl groups of interest, the compound can be converted into the corresponding compound of carboxylic acid by treatment in acidic or basic conditions, which are normally used for hydrolysis of esters of carboxylic acids.

When Y1represents a structure of formula (IV), its conversion to the corresponding connection carboxylic acid can be performed, giving the compound (III) opportunity to interact with compound (V), and then processing it in acidic or basic conditions.

In addition, when you unprotect interest compound represented by formula (I)can be obtained by removing the protective group suitable conditions for this protective group.

The compound of formula (V) may be obtained in various ways, and, although this is not specifically ogran is ensured, as a preferred example, it can be synthesized by the method shown in the reference examples, where the synthesis of 3-[1-(S)-amino-1-cycloalkyl]methylpyrrolidine described as synthetic example 3-[1-amino-1-cycloalkyl]methylpyrrolidine, so that the compound of formula (V) can be obtained in accordance with this method using a known optically active cycloalkylation derivative of glycine.

CIS-2-ferricopiapite containing pure isomer, which is desirable for the synthesis of compounds of formula (I)containing pure isomer can be synthesized, for example, a method described in JP-A-2-231475 (the term “JP-A”as used herein, means “not passed the examination published a patent application in Japan”). The synthesis of compounds of formula (I)containing pure isomer can be carried out using as the substance thus obtained optically active derivative of CIS-2-versicolorin in accordance with the method described, for example, in JP-A-2-231475.

The following can be cited as illustrative examples of the compounds of the present invention.

10-[3-(R)-[1-(S)-Amino-1-cyclopropyl]methylpyrrolidine-1-yl]-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazine-6-carboxylic acid;

8-amino-10-[3-(R)-[1-(S)-AMI is about-1-cyclopropyl]methylpyrrolidine-1-yl]-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazine-6-carboxylic acid;

7-[3-(R)-[1-(S)-amino-1-cyclopropyl]methylpyrrolidine-1-yl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoindole-3-carboxylic acid;

5-amino-7-[3-(R)-[1-(S)-amino-1-cyclopropyl]methylpyrrolidine-1-yl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoindole-3-carboxylic acid;

7-[3-(R)-[1-(S)-amino-1-cyclopropyl]methylpyrrolidine-1-yl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoindole-3-carboxylic acid;

5-amino-7-[3-(R)-[1-(S)-amino-1-cyclopropyl]methylpyrrolidine-1-yl]-6,8-debtor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid and

5-amino-7-[3-(R)-[1-(S)-cyclopropyl-1-N-methylamino]methylpyrrolidine-1-yl]-6,8-debtor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid.

These compounds have the following structure

Since the compound of the present invention has a strong antibacterial effect, it can be used as drugs for use for people, animals and fish, or as preservatives, agricultural chemicals and food.

When the compound of the present invention is used as a drug for humans, its dose is in the range of 50 mg to 1 g, preferably from 100 mg to 300 mg per day for adult what about the person.

Dose of a drug for use in animals varies depending on the purpose of the introduction (treatment or prevention), the type and size of each animal being treated, and the type and degree of infection of each infective pathogenic bacteria, but the dose can usually be in the range from 1 mg to 200 mg, preferably 5 mg to 100 mg, per 1 kg of body weight per day.

Daily dose can be used once a day or divided it into 2-4 doses per day. If necessary, the daily dose may exceed the above range.

Because the connection of the present invention are active against a wide range of microorganisms causing various infectious diseases, it is effective for treatment, prevention or relief of diseases caused by these pathogens.

Illustrative examples of bacteria and bacteriogenic microorganisms against which effective connection of the present invention include those belonging to the genus Staphylococcus, Streptococcus pyogens, hemolytic Streptococcus, Enterococcus, pneumococcus, belonging to the genus Peptostreptococcus, Neisseria gonorrhoeae, Escherichia coli belonging to the genus Citrobacter and Shigella, Klebsiella pneumoniae belonging to the genus Enterobacter, Serratia, and Proteus, Pseudomonas aeruginosa, Haemophilus influenzae, belonging to the genus Aclnetobacter, Campylobacter and Chlamydia trachomatis. Illustrative examples of diseases that you shall see these pathogens, include folliculitis, furuncle, carbuncle, a face, a phlegmon, lymphangitis/lymphadenitis, purulent inflammation of the finger pad, subcutaneous abscess, hydradenitis, follicular dermatitis, infectious atheroma, perirectal abscess, mastitis, superficial secondary infection after a wound, a burn wound, surgical wound, and the like, pharyngitis, acute bronchitis, tonsillitis, chronic bronchitis, bronchiectasis, diffuse capillary bronchitis, secondary infection of chronic respiratory disease, pneumonia, pyelonephritis, cystitis, prostatitis, epididymitis, gonococcal urethritis, non-specific urethritis, cholecystitis, cholangitis, bacillol dysentery, enteritis, inflammation of the uterus, intrauterine infection, inflammation of bartolinis cancer, blepharitis, hordeolum, dacryocystitis, TradeNet, ulcers of the cornea, the Central octet, sinusitis, periodontal disease, pericolonic, jaw infection, peritonitis, endocarditis, sepsis, meningitis, and skin infection.

The compound of the present invention is also effective against various microorganisms that cause infectious disease in animals, such as belonging to the genus Escherichia, Salmonella, Pasteurella, Haemophilus, Bordetella, Staphylococcus, and Mycoplasma. Illustrative examples of such diseases include colibacteriosis, disease Chicks, avian paratyphoid, bird cholera, acute infectious Rin is t, aureus, mycoplasmataceae and similar infections in birds; colibacteriosis, salmonellosis, pasteurellosis, Haemophilus infection, atrophic rhinitis, exudative epidermic, mycoplasmataceae infection and the like in the case of pigs; colibacteriosis, salmonellosis, hemorrhagic septicemia, mycoplasmataceae infection, bovine pleuropneumonia, bovine mastitis and the like in the case of cattle; alisasis, Salmonella infection, hemorrhagic sepsis, abscess of the uterus, cystitis and the like in the case of dogs and exudative pleurisy, cystitis, chronic rhinitis, Haemophilus infection, cat diarrhea, mycoplasmataceae infection and the like in the case of cats.

An antimicrobial agent which contains a compound of the present invention, can be obtained by selection of the appropriate treatment depending on each mode of introduction and use of commonly used different methods to obtain. As for the dosage forms of antibiotic in which the active agent is used, the compound of the present invention, examples of oral medicines can be tablets, powders, granules, capsules, solutions, syrups, elixirs, oily or aqueous suspensions, and the like.

As for the injections, the drug can be used stabil shiroudi agent, antiseptic agent and solubilizers agent or solution, which may contain auxiliary agents can be placed in a container in the form of a solid preparation, obtained by freeze drying or the like ways, and can be used to reverse the dissolution in the application. In addition, a single dose may be contained in a single container or multiple doses may be contained in the same container.

Can also be given as examples of drugs for external use solutions, suspensions, emulsions, ointments, gels, creams, lotions, sprays and the like.

Solid preparations may contain together with the active compound in pharmaceutically acceptable additives, and can be obtained for example by mixing the compounds with additives, optionally selected from fillers, dry diluents, binding agents, disintegrators, increasing the solubilization agents, wetting agents, lubricating agents and the like. As liquid preparations as an example can be given solutions, suspensions, emulsions and the like, which may contain suspendisse agent, emulsifying agent and the like as an auxiliary additives.

Examples of the method of administration of the compounds of the present invention to animals include the way in which the th administered orally directly or mixed with food, the way in which get the solution and then administered it orally directly or by mixing with water to drink or food, and the way in which the introduction is carried out by injection.

With regard to pharmaceutical preparations for use in introducing the compound of the present invention to animals, they are optional, can be obtained in the form of powders, fine powders, soluble powders, syrups, solutions or injections using commonly used in this field.

Examples of pharmaceutical compositions are listed below.

Example compositions 1 (Capsules):

Connection example of invention 2 100.0 mg

Corn starch 23,0 mg

Calcium carboxymethylcellulose 22,5 mg

Hydroxymethylcellulose 3.0 mg

Magnesium stearate 1.5 mg

Just 150,0 mg

Example composition 2 (Solutions):

Connection example of invention 2 1-10 g

Acetic acid or sodium hydroxide 0.5 to 2 g

Ethyl-parahydroxybenzoate 0.1 g

Purified water 88,9-98,4 g

Just 100 g

Example of composition 3 (Powders for mixing with food):

Connection example of invention 2 1-10 g

Corn starch 98,5-89,5 g

Clarified anhydrous silicic acid 0.5 g

Just 100 g

The best way of carrying out the invention

Examples of the present invention is described here as the ill is ation, and not as a constraint.

[Reference Example 1] 1-Cyclopropyl-2-propen-1-he

Cyclopropylmethyl (6,33 g, 75.2 mmol) was dissolved in anhydrous tetrahydrofuran (75 ml) in a stream of nitrogen. Under stirring and cooling with ice to the solution was added dropwise a solution, which was obtained by dissolving trifenatate N-methylaniline (25,0 g, 113 mmol) in 37%aqueous solution of formaldehyde (10,2 ml) under cooling with ice. After adding dropwise, the reaction solution was heated at the boil under reflux for 7 hours. After cooling, the reaction solution was mixed with diethyl ether (100 ml) and stirred, and then the organic layer was separated.

The aqueous layer was extracted with diethyl ether (50 ml). The organic layers were combined, gradually mixed with saturated aqueous sodium bicarbonate (100 ml) and stirred, and then the organic layer was separated. Separated thus the organic layer was washed saturated aqueous sodium chloride (100 ml). Layer was dried over anhydrous magnesium sulfate, filtered and then concentrated to 8.01 g under reduced pressure at 150 mm Od, thus obtaining a yellow oil containing specified in the header connection. This product was used in subsequent reactions without purification.

1H-NMR (400 MHz, CDCl3) δ : 0,90-to 0.96 (2H, m), 1,08 is 1.13 (2H, m), 2,4-of 2.25 (1H, m), of 5.82 (1H, DD, J=a 10.74, 1,47 Hz), of 6.29 (1H, DD, J=17,57, 1,47 Hz), 6,47 (1H, DD, J=17,57, a 10.74 Hz).

[Referential Example 2] Cyclopropyl[1-[1-(R)-phenylethyl]-pyrrolidin-3-yl]ketone

The product containing 1-cyclopropyl-2-propen-1-he described in reference example 1 (8,01 g) and N-(normal-butoxymethyl)-N-[1-(R)-phenylethyl]trimethylsilylmethylamine (23, 2 g, 79,9 mmol) was dissolved in anhydrous dichloroethane (350 ml)to which was subsequently added dropwise triperoxonane acid (500 μl). After 12 hours stirring at room temperature the reaction solution was washed with saturated aqueous sodium bicarbonate solution (100 ml) and saturated aqueous sodium chloride (100 ml) in this order. This solution was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel and was suirable a mixture of n-hexane:ethyl acetate=2:1, thus obtaining the remaining 9.08 g (49.6 per cent) indicated in the title compounds as colorless oils. In this regard, the product was obtained as a mixture of diastereoisomers in the ratio of 1:1.

1H-NMR (400 MHz, Dl3) δ : 0,83-0,88 (2H, m), 0,99-1,02 (2H, m)to 1.38 (3H × 1/2, d, J=2,93 Hz)of 1.40 (3H × 1/2, d, J=2,44 Hz), 1,62 to 1.76 (1H, m), 1,90-2,17 (2H, m), 2,35-of 2.93 (4H, m), 3,22-3,26 (2H, m), 7.23 percent-7,34 (5H, m).

[Referential Example 3] 3-[1-(tert-Butoxycarbonyl)amino-1-cyclopropyl]methyl-1-[1-(R)-phenylethyl]pyrrolidin

Cyclopropyl[1-[1-(R)-phenylethyl]pyrrolidin-3-yl]ketone (1,563 g 7,793 mmol) was dissolved in anhydrous methanol (25 ml). To this solution was added ammonium acetate (5,236 g, 67,93 mmol), cyanoborohydride sodium (435,2 mg, 6,925 mmol) and powdered molecular sieves 4(1.86 g) and the mixture was stirred at room temperature for 16 hours in a stream of nitrogen. The reaction solution was filtered through celite and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in dichloromethane (100 ml) and the solution was washed with saturated aqueous sodium bicarbonate solution (50 ml) and saturated aqueous sodium chloride (50 ml) in sequence, then dried over anhydrous magnesium sulfate. After filtration the solvent was concentrated under reduced pressure. Thus obtained residue was dissolved in anhydrous dichloromethane (25 ml), then to the solution under ice cooling was added dropwise a solution in dichloromethane (5 ml) di-tert-butylboronic (2,225 g, 10,19 mmol). The reaction solution was stirred at room temperature for 2 hours and then concentrated under reduced pressure. Thus obtained residue was subjected to flash chromatography on silica gel and was suirable a mixture of chloroform:methanol=10:1, thus obtaining 1,299 g (55,5%) specified in the connection header in the ideal colorless oil. In this regard, the product was obtained as a mixture of four optical isomers.

1H-NMR (400 MHz, CDCl3) δ : 0,20-0,30, 0,35-0,52, 0,68-0,78 (4H, m)of 1.36 (3H × 1/4, d, J=5,86 Hz)of 1.39 (3H × 3/4, d, J =5,86 Hz), 1,43 (N × 1/4, (C), 1,45 (N × 3/4, (C), 1,61-of 1.74 (1H, m,), 2,25-2,76, 2,80-3,07, 3,18-3,26 (N, m), 5,28 (1H, users), 7.23 percent-7,34 (5H, m).

[Reference Example 4] 1-Benzyloxycarbonyl-3-[1-(tert-butoxycarbonyl)amino-1-cyclopropyl]methylpyrrolidine (F1, F2, F3 and F4)

3-[1-(tert-Butoxycarbonyl)amino-1-cyclopropyl]methyl-1-[1-(R)-phenylethyl]pyrrolidine (1,234 g 3,582 mmol) was dissolved in anhydrous dichloromethane (20 ml), then to the solution under ice cooling was added dropwise benzylchloride (1278 μl, 8,955 mmol). After 8 hours of stirring at room temperature the reaction solution was concentrated under reduced pressure. Thus obtained residue was subjected to flash chromatography on silica gel and was suirable a mixture of n-hexane:ethyl acetate=2:1, thus obtaining 959 mg (71,5%) specified in the title compounds as colorless oils.

After this, the product was subjected to fractional HPLC using a chiral column for separation and purification of the four optical isomers.

Conditions of HPLC fractional division;

Column: CHIRALPAKAD (Daicel Chemical Industries), 2 cm × 25 cm

Mobile phase: n-hexane:2-propanol = 80:20 (V/V)

Flow rate: 5.0 ml/min

Pace is the atur: room temperature

Detection: UV (254 nm)

The retention time of each optical isomer

F1: 18 minutes; F2: 23 minutes; F3: 26 minutes; F4: 30 minutes

- Isomer F1: colorless amorphous, 229 mg (17,0%);

1H-NMR (400 MHz, CDCl3) δ : 0,27-0,32 (2H, m), 0,41-0,45 (1H, m), 0,54-0,61 (1H, m), 0,72-of 0.79 (1H, m), USD 1.43 (N, C), 1,66-of 1.78 (1H, m), 1,99-of 2.08 (1H, m), 2,30-of 2.36 (1H, m), 2,90-3,03 (1H, m), 3,12-3,26 (1H, m), 3,28-to 3.36 (1H, m), 3,49-and 3.72 (2H, m), 4,50 (1H, users), to 5.13 (2H, s), 7,30-7,37 (5H, m).

- Isomer F2: colorless amorphous, 96 mg (7.2 per cent);

1H-NMR (400 MHz, Dl3) δ : of 0.29 and 0.37 (2H, m), 0,40-0,45 (1H, m), 0,57-0,62 (1H, m), 0.76 to 0.79, which (1H, m), USD 1.43 (N, C), 1,68-of 1.78 (1H, m), 2,04-of 2.09 (1H, m), a 2.36-2.40 a (1H, m), 2.95 and-to 3.09 (1H, m), and 3.16 (1H, t, J=a 10.74 Hz), 3,31-3,39 (1H, m), 3,54-3,68 (2H, m), 4,47 (1H, users), to 5.13 (2H, s), 7,29-7,37 (5H, m).

- Isomer F3: colorless amorphous, 140 mg (10.4 per cent);

1H-NMR (400 MHz, CDCl3) δ : of 0.27 to 0.39 (2H, m), 0,41-0,45 (1H, m), 0,54-0,62 (1H, m), 0,72-0,80 (1H, m), USD 1.43 (N, C), 1,66-to 1.79 (1H, m), 2,04-of 2.09 (1H, m), 2,37-to 2.40 (1H, m), 2.95 and-is 3.08 (1H, m), and 3.16 (1H, t, J=a 10.74 Hz), 3,32-3,39 (1H, m), 3,54-3,68 (2H, m), 4,48 (1H, users), to 5.13 (2H, s), 7,30-7,37 (5H, m).

- Isomer F4: colorless amorphous, 296 mg (22.1 per cent);

1H-NMR (400 MHz, CDCl3) δ : 0,27-0,33 (2H, m), 0,41-0,45 (1H, m), 0,54-0,62 (1H, m), 0,72-0,80 (1H, m), USD 1.43 (N, m), 1,68-of 1.78 (1H, m), 1,99-of 2.09 (1H, m), 2,29-2,39 (1H, m), 2,90-3,03 (1H, m), 3,12-3,26 (1H, m), 3,28-3,37 (1H, m), 3,49-to 3.73 (2H, m), 4,50 (1H, users), to 5.13 (2H, s), 7,30-7,37 (5H, m).

Based on the results of the analysis of these data1H-NMR, it was confirmed that each combination of F1 and F4, and F2 and F3 is enantiomorphous mutual is against.

[Example of the invention 1] 5-Amino-7-[3-(1-amino-1-cyclopropyl)methylpyrrolidine-1-yl]-6,8-debtor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid (the substituent in the 7-position obtained from F1)

1-Benzyloxycarbonyl-3-[1-(tert-butoxycarbonyl)amino-1-cyclopropyl]methylpyrrolidine (derived from the F1 of the reference example 4; 185 mg, 0,494 mmol) was dissolved in anhydrous methanol (30 ml) and the solution was mixed with the catalyst is 10%palladium-on-coal (water content 50%, 200 mg), and stirred at room temperature for 1 hour in an atmosphere of hydrogen at atmospheric pressure. After filtration of the reaction solution through celite, the obtained filtrate was concentrated under reduced pressure. Thus obtained residue and triethylamine (2 ml) was added to the dry acetonitrile (10 ml) and the mixture is further mixed with 5-amino-6,7,8-Cryptor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid (130 mg, 0,412 mmol) and was heated at the boil under reflux for 16 hours. After cooling, the reaction solution is precipitated crystals thus collected by filtration, washed with acetonitrile, mixed with concentrated hydrochloric acid (10 ml) under ice cooling and then stirred at room temperature for 5 minutes. This mixture was mixed with distilled water (15 ml) and the received thus acidic aqueous solution was washed with dichloromethane (20 ml × 2), brought to pH 11 with aqueous solution of sodium hydroxide under ice cooling, and then washed with chloroform (10 ml). Received basic aqueous solution was brought to pH 7.4 1 N. hydrochloric acid and was extracted with chloroform (100 ml × 4). After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by recrystallization from a mixture of ethanol and 28%aqueous ammonia, and then dried under reduced pressure, thus obtaining 160 mg (88,9%) specified in the title compounds as yellow needle crystals.

1H-NMR (400 MHz, 0.1 N. NaOD) δ : 0,11-0,18 (2H, m)to 0.39 (2H, d, J=7,81 Hz), 0,57 is 0.67 (1H, m), 1,24-of 1.35 (1H, m), 1,43-to 1.61 (3H, m), 1.93 and e 2.06 (2H, m), 3,20-3,26 (1H, m), 3,37-to 3.49 (2H, m), 3,59-and 3.72 (2H, m), equal to 4.97 (1H, DM, J=64,16 Hz), 8,21 (1H, s).

Melting point: 185-193°

The data of elemental analysis for C21H23F3N4O3·0,25H2O

Calculated: 57,20; N lower than the 5.37; N 12,71

Found: 57,16; N. Of 5.39; N 12,88

[Example of invention 2] 5-Amino-7-[3-(1-amino-1-cyclopropyl)methylpyrrolidine-1-yl]-6,8-debtor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid (the substituent in the 7-position is obtained from F2)

1-Benzyloxycarbonyl-3-[1-(tert-butoxycarbonyl)amino-1-cyclopropyl]methylpyrrolidine (derived from the F2 reference example 4; 75 mg, 0,200 mmol) was dissolved in anhydrous methane is e (15 ml) and the solution was mixed with catalyst 10%palladium-on-coal (water content 50%, 100 mg) and stirred at room temperature for 1 hour in an atmosphere of hydrogen at atmospheric pressure. After filtration of the reaction solution through celite, the obtained filtrate was concentrated under reduced pressure. Thus obtained residue and triethylamine (1 ml) was added to the dry acetonitrile (5 ml) and the mixture was further mixed with 5-amino-6,7,8-Cryptor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid (53 mg, 0,167 mmol) and was heated at the boil under reflux for 12 hours. After cooling, the reaction solution is precipitated crystals thus collected by filtration, washed with acetonitrile, mixed with concentrated hydrochloric acid (5 ml) under ice cooling, and then stirred at room temperature for 5 minutes. This mixture was mixed with distilled water (10 ml) and the thus obtained acidic aqueous solution was washed with dichloromethane (15 ml × 2), brought to pH 11 with aqueous solution of sodium hydroxide under ice cooling, and then washed with chloroform (10 ml). Received basic aqueous solution was brought to pH 7.4 1 N. hydrochloric acid and was extracted with chloroform (80 ml × 3). After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. From this moment received the hydrated residue was purified by recrystallization from a mixture of ethanol and 28%aqueous ammonia and then dried under reduced pressure, while receiving 55 mg (75,5%) specified in the title compounds as yellow needle crystals.

1H-NMR (400 MHz, 0.1 N. NaOD) δ : of 0.13 to 0.19 (1H, m), 0,22-0,30 (1H, m), 0,41-0,49 (1H, m), 0,52-0,60 (1H, m), 0,73-0,84 (1H, m), 1,53-1,72 (3H, m)to 1.86 (1H, t, J-9.28 are Hz), 2,11-to 2.29 (2H, m), 3,44 is 3.57 (2H, m), 3,62-3,68 (1H, m), 3.72 points-of 3.95 (2H, m), 4,96 (1H, DM, J=63,95 Hz), 8,24 (1H, s).

Melting point: 190-192° C.

The data of elemental analysis for C21H23F3N4O3·0,25H2O

Calculated: 57,20; N lower than the 5.37; N 12,71

Found: 57,27; N Are 5.36; N 12,65

[Example of the invention 3] 5-Amino-7-[3-(1-amino-1-cyclopropyl)methylpyrrolidine-1-yl]-6,8-debtor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid (the substituent in the 7-position obtained from F3)

1-Benzyloxycarbonyl-3-[1-(tert-butoxycarbonyl)amino-1-cyclopropyl]methylpyrrolidine (derived from F3 reference example 4; 100 mg, 0,267 mmol) was dissolved in anhydrous methanol (20 ml) and the solution was mixed with the catalyst is 10%palladium-on-coal (water content 50%, 100 mg) and stirred at room temperature for 1 hour in an atmosphere of hydrogen at atmospheric pressure. After filtration of the reaction solution through celite, the obtained filtrate was concentrated under reduced pressure. Thus obtained residue and triethylamine (2 ml) was added to the dry acetonitrile (8 ml) and the mixture is further mixed with amino-6,7,8-Cryptor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid (80 mg, 0,222 mmol) and was heated at the boil under reflux for 16 hours. After cooling, the reaction solution is precipitated crystals thus collected by filtration, washed with acetonitrile, mixed with concentrated hydrochloric acid (10 ml) under ice cooling, and then stirred at room temperature for 5 minutes. This mixture was mixed with distilled water (15 ml) and the thus obtained acidic aqueous solution was washed with dichloromethane (20 ml × 2), brought to pH 11 with aqueous solution of sodium hydroxide under ice cooling, and then washed with chloroform (20 ml). Received basic aqueous solution was brought to pH 7.4 1 N. hydrochloric acid and was extracted with chloroform (80 ml × 4). After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by recrystallization from a mixture of ethanol and 28%aqueous ammonia and then dried under reduced pressure, thus obtaining 59 mg (60.8 per cent) indicated in the title compounds as yellow needle crystals.

1H-NMR (400 MHz, 0.1 N. NaOD) δ : 0,12-0,17 (1H, m), of 0.21 to 0.28 (1H, m), 0,41-0,48 (1H, m), of 0.51 to 0.60 (1H, m), 0,72-of 0.82 (1H, m), 1,44-of 1.53 (3H, m), is 1.81 (1H, t, J=8,79 Hz), 2,09-of 2.28 (2H, m), 3,41-3,47 (1H, m), 3,49 is 3.57 (1H, m), 3,59-3,66 (1H, m), 3.72 points-of 3.80 (2H, m), of 4.95 (1H, DM, J=65,11 Hz), 8,19 (1H, s).

Melting point: 193-194° C.

The data element is about analysis for C 21H23F3N4O3·0,25N2About

Calculated: 57,20; N lower than the 5.37; N 12,71

Found: 57,21; N lower than the 5.37; N 12,70

[Example of the invention 4] 5-Amino-7-[3-(1-amino-1-cyclopropyl)methylpyrrolidine-1-yl]-6,8-debtor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid (the substituent in the 7-position obtained from F4)

1-Benzyloxycarbonyl-3-[1-(tert-butoxycarbonyl)amino-1-cyclopropyl]methylpyrrolidine (derived from F4 reference example 4; 200 mg, 0,534 mmol) was dissolved in anhydrous methanol (20 ml) and the solution was mixed with the catalyst is 10%palladium-on-coal (water content 50%, 200 mg), and stirred at room temperature for 1 hour in an atmosphere of hydrogen at atmospheric pressure. After filtration of the reaction solution through celite, the obtained filtrate was concentrated under reduced pressure. Thus obtained residue and triethylamine (3 ml) was added to the dry acetonitrile (15 ml) and the mixture was then mixed with 5-amino-6,7,8-Cryptor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1, 4-dihydro-4-oxoindole-3-carboxylic acid (141 mg, 0,445 mmol) and was heated at the boil under reflux for 16 hours. After cooling, the reaction solution is precipitated crystals thus collected by filtration, washed with acetonitrile, mixed with concentrated hydrochloric acid (10 ml) under ice cooling, and C is the was stirred at room temperature for 5 minutes. This mixture was mixed with distilled water (20 ml) and the thus obtained acidic aqueous solution was washed with dichloromethane (20 ml × 2), brought to pH 11 with aqueous solution of sodium hydroxide under ice cooling, and then washed with chloroform (20 ml). Received basic aqueous solution was brought to pH 7.4 1 N. hydrochloric acid and was extracted with chloroform (100 ml × 4). After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by recrystallization from a mixture of ethanol and 28%aqueous ammonia and then dried under reduced pressure, thus obtaining 138 mg (71,1%) specified in the title compounds as yellow needle crystals.

1H-NMR (400 MHz, 0.1 N. NaOD) δ : 0,12-0,23 (2H, m), 0,41-of 0.51 (2H, m), 0.70 to 0.87 for (1H, m), 1,46-of 1.66 (3H, m), 1,80-of 1.88 (1H, m), 2,08-of 2.30 (2H, m), 3.46 in-of 3.60 (2H, m), 3,62 at 3.69 (1H, m), 3.72 points-is 3.82 (2H, m), 4,96 (1H, DM, J=63,89 Hz), 8,19 (1H, s).

Melting point: 188-194° C.

The data of elemental analysis for C21H23F3N4O3

Calculated: 57,79; N 5,31; N 12,84

Found: 57,56; N. Of 5.39; N 12,88

[Reference Example 5] Ethyl 4-(S)-benzyloxycarbonylamino-4-cyclopropyl-3-oxobutanoate

Monotropy ester of malonic acid (988,4 mg, 7,482 mmol) was dissolved in anhydrous tetrahydrofuran (20 ml) and was mixed solution with ethoxide magnesium (488 mg, 3.93 mmol) in a cooling gap is drop ice and then was stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness under reduced pressure and the thus obtained powder was dissolved in anhydrous tetrahydrofuran (30 ml).

L-N-Benzyloxycarbonyl-cyclopropylamine (1,332 g 5,334 mmol) was dissolved in anhydrous tetrahydrofuran (20 ml) and the solution was mixed with N,N'-carbonyl diimidazol (910 mg, 5,61 mmol) under ice cooling and then stirred at room temperature for 2 hours. Under ice cooling to just the resulting solution was added dropwise the above-mentioned prior tertrahydrofuran ring solution and the mixture was stirred at room temperature for 16 hours.

The reaction solution was concentrated under reduced pressure and the obtained residue was mixed with toluene (60 ml) and 10%aqueous citric acid solution (50 ml) and stirred at room temperature for 5 minutes. The organic layer was separated, and the aqueous layer was extracted with toluene (20 ml × 2). The organic layers were combined, washed with water (50 ml) and saturated aqueous sodium chloride (50 ml) in sequence, then dried over anhydrous magnesium sulfate. After filtration the solvent was evaporated under reduced pressure and the obtained residue was subjected to flash chromatography on silica gel, luira a mixture of n-hexane:ethyl acetate=2:1, thus receiving 1,527 g (89.4 per cent) indicated in the title compounds as colorless oils.

1H-NMR (400 MHz, Dl3) δ : 0,53-0,61 (3H, m), 0.67 and was 0.77 (1H, m), 0,90-a 1.01 (1H, m)of 1.27 (3H, t, J=7,33 Hz), the 3.65 (2H, s), 3,89-3,93 (1H, m), 4,20 (2H, q, J=7,33 Hz), 5,10 (2H, m), vs. 5.47 (1H, users), 7,31-to 7.35 (5H, m).

[Reference Example 6] Ethyl 4-(S)-benzyloxycarbonylamino-4-cyclopropyl-3-hydroxybutanoic

Ethyl 4-(S)-benzyloxycarbonylamino-4-cyclopropyl-3-oxobutanoate (1,526 g 4,778 mmol) was dissolved in anhydrous ethanol (15 ml) and the solution was mixed with sodium borohydride (94,6 mg of 2.50 mmol) under ice cooling and stirred at the same temperature for 1 hour. Under ice cooling, the reaction solution was mixed with water (20 ml), and then ethanol was evaporated under reduced pressure. Thus obtained residue was mixed with chloroform (50 ml) and was stirred and then separated so the chloroform layer was washed saturated aqueous sodium chloride (30 ml) and dried over anhydrous magnesium sulfate. After filtration the solvent was evaporated to dryness under reduced pressure, thus obtaining 1,509 g (98,3%) specified in the title compounds as colorless oils. This product was used in subsequent reactions without purification.

1H-NMR (400 MHz, CDCl3) δ : 0.24 to 0.67 and (4H, m), 0,96 was 1.06 and 1.08-1,16 (total 1H, each m)of 1.27 (3H, t, J=to 7.32 Hz), 2,45-of 2.58 (1H, m), 2,66-by 2.73 (1H, m),2,84-a 3.01 (1H, m)to 3.33 (1H, users), to 4.17 (2H, q, J=to 7.32 Hz), 5,09 (2H, s), 5,18 and 5,28 (total 1H, users each), 7,30-7,37 (5H, m).

[Referential Example 7] Ethyl 4-(S)benzyloxycarbonylamino-4-cyclopropyl-2-butenoate

Ethyl 4-(S)-benzyloxycarbonylamino-4-cyclopropyl-3-hydroxybutanoic (1,488 g 4,630 mmol) was dissolved in anhydrous dichloromethane (50 ml) and stirred at -15° adding triethylamine (1,291 μl, 9,260 mmol), and then to the mixture was added dropwise methanesulfonanilide (449 μl, 5,80 mmol) and the mixture was stirred at the same temperature for 1 hour. To the reaction solution was added dropwise 1,8-diazabicyclo[5,4,0]-7-undecene (1,486 μl, 1,955 mmol) and the mixture was gradually heated to room temperature and then was stirred for 15 hours. The reaction solution washed with 10%aqueous citric acid solution (50 ml), the organic layer was separated and then the aqueous layer was extracted with chloroform (30 ml). The organic layers were combined, washed with water (50 ml) and saturated aqueous sodium chloride (50 ml) in sequence, then dried over anhydrous magnesium sulfate. After filtration the solvent was evaporated under reduced pressure and the thus obtained residue was subjected to flash chromatography on silica gel, elwira a mixture of n-hexane:ethyl acetate = 4:1, thus obtaining 1,174 g (87,2%) specified in the title compound as light yellow is about oil.

1H-NMR (400 MHz, CDCl3) δ : 0,31-0,37 (1H, m), 0,39-0,48 (1H, m), 0,52-0,65 (1H, m), 0,86-of 0.95 (1H, m)of 1.29 (3H, t, J=7,33 Hz), to 3.73 (1H, users), 4,20 (2H, q, J=7,33 Hz)to 4.92 (1H, users), 5,11 (2H, s), 5,97 (1H, d, J=15,63 Hz), 6,91 (1H, DD, J=15,63, lower than the 5.37 Hz), 7,31 and 7.36 (5H, m).

[Referential Example 8] Ethyl 4-(S)-benzyloxycarbonylamino-4-cyclopropyl-3-nitromethylene

Ethyl 4-(S)-benzyloxycarbonylamino-4-cyclopropyl-2-butenoate was dissolved in anhydrous nitromethane (15 ml) and the solution was mixed with 1,1,3,3-tetramethylguanidine (133 μl, 1.05 mmol) and stirred at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in chloroform (50 ml) and the solution washed with 10%aqueous citric acid solution (50 ml) and saturated aqueous sodium chloride (50 ml) in sequence, then dried over anhydrous magnesium sulfate, thus obtaining 1,207 g (96.1 per cent) indicated in the title compound as a yellow oil.

This product (mixture of diastereomers) was used in subsequent reactions without purification.

1H-NMR (400 MHz, Dl3) δ : 0,31-0,45 (1H, m), 0,48-0,56 (1H, m), and 0.61 to 0.70 (1H, m), of 0.82 to 0.92 (1H, m)of 1.26 (3H, t, J=7,33 Hz), 2.49 USD (d, J=to 7.32 Hz), 2,53 (d, J=6,34 Hz)to 2.67 (d, J=5,72 Hz), 2,71 (d, J=5,86 Hz), 2,49, 2,53, 2,67, 2,67, (all 1H), 3,00 (1H, q, J=6,34 Hz), 3,13 (1H, q, J=7,32 Hz)to 4.15 (2H, q, J=7,33 Hz), of 4.57 and 4.59 (total 2H, d, J=7,33 Hz), a 4.86 (1H, users), 5,10 (2H, s), 7,31 and 7.36 (5H, m).

Ethyl 4-(S)-benzyloxycarbonylamino-4-cyclopropyl-3-nitromethylene (16.4 g, 41,0 mmol) was dissolved in ethanol (500 ml) and the solution was mixed with the catalyst is 10% palladium-on-coal (water content 50%, 16 g) and subjected to catalytic hydrogenation at room temperature for 5 hours. After removal of catalyst by filtration through celite, the obtained filtrate was heated at the boil under reflux for 6 hours. The solvent was evaporated under reduced pressure, the obtained residue was dissolved in anhydrous dichloromethane, the resulting solution was mixed with triethylamine (8,24 ml, 59,1 mmol), and then di-tert-butylborane (11,32 ml, and 49.2 mmol) and the mixture is then stirred at room temperature for 6 hours. After concentrating the reaction solution under reduced pressure, the thus obtained residue was subjected to flash chromatography on silica gel, elwira a mixture of chloroform:methanol = 95:5, the thus obtained crystals were purified by recrystallization from the system chloroform-n-hexane, thus obtaining 3,34 g (32,0%) of one diastereoisomer is specified in the header connection in the form of a single compound (isomer) as white crystals.

1H-NMR (400 MHz, CDCl3) δ : 0,34-0,35 (2H, m), 0,44-0,48 (1H, m), is 0.58-0.65 (1H, m), 0,72-of 0.79 (1H, m), 1,44 (N, C), 2,28 (1H, DD, J=17,09, 9,04 Hz), 2,44 (1H, DD, J=17,09, 8,44 Hz), 2,67-by 2.73 (1H, m), 3,043,06 (1H, m), 3.25 to 3,30 (1H, m), 3,47 (1H, t, J=8,79 Hz), of 4.57 (1H, s), of 5.84 (1H, s).

[Referential Example 10] 1-Benzyl-4-[1-(S)-tert-butoxycarbonylamino-1-cyclopropyl]methylpyrrolidine-2-he (isomer A)

In a stream of nitrogen 4-[1-(S)-tert-butoxycarbonylamino-1-cyclopropyl]methylpyrrolidine-2-he (3,15 g, 12.4 mmol) was dissolved in anhydrous dimethylformamide (60 ml) and the solution was mixed with 60% sodium hydride in oil (685 mg, 16,1 mmol) under cooling with ice. After 30 minutes stirring at room temperature the reaction mixture was mixed with benzylbromide (2,04 ml, at 16.1 mmol) under ice cooling and the mixture was stirred at room temperature for 13 hours. The reaction solution was mixed with water (200 ml) under cooling with ice and extracted with ethyl acetate (250 ml). Separated thus the organic layer was washed with water (200 ml × 2) and saturated aqueous sodium chloride (150 ml) in sequence, then dried over anhydrous magnesium sulfate. After filtration the solution was subjected to flash chromatography on silica gel, elwira a mixture of n-hexane:ethyl acetate=1:1, thus obtaining 2,74 g (64,2%) specified in the title compounds as a colorless amorphous substance.

1H-NMR (400 MHz, CDCl3) δ : of 0.27 to 0.28 (2H, m), 0,39-0,43 (1H, m), 0,52-0,56 (1H, m), 0,66-0,72 (1H, m), 1.41 to (N, C), 2,39-to 2.42 (1H, m), 2,54-2,62 (2H, m), 3,01 (1H, s), 3,29-to 3.33 (1H, m), and 4.40 (1H, s), 4,33, 4,55 (each 1H, ABq, J=14.4 Hz), 7.23 percent and 7.36 (5H, m).

Reference Example 11] 1-Benzyl-3-[1-(S)-tert-butoxycarbonylamino-1-cyclopropyl]methylpyrrolidine (isomer A)

In a stream of nitrogen 1-benzyl-4-[1-(S)-tert-butoxycarbonylamino-1-cyclopropyl]methylpyrrolidine-2-he (2,74 g of 7.95 mmol) was dissolved in anhydrous tetrahydrofuran (70 ml)to the solution under ice cooling and then was added dropwise a complex of borane-tetrahydrofuran (1,0 N. solution in tetrahydrofuran; 47,7 ml of 47.7 mmol). Upon completion of the dropwise and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, mixed with a solution of ethanol:water=10:1 (130 ml) and triethylamine (20 ml) and then heated at the boil under reflux for 4 hours. The reaction solution was concentrated under reduced pressure and mixed with chloroform (100 ml), separated thus the organic layer was washed with water (100 ml) and saturated aqueous sodium chloride (50 ml) in the specified order and then dried over anhydrous sodium sulfate. After filtration the solvent was evaporated under reduced pressure and the thus obtained residue was subjected to flash chromatography on silica gel and was suirable a mixture of chloroform:methanol=95:5, thus obtaining 2,63 g (100%) specified in the title compounds as colorless oils.

1H-NMR (400 MHz, Dl3) δ : for 0,19 0,23 (1H, m), of 0.35 to 0.44 (3H, m), 0,73-0,76 (1H, m), 1,44 (N, s), 1.60-to of 1.66 (1H, m), 1,94 is 2.00 (1H, m), a 2.36-to 2.42 (2H, m), of 2.51-of 2.66 (3H, m), 2.95 and-to 3.02 (1H, m), 3.52, the 3,67 (to whom gdy 1H, ABq, J=12.9 Hz), 4,58 (1H, s), 7.24 to 7,34 (5H, m).

[Reference Example 12] 1-Benzyloxycarbonyl-3-[1-(S)-tert-butoxycarbonylamino-1-cyclopropyl]methylpyrrolidine (isomer A = isomer F3 reference example 3)

1-Benzyl-3-[1-(S)-tert-butoxycarbonylamino-1-cyclopropyl]-methylpyrrolidine (isomer A; 238 mg, determined as 0.720 mmol) was dissolved in anhydrous dichloromethane (10 ml)to which was subsequently added dropwise benzylchloride (309 μl, of 2.16 mmol) under cooling with ice. After 8 hours of stirring at room temperature the reaction solution was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel, elwira a mixture of n-hexane:ethyl acetate=2:1, thus obtaining 197 mg (73.1 per cent) indicated in the title compounds as a colorless amorphous substance.

The Rf value for TLC (thin layer chromatography, the manifestation of a mixture of n-hexane:ethyl acetate=1:1) and data1H-NMR (shown below) this product is consistent with the data for isomer F3 described in reference example 4. In addition, when this product was checked by HPLC analysis using chiral column, its retention time in HPLC coincided with the retention time of the optical isomer F3 reference example 4. In the result, it was confirmed that this product (isomer A) is an optical isomer F3 described in reference example 4

1H-NMR (400 MHz, Dl3) δ : 0,28-0,40 (2H, m), 0,41-0,45 (1H, m), of 0.53 to 0.63 (1H, m), 0,72 is 0.81 (1H, m), USD 1.43 (N, C), 1,67-to 1.79 (1H, m), 2,03-of 2.09 (1H, m), 2,37-to 2.40 (1H, m), 2.95 and-is 3.08 (1H, m), and 3.16 (1H, t, J=a 10.74 Hz), 3,32-3,39 (1H, m), 3,54 at 3.69 (2H, m), 4,48 (1H, users), to 5.13 (2H, s), 7,31-7,37 (5H, m).

The conditions of HPLC analysis;

Column: CHIRALPAKAD (Daicel Chemical Industries), and 0.46 cm × 25 cm

Mobile phase: n-hexane:2-propanol = 80:20 (V/V)

Flow rate: 1.0 ml/min

Temperature: room temperature

Detection: UV (254 nm)

The retention time of isomer A (F3): 8,16 minutes

Optical purity: 99% EE (enantiomeric excess)

[Reference Example 13] 3-[1-(S)-tert-Butoxycarbonylamino-1-cyclopropyl]methylpyrrolidine (isomer A: F3)

1-Benzyl-3-[1-(S)-tert-butoxycarbonylamino-1-cyclopropyl]-methylpyrrolidine (isomer A; 744 mg, 2.25 mmol) was dissolved in anhydrous ethanol (30 ml) and mixed solution of catalyst (10%palladium-on-coal (water content 50%; 750 mg), and stirred at 45° C (external temperature) for 1 hour in an atmosphere of hydrogen at atmospheric pressure. The reaction solution was filtered through celite and the resulting filtrate was concentrated under reduced pressure, thus obtaining 542 mg (quantitative) specified in the title compound as white crystals.

1H-NMR (400 MHz, CDCl3) δ : 0,27 at 0.42 (2H, m), 0,53-0,57 (1H, m), 0.74 and is 0.81 (1H, m), USD 1.43 (N, C), 1,55-1,60 (1H, m), 1,89-of 1.95 (1H, m), 2,23-of 2.26 (3H m), 2,73-2,77 (1H, m), 2,85-2,90 (1H, m), 2.95 and-a 3.01 (2H, m).

[Example of the invention 5] 5-Amino-7-[3-[1-(S)-amino-1-cyclopropyl]methylpyrrolidine-1-yl)-6,8-debtor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid (the substituent in the 7-position derived from isomer A, F3)

3-[1-(S)-tert-Butoxycarbonylamino-1-cyclopropyl]methylpyrrolidine (isomer A: F3; 541 mg, 2.25 mmol) and triethylamine (6 ml) was added to the dry acetonitrile (30 ml) and then mixed with 5-amino-6,7,8-Cryptor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid (548 mg, at 1.73 mmol) and heated at boiling with reverse refrigerator for 15 hours. After cooling, the reaction solution is precipitated crystals thus collected filtrowanie, washed with acetonitrile, mixed with concentrated hydrochloric acid (15 ml) under ice cooling and then stirred at room temperature for 5 minutes. This mixture was mixed with distilled water (15 ml) and the thus obtained acidic aqueous solution was washed with dichloromethane (20 ml × 3), brought to pH 11 with aqueous solution of sodium hydroxide under ice cooling, and then washed with chloroform (30 ml). Received basic aqueous solution was brought to pH 7.4 1 N. hydrochloric acid and was extracted with chloroform (100 ml × 5). After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced is the making. The resulting residue was purified by recrystallization from a mixture of ethanol and 28% aqueous ammonia and then dried under reduced pressure, thus obtaining 569 mg (75,3%) specified in the title compounds as yellow needle crystals.

The Rf value in TLC (thin layer chromatography, the manifestation of using a mixture of chloroform:methanol:water=7:3:1 in the lower layer) and data1H-NMR (below) of this product was consistent with the data described in the example of the invention 3.

1H-NMR (400 MHz, 0.1 N. NaOD) δ : 0,13-0,17 (1H, m), 0,21-0,29 (1H, m), 0,41-0,48 (1H, m), 0,51-0,61 (1H, m), 0,73-of 0.82 (1H, m), USD 1.43-of 1.53 (3H, m), is 1.81 (1H, t, J=8,79 Hz), 2,10-of 2.27 (2H, m), 3,41-3,47 (1H, m), 3,49-to 3.58 (1H, m), 3,59-3,66 (1H, m), of 3.73-3,81 (2H, m), of 4.95 (1H, DM, J=65,11 Hz), 8,19 (1H, s).

Melting point: 192.5 kg-194,5° C.

The data of elemental analysis for C21H23F3N4About3·0,25N2O

Calculated: 57,20; N lower than the 5.37; N 12,71

Found: 57,18; N. Of 5.39; N 12,78

Specific rotation: [α ]

20
D
=-146,1° (from 0.32, 0.1 G. of NaOH)

[Example of the invention 6] 7-[3-[1-(S)-Amino-1-cyclopropyl]methylpyrrolidine-1-yl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoindole-3-carboxylic acid (the substituent in the 7-position derived from isomer A, F3)

4-[1-(S)-tert-Butoxycarbonylamino-1-cyclopropyl]met pyrrolidine (isomer A: F3; 240 mg, 1.00 mmol) and triethylamine (0,279 ml, 2.00 mmol) was added to the anhydrous dimethylsulfoxide (1.5 ml). To this mixture was then added to chelate 6,7-debtor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoindole-3-carboxylic acid-F2(328 mg, 0,909 mmol) and the mixture was stirred at room temperature for 17 hours and then at 35° C for 4 hours. After concentrating the reaction solution under reduced pressure, the obtained residue was mixed with water and precipitated thus, the solid was collected by filtration and washed with water. The thus obtained solid matter suspended in a solution of ethanol:water=10:1, and mixing the suspension with triethylamine (2 ml) and was heated at the boil under reflux for 3 hours. After cooling, the reaction solution was concentrated under reduced pressure and the obtained residue was dissolved in chloroform (100 ml). The organic layer is washed with 10%aqueous citric acid solution (50 ml) and then dried over anhydrous sodium sulfate. After filtration, the obtained filtrate was concentrated under reduced pressure, was added dropwise to the thus obtained residue concentrated hydrochloric acid (5 ml) under ice cooling, and then stirred the mixture at room temperature for 30 minutes. The reaction solution was mixed with 1 N. hydrochloric the acid (5 ml), thus obtained yellow acidic aqueous solution was washed with chloroform (50 ml × 5) and brought to a pH of 12.0 with an aqueous solution of sodium hydroxide, and then the insoluble substance was removed by filtration. Received basic aqueous solution was brought to pH 7.4 1 N. hydrochloric acid and was extracted with chloroform (100 ml × 4). After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by recrystallization from ethanol and then dried under reduced pressure, thus obtaining 285 mg (67,3%) specified in the title compound as yellow crystals.

1H-NMR (400 MHz, 0.1 N. NaOD) δ : 0,01-0,05 (1H, m), 0.29 to 0,32 (1H, m), 0,39-0,40 (1H, m), of 0.64 to 0.66 (1H, m), 1,15-1,22 (1H, m), 1,33-of 1.40 (1H, m), 1,43-and 1.54 (1H, m), 1,73-to 1.77 (1H, m), 1,96-to 1.98 (1H, m), 2,12-2,14 (1H, m), 3,28-3,51 (4H, m), 3,42 (3H, s), 3,81-3,86 (1H, m), a 4.86 (1H, DM, J=66,6 Hz), 7,49 (1H, d, J=4,56 Hz), of 8.25 (1H, d, J=3.42 Hz).

Melting point: 197,5-198,5° C.

The data of elemental analysis for C22H25F2N3O4·0,5H2O· 0,5EtOH

Calculated: 59,50; N 6,28; N 9,03

Found: 59,50; N To 6.39; N 8,87

Specific rotation: [α ]

20
D
=-105,5° (0,88, 0.1 G. of NaOH)

[Example of the invention 7] 5-Amino-7-[3-[1-(S)-amino-1-cyclopropyl]methylpyrrolidine-1-yl]-6-ft is R-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoindole-3-carboxylic acid (the substituent in the 7-position derived from isomer A, F3)

4-[1-(S)-tert-Butoxycarbonylamino-1-cyclopropyl]methylpyrrolidine (481 mg, 2.00 mmol) and triethylamine (1.5 ml) was added to the anhydrous dimethylsulfoxide (2 ml) and the mixture was further mixed with 5-amino-6,7-debtor-1-(2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoindole-3-carboxylic acid (416 mg, of 1.33 mmol) and heated at boiling with reverse a refrigerator for 72 hours under nitrogen atmosphere. After concentrating the reaction solution under reduced pressure, the obtained residue was dissolved in chloroform (100 ml). The organic layer is washed with 10%aqueous citric acid solution (50 ml) and then dried over anhydrous sodium sulfate. After filtration, the obtained filtrate was concentrated under reduced pressure, the thus obtained residue under ice cooling was added dropwise concentrated hydrochloric acid (5 ml) and the mixture is then stirred at room temperature for 30 minutes. The reaction solution was mixed with 1 N. hydrochloric acid (5 ml)thus obtained yellow acidic aqueous solution was washed with chloroform (50 ml × 5) and brought to a pH of 12.0 with an aqueous solution of sodium hydroxide, then nerastvorimaya substance was removed by filtration. Received basic aqueous solution was brought to pH 7.4 1 N. hydrochloric acid and was extracted with chloroform (100 ml × 3). After drying over anhydrous sulfate on the rija the solvent was evaporated under reduced pressure. The resulting residue was purified preparative thin-layer chromatography (manifestation of using a mixture of chloroform:methanol:water=7:3:1 in the lower layer), recrystallized from isopropyl alcohol and then dried under reduced pressure, thus obtaining 70.0 mg (12.1 per cent) indicated in the title compound as yellow crystals.

1H-NMR (400 MHz, 0.1 N. NaOD) δ : 0,01-0,10 (2H, m), of 0.27 to 0.39 (2H, m), 0,58-of 0.64 (1H, m), 0.88 to 0.97 (1H, m), 1,33-to 1.45 (2H, m), 1,71-of 1.74 (1H, m), 1,97 is 2.10 (2H, m), of 2.08 (3H, s), 3,01 was 3.05 (1H, m), 3,17-is 3.21 (1H, m), 3,34-to 3.38 (1H, m), to 3.58-3,62 (1H, m), 3.75 to with 3.79 (1H, m), the 4.90(1H, DM), to 8.14 (1H, s).

Melting point: of 226.7-227,9° C.

The data of elemental analysis for C22H26F2N4About3

Calculated: 61,10; N The 6.06; N 12,96

Found: 60,84; N 6,07; N 12,98

Specific rotation: [α ]

20
D
=-329,0° (0,20, 0.1 G. of NaOH)

[Example of the invention 8]

7-[3-[1-(S)-Amino-1-cyclopropyl)methylpyrrolidine-1-yl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxoindole-3-carboxylic acid (the substituent in the 7-position derived from isomer A, F3)

4-[1-(S)-tert-Butoxycarbonylamino-1-cyclopropyl]methylpyrrolidine (isomer A: F3; 330 mg, 1.37 mmol) and triethylamine (0,485 ml of 3.48 mmol) was added to 3.0 ml of anhydrous dimethyl sulfoxide and the mixture was further mixed with 6-fluoro-1-cyclopropyl-1,4-dig the draw-8-methoxy-4-oxoindole-3-carboxylic acid (321 mg, to 1.16 mmol) and stirred at 100° C for 15 hours. After concentrating the reaction solution under reduced pressure, the obtained residue was dissolved in 100 ml of chloroform. The organic layer was washed with 50 ml of 10%aqueous citric acid solution and then dried over anhydrous sodium sulfate. After filtration, the obtained filtrate was concentrated under reduced pressure, the thus obtained residue under ice cooling was added dropwise 5 ml of concentrated hydrochloric acid and then the mixture was stirred at room temperature for 30 minutes. The reaction solution was mixed with 5 ml of 1 N. hydrochloric acid and the thus obtained yellow acidic aqueous solution was washed with chloroform (50 ml × 4)obtained nerastvorimaya substance was removed by filtration, and then the solution was brought to pH to 12.0 with an aqueous solution of sodium hydroxide. Received basic aqueous solution was brought to pH 7.4 1 N. hydrochloric acid and was extracted with chloroform (100 ml × 4). After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by recrystallization from a mixture of ethanol-aqueous ammonia and then dried under reduced pressure, thus obtaining 230 mg (49.9 percent) specified in the title compound as yellow crystals.

1H-NMR (400 MG IS, 0.1 N. NaOD) δ : 0,17-0,18 (1H, m), 0,28-0,29 (1H, m), 0,46-0,47 (1H, m), 0,57 is 0.58 (1H, m), 0.77-a of 0.79 (2H, m), 1,02 of-1.04 (2H, m), 1,17-to 1.21 (2H, m), 1,69-of 1.81 (1H, m), 1,92-of 1.95 (1H, m), 2,18-of 2.27 (1H, m), 2,35-is 2.40 (1H, m), 3.33 and-to 3.52 (3H, m), 3,52 (3H, s), 4,01-4,11 (1H, m), 7,03 (1H, d, J=8,79 Hz), to $ 7.91 (1H, d, J=9,03 Hz), 8,48 (1H, s).

Melting point: 220-221° C.

The data of elemental analysis for C22H27N3O4·0.5 H2O

Calculated: 65,74; N 6,90; N 10,45

Found: 65,96; N 6,90; N 10,36

[Referential Example 14]

1-[1-(R)-Phenylethyl]-5-oxopyrrolidin-3-(R)-(N-methyl-N-methoxy)carboxamide

To a solution of 1-[1-(R)-phenylethyl]-5-oxopyrrolidin-3-(R)-carboxylic acid (11.7 g, 50.0 mmol) in dichloromethane (200 ml) under ice cooling was added oxalicacid (6,54 ml of 75.0 mmol) and dimethylformamide (3 drops) and the mixture was stirred at room temperature for a whole day and night. After evaporation of the solvent under reduced pressure, to the obtained residue were added toluene (100 ml) and then the solvent was again evaporated under reduced pressure. Thus obtained residue was mixed with dichloromethane (200 ml) and the hydrochloride of N,O-methylhydroxylamine (vs. 5.47 g of 55.5 mmol) and then to the mixture under stirring and ice cooling was added dropwise over 15 minutes a solution of triethylamine (of 17.4 ml, 125 mmol) in dichloromethane (50 ml). The reaction mixture was stirred under ice cooling for 30 minutes and then at room temperature in accordance with the s 3 hours. The reaction solution washed with 10%aqueous citric acid solution (100 ml), water (100 ml) and saturated aqueous sodium bicarbonate (100 ml) in sequence, then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to column chromatography on silica gel and was suirable gradient mixture of chloroform:methanol = 50:1 to 20:1, thus obtaining 11.3 g (82%) indicated in the title compound as a brown oil.

1H-NMR (400 MHz, CDCl3) 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, q, J=6,84 Hz), 7,28-7,37 (5H, m).

[Referential Example 15]

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

In the atmosphere of nitrogen cyclobutylamine (1 n solution in tetrahydrofuran, 28 ml), obtained from chlorocyclobutane, was added dropwise to the solution in tetrahydrofuran (50 ml) of 1-[1-(R)-phenylethyl]-5-oxopyrrolidin-3-(R)-(N-methyl-N-methoxy)carboxamide (1,93 g, 7,00 mmol) and the mixture was stirred at room temperature for 30 minutes. The reaction solution was mixed with 1 N. hydrochloric acid (50 ml) under cooling with ice and extracted with ethyl acetate (80 ml × 2), the organic layer was washed saturated aqueous sodium chloride (100 ml) and then dried over betwo the major sodium sulfate. The solvent was evaporated under reduced pressure and the thus obtained residue was subjected to column chromatography on silica gel, elwira a mixture of n-hexane:ethyl acetate=1:2, thus obtaining 1.47 g (78%) indicated in the title compound as a pale yellow oil.

1H-NMR (400 MHz, CDCl3) δ : of 1.53 (3H, d, J=7,33 Hz), 1,78-1,89 (1H, m), 1,92 e 2.06 (1H, m), 2.06 to 2,31 (4H, m), 2,58-to 2.65 (2H, m), 3,05 (1H, DD, J=9.28 are, 8,79 Hz), 3,13-is 3.21 (1H, m), and 3.31 (1H, quintet, J=8,30 Hz), 3,53 (1H, DD, J=9.28 are, 6,83 Hz), of 5.48 (1H, q, J=7,33 Hz), 7,27-7,37 (5H, m).

[Referential Example 16]

4-(R)-(1-Cyclobutyl-1-hydroxy)methyl-1-[1-(R)-phenylethyl]-2-pyrrolidone

Under ice cooling sodium borohydride (295 mg) was added to a solution of 4-(R)-cyclobutanecarbonyl-1-[1-(R)-phenylethyl]-2-pyrrolidone (2,12 g, 7,80 mmol) in ethanol (40 ml) and the mixture was stirred at the same temperature for 1 hour. The reaction solution was mixed with 10%citric acid (50 ml) under ice cooling, the ethanol was evaporated under reduced pressure, the resulting residue was extracted with chloroform (80 ml × 2) and then the organic layer was washed saturated aqueous sodium chloride (100 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the thus obtained residue was subjected to column chromatography on silica gel and was suirable gradient, starting from a mixture of n-hexane:ethyl acetate = 1:3 d is ethyl acetate, thus receiving 2,10 g (98%) indicated in the title compound as a pale yellow oil (mixture of isomers).

1H-NMR (400 MHz, CDCl3) δ : of 1.50 (3H, d, J=6,83 Hz), 1,68 is 2.01 (6N, m), 2,14 at 2.45 (3H, m), 2,45-of 2.56 (1H, m), 2.91 in was 3.05 (1H, m), 3,19-of 3.31 (1H, m), 3,41-to 3.49 (1H, m), 5,42-5,49 (1H, m), 7,24 and 7.36 (5H, m).

[Reference Example 17]

4-(R)-(1-Azido-1-cyclobutyl)methyl-1-[1-(R)-phenylethyl]-2-pyrrolidone

To a solution of 4-(R)-(1-cyclobutyl-1-hydroxy)methyl-1-[1-(R)-phenylethyl]-2-pyrrolidone (2,05 g, 7,50 mmol) in dichloromethane (35 ml) under ice cooling was added triethylamine (1,36 ml of 9.80 mmol), and then methanesulfonanilide (640 μl, 8,30 mmol) and the mixture was stirred at the same temperature for 1 hour. The reaction solution was mixed with 10%citric acid (35 ml) under cooling with ice and was extracted with chloroform (50 ml × 2), the organic layer was washed saturated aqueous sodium chloride (150 ml) and then dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure the resulting residue was dissolved in N,N'-dimethylformamide (30 ml), the solution was mixed with sodium azide (1,46 g of 22.5 mmol) and stirred at 60° C for 3 hours. After cooling, the reaction solution was mixed with water (150 ml) under cooling with ice and extracted with ethyl acetate (150 ml × 3), the organic layer was washed saturated aqueous sodium chloride (150 ml) and then dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, the thus obtained residue was subjected to column chromatography on silica gel and was suirable a mixture of n-hexane:ethyl acetate=3:2, thus obtaining 898 mg (40%) specified in the header compounds with low polarity (isomer B1) as a colourless oil, and then a mixture of n-hexane:ethyl acetate = 2:3, thus obtaining 847 mg (38%) indicated in the title compounds with high polarity (isomer B2) in the form of colorless crystals.

Isomer B1

1H-NMR (400 MHz, CDCl3) δ : of 1.52 (3H, d, J=6,83 Hz), 1,72 is 2.01 (5H, m), 2,07-2,17 (1H, m), 2.26 and-to 2.41 (3H, m), 2,45-of 2.56 (1H, m), 2,98 (1H, DD, J=9,77, 7,81 Hz), 3,14 (1H, DD, J=9,77, to 7.32 Hz), 3,32 (1H, DD, J=8,76, 3,91 Hz), vs. 5.47 (1H, kV, J=6,83 Hz), 7,25-to 7.35 (5H, m).

Isomer B2

1H-NMR (400 MHz, CDCl3) δ : of 1.52 (3H, d, J=6,83 Hz), 1,75-2,03 (5H, m), 2,03-2,17 (1H, m), 2,19-of 2.38 (2H, m), 2,40-of 2.56 (2H, m)to 2.99 (1H, DD, J=9,77, 8,30 Hz), 3,14 (1H, DD, J=9,77, to 7.32 Hz), 3,30 (1H, DD, J=8,30, 6,34 Hz), vs. 5.47 (1H, kV, J=6,83 Hz), 7,25-to 7.35 (5H, m).

[Referential Example 18]

4-(R)-[1-(tert-Butoxycarbonyl)amino-1-cyclobutyl]methyl-1-[1-(R)-phenylethyl]-2-pyrrolidone (isomer B1)

A solution of 4-(R)-(1-azido-1-cyclobutyl)methyl-1-[1-(R)-phenylethyl]-2-pyrrolidone (isomer B1) (835 mg, 2,80 mmol) in ethanol (50 ml) was mixed with catalyst (10%palladium-on-coal (water content 53,8%, 850 mg) and was carried out by catalytic hydrogenation for 5 hours at room temperature in an atmosphere of hydrogen is at atmospheric pressure. The reaction solution was filtered and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in dichloromethane (20 ml), the solution was mixed with di-tert-butylborane (917 mg) and triethylamine (780 μl) and stirred at room temperature for 15 hours. The reaction solution was mixed with chloroform (50 ml) and washed with 10%citric acid (80 ml) and water (80 ml) and then the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the thus obtained residue was subjected to column chromatography on silica gel and was suirable gradient mixture of n-hexane:ethyl acetate = 3:2 to 1:1, thus obtaining 809 mg (78%) indicated in the title compound as a white amorphous substance.

1H-NMR (400 MHz, CDCl3) δ : 1,44 (N, C)to 1.48 (3H, d, J=to 7.32 Hz), 1,66-1,98 (6N, m), 2,17 is 2.43 (4H, m), 2,94-3,03 (1H, m), 3,09-3,18 (1H, m), 3,59-3,68 (1H, m), 4,46-4,58 (1H, m), 5,46 (1H, q, J=to 7.32 Hz), 7,27-to 7.35 (5H, m).

[Reference Example 19]

4-(R)-[1-(tert-butoxycarbonyl)amino-1-cyclobutyl]methyl-1-[1-(R)-phenylethyl]-2-pyrrolidone (isomer B2)

A solution of 4-(R)-(1-azido-1-cyclobutyl)-methyl-1-[1-(R)-phenylethyl]-2-pyrrolidone (isomer B2) (776 mg, 2,60 mmol) in ethanol (40 ml) was mixed with catalyst (10%palladium-on-coal (water content 53,8%, 800 mg) and within 5 hours was carried out by catalytic hydrogenation at room temperature in which atmosphere hydrogen at atmospheric pressure. The reaction solution was filtered and the solvent was evaporated under reduced pressure. Thus obtained residue was dissolved in dichloromethane (20 ml), the solution was mixed with di-tert-butylborane (851 mg) and triethylamine (725 μl) and stirred at room temperature for 15 hours. The reaction solution was mixed with chloroform (50 ml) and washed with 10%citric acid (80 ml) and water (80 ml), and then the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the thus obtained residue was subjected to column chromatography on silica gel and was suirable gradient mixture of n-hexane:ethyl acetate = 1:1 to 2:3, thus obtaining 846 mg (87%) indicated in the title compound as a white amorphous substance.

1H-NMR (400 MHz, CDCl3) δ : 1,43 (N, C)a 1.50 (3H, d, J=to 7.32 Hz), 1.70 to 1,96 (6N, m), 2,08-2,22 (1H, m), 2,22-of 2.36 (2H, m), a 2.36-2,47 (1H, m), 2,96 (1H, DD, J=9,27, 8,30 Hz), 3,10 (1H, DD, J=9,27, 8,79 Hz), 3,55-3,62 (1H, m), 4,28 (1H, d, J=9,77 Hz), 5,46 (1H, q, J=to 7.32 Hz), 7,25-to 7.35 (5H, m).

[Referential Example 20]

3-(R)-[1-(tert-Butoxycarbonyl)amino-1-cyclobutyl]methyl-1-[1-(R)-phenylethyl]pyrrolidine (isomer B1)

In a nitrogen atmosphere of 1 M solution of the complex of borane-tetrahydrofuran (5.6 ml) was added dropwise to a solution of 4-(R)-[1-(tert-butoxycarbonyl)amino-1-cyclobutyl]methyl-1-[1-(R)-phenylethyl]-2-pyrrolidone (isomer B1) (700 mg, 1.88 mmol) in tetrahydrof is ane (15 ml) under ice cooling and the mixture was stirred at room temperature for 13 hours. The solvent was evaporated under reduced pressure, the obtained residue was mixed with 80%aqueous ethanol (15 ml) and triethylamine (3 ml) and was heated at the boil under reflux for 4 hours. After cooling, the solvent was evaporated under reduced pressure, the thus obtained residue was mixed with chloroform (30 ml), washed with water (10 ml) and saturated aqueous sodium chloride (10 ml) and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the thus obtained residue was subjected to column chromatography on silica gel and was suirable a mixture of chloroform:methanol = 20:1, thus obtaining 565 mg (84%) indicated in the title compounds as colorless crystals.

1H-NMR (400 MHz, Dl3) δ : of 1.36 (3H, d, J=6,84 Hz), 1,45 (N, C), 1,66-of 1.95 (7H, m), 2.05 is-2,22 (2H, m), 2,22-of 2.34 (1H, m), 2,34 at 2.45 (2H, m)and 3.15 (1H, q, J=6,84 Hz), 3.43 points-of 3.53 (1H, m), 4,54-to 4.62 (1H, m), 7,21-7,31 (5H, m).

[Referential Example 21]

3-(R)-[1-(tert-Butoxycarbonyl)amino-1-cyclobutyl]methyl-1-[1-(R)-phenylethyl]pyrrolidine (isomer B2)

In a nitrogen atmosphere of 1 M solution of the complex of borane-tetrahydrofuran (6.4 ml) was added dropwise to tertrahydrofuran ring solution (15 ml) of 4-(R)-[1-(tert-butoxycarbonyl)amino-1-cyclobutyl]methyl-1-[1-(R)-phenylethyl]-2-pyrrolidone (isomer B2) (797 mg, 2.14 mmol) under ice cooling and the mixture was stirred at room temp is the temperature for 13 hours. The solvent was evaporated under reduced pressure and the obtained residue was mixed with 80%aqueous ethanol (15 ml) and triethylamine (3 ml) and was heated at the boil under reflux for 4 hours. After cooling, the solvent was evaporated under reduced pressure and the thus obtained residue was mixed with chloroform (30 ml), washed with water (10 ml) and saturated aqueous sodium chloride (10 ml) and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the thus obtained residue was subjected to column chromatography on silica gel and was suirable a mixture of chloroform:methanol = 20:1, thus obtaining 743 mg (97%) indicated in the title compounds as colorless oils.

1H-NMR (400 MHz, Dl3) δ : of 1.37 (3H, d, J=6,83 Hz), 1,46 (N, C), 1,64-of 1.93 (8H, m), 2,10-of 2.30 (3H, m), 2,30 is 2.51 (1H, m), of 2.51-2,69 (2H, m), 3,11-of 3.23 (1H, m), 3.43 points-to 3.52 (1H, m), 4.92 in-5,01 (1H, m), 7,22-to 7.32 (5H, m).

[Referential Example 22] 3-(R)-[1-(tert-Butoxycarbonyl)amino-1-cyclobutyl]methylpyrrolidine (isomer B1)

The catalyst is 10%palladium-on-coal (water content 53,8%, 500 mg) was added to a solution of 3-(R)-[1-(tert-butoxycarbonyl)amino-1-cyclobutyl]methyl-1-[1-(R)-phenylethyl]-pyrrolidine (isomer B1) (516 mg, 1.44 mmol) in ethanol (30 ml) and the mixture was subjected to catalytic hydrogenation for 5 hours at an external temperature of 50° C in an atmosphere of hydrogen is at atmospheric pressure. The reaction solution was filtered and the solvent was evaporated under reduced pressure, thus obtaining 366 mg (quantitative) specified in the title compounds as colorless crystals. This product was used in subsequent reactions without purification.

[Reference Example 23] 3-(R)-[1-(tert-Butoxycarbonyl) amino-1-cyclobutyl]methylpyrrolidine (isomer B2)

The catalyst is 10%palladium-on-coal (water content 53,8%, 650 mg) was added to a solution of 3-(R)-[1-(tert-butoxycarbonyl)amino-1-cyclobutyl]methyl-1-[1-(R)-phenylethyl]-pyrrolidine (isomer B2) (645 mg, of 1.80 mmol) in ethanol (40 ml) and the mixture was subjected to catalytic hydrogenation for 5 hours at an external temperature of 50° C in an atmosphere of hydrogen at atmospheric pressure. The reaction solution was filtered and the solvent was evaporated under reduced pressure, thus obtaining 458 mg (quantitative) specified in the title compounds as colorless crystals. This product was used in subsequent reactions without purification.

[Example of the invention 9] 5-Amino-7-[3-(R)-(1-amino-1-cyclobutyl)methyl]pyrrolidin-1-yl]-6,8-debtor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid (the substituent in the 7-position is obtained from B1)

5-Amino-6,7,8-Cryptor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid (379 mg, 1.20 mmol), 3-(R)-[1-(tert-butoxycarbonyl)amino-1-kilobytes]-methylpyrrolidine (isomer B1) (366 mg, 1.44 mmol) and triethylamine (3 ml) was added to acetonitrile (15 ml) and was heated at the boil under reflux for 8 hours. After cooling, the reaction solution was concentrated under reduced pressure and the thus obtained residue was mixed with concentrated hydrochloric acid (15 ml) under ice cooling, and then stirred at room temperature for 10 minutes. This solution, containing hydrochloric acid, washed with chloroform (20 ml × 3) and podslushivaet by adding 30%aqueous solution of sodium hydroxide under ice cooling, and then stirred at room temperature for 1 hour. This suspension was brought to pH to 7.6 by the addition of concentrated hydrochloric acid and 1 N. hydrochloric acid and then was extracted with chloroform (100 ml × 3). The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The resulting residue was purified by recrystallization from a mixture of ethanol-n-hexane and then dried under reduced pressure, thus obtaining 386 mg (74%) indicated in the title compound as light yellow crystals.

1H-NMR (400 MHz, 0.1 N. NaOD) δ : 1,22-1,83 (11H, m), 1,83-of 1.97 (1H, m), 1,97-to 2.18 (2H, m), 2,18-to 2.29 (1H, m), 3,07 of 3.28 (2H, m), 3,35-of 3.46 (1H, m), 3,53 at 3.69 (2H, m), 4,78-4,89 (0,5H, m), 4,93-5,02 (0,5H, m), 8,17 (1H, s).

Melting point: 175,3-177,6° (Razlog.)

D is by elemental analysis for C 22H25F3N4O3

Calculated: 58,66; N 5,59; N to 12.44

Found: 58,55; N 5,61; N of 12.33

[Example of the invention 10]

5-Amino-7-[3-(R)-(1-amino-1-cyclobutyl)methyl]pyrrolidin-1-yl]-6,8-debtor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid (the substituent in the 7-position is obtained from B2)

5-Amino-6,7,8-Cryptor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid (474 mg, 1.50 mmol), 3-(R)-[1-(tert-butoxycarbonyl)amino)-1-cyclobutyl]-methylpyrrolidine (isomer B2) (458 mg, of 1.80 mmol) and triethylamine (4 ml) was added to acetonitrile (20 ml) and heated at boiling with reverse refrigerator for 8 hours. After cooling, the reaction solution was concentrated under reduced pressure and the thus obtained residue was mixed with concentrated hydrochloric acid (15 ml) under ice cooling and then stirred at room temperature for 10 minutes. This solution, containing hydrochloric acid, washed with chloroform (20 ml × 3) and podslushivaet the addition of 30%aqueous sodium hydroxide solution under ice cooling and then stirred at room temperature for 1 hour. This suspension was brought to pH to 7.6 by the addition of concentrated hydrochloric acid and 1 N. hydrochloric acid and then was extracted with chloroform (100 ml × 3). The organic layer was dried over anhydrous sulfate is the atrium and the solvent was evaporated under reduced pressure. The resulting residue was purified by recrystallization from a mixture of chloroform-n-hexane and then dried under reduced pressure, thus obtaining 386 mg (74%) indicated in the title compound as light yellow crystals.

1H-NMR (400 MHz, 0.1 N. NaOD) δ : 1,27 to 1.76 (7H, m), 1,76-1,99 (6N, m), 2,17-of 2.28 (1H, m), 2,34-to 2.42 (1H, m), 3,36-3,50 (2H, m), 3,50-3,59 (1H, m), 3,64-with 3.79 (2H, m), 4,79-4,89 (0,5H, m), 4,98-5,06 (0,5H, m), 8,19 (1H, s).

Melting point: 198,2-201,4° (Razlog.)

The data of elemental analysis for C22H25F3N4O3·1,0 H2About

Calculated: 56,40; N. Of 5.81; N 11,96

Found: 56,34; N. Of 5.84; N 11,75

Antibacterial activity of each compound of the present invention was measured in accordance with the standard method specified by the Japanese Society of Chemotherapy (Japan Society of Chemotherapy), the results are presented in the table in the form of MIC values (μg/ml). In this connection also shows the MIC for levofloxacin (LVFX) and ciprofloxacin (CPFX) for comparison with the MIC values of the compounds of the present invention.

Table
StrainsConnection (Sample of the invention No.)
 1245
E. coli, NIHJ0,006 0,013≤ 0,003≤ 0,003
S.flexneri, 2A 55030,0250,05≤ 0,003≤ 0,003
Pr. vulgaris, 086010,20,10,050,013
K.pneumoniae TYPE 10,10,10,0250,013
Ser.marcescens, 101000,20,20,050,025
Ps. aeruginosa, 321040,390,780,10,05
Ps. aeruginosa, 321210,20,20,050,025
X.maltophilia, IID 12750,390,390,050,05
S.aureus, FDA 209P0,0250,025≤ 0,003≤ 0,003
S. epid.ermid.is, 565000,10,1≤ 0,003≤ 0,003
Str. pyogenes, G-360,390.2≤ 0,003≤ 0,003
E. faecalis ATCC 194330,20,20,0250,013
S. aureus, 8703073,133,130,050,025
Str. Pneumoniae, J240,1 0,1≤ 0,003≤ 0,003
StrainsConnection (Sample of the invention No.)
 6789
E. coli, NIHJ≤ 0,003≤ 0,0030,006≤ 0,003
S.flexneri, 2A 55030,006≤ 0,0030,10,005
Pr. vulgaris, 086010,0130,0130,050,1
K.pneumoniae TYPE 10,050,0250,10,025
Ser.marcescens, 101000,10,050,20,1
Ps. aeruginosa, 321040,10,050,390,2

Ps. aeruginosa, 321210,050,0250,20,1
X.maltophilia, IID 12750,20,050,20,1
S.aureus, FDA 209P≤ 0,003≤ 0,0030,006≤ 0,003
S.epidermidis, 565000,006≤ 0,0030,025^0,003
Str. pyogenes, G-6 ≤ 0,003≤ 0,0030,0130,013
E. faecalis ATCC 194330,0250,0130,050,05
S. aureus, 8703070,10,0250,20,10
Str. Pneumoniae, J24≤ 0,003≤ 0,0030,0060,006
StrainsConnection (Sample of the invention No.)
 10LVFXCPFX
E. coli, NIHJ≤ 0,0030,013≤ 0,003
S.flexneri, 2A 5503≤ 0,0030,0250,006
Pr. Vulgaris, 086010,050,13≤ 0,003
K.pneumoniae TYPE 10,0250,10,025
Ser.marcescens, 101000,050,10,025
Ps. aeruginosa, 321040,20,20,05
Ps. aeruginosa, 321210,20,10,025
X.maltophilia, IID 12750,050,39 0,78
S.aureus, FDA 209P≤ 0,0030,20,1
S.epidermidis, 56500≤ 0,0030,390,2
Str. pyogenes, G-36≤ 0/0030,21,56
E. faecalis ATCC 194330,0130,780,78
S. aureus, 8703070,05>6,253,13
Str. pneumoniae, J24≤ 0,0030,780,1

INDUSTRIAL APPLICABILITY

The compound of the present invention has excellent antibacterial activity against a wide range of gram-negative and gram-positive bacteria, demonstrating particularly strong antibacterial activity against methicillin-resistant Staphylococcus aureus resistant to penicillin pneumococcus, Enterococcus, and other gram-positive bacteria and hinolan-resistant bacteria, and it also has excellent security and good pharmacokinetics, as, for example, the weakening of the micronuclear test, so it can be used as antibacterial compounds for use in the chemotherapy of bacterial infections.

1. Connected to the e, represented by the following formula (I), its salts and hydrates:

where each of R1and R2represents a hydrogen atom;

n represents an integer from 1 to 4; and

Q represents a structural unit represented by the following formula (Ia):

where R3represents a cyclic alkyl group having 3 to 6 carbon atoms, which may have a Deputy;

R4represents a hydrogen atom;

R5represents a hydrogen atom or an amino group;

X1represents a halogen atom or a hydrogen atom;

And1represents a nitrogen atom or a structural unit represented by formula (II)

where X2represents a hydrogen atom, halogen atom or alkyl group having from 1 to 6 carbon atoms, or CNS group having from 1 to 6 carbon atoms; and

X2and R3may form, together with part of the original skeletal ring structure, optionally containing oxygen atom, nitrogen atom or sulfur atom as a forming ring atoms and optionally having an alkyl group containing from 1 to 6 carbon atoms as a substituent; and

Y represents an atom in Dorada.

2. Connection, its salts and hydrates of claim 1, 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-strong group.

3. Connection, its salts and hydrates according to claim 1 or 2, where the compound of formula (I) is the stereochemical net connection.

4. Connection, its salts and hydrates of claim 1, where R3in the formula (I) is halogencontaining group.

5. Connection, its salts and hydrates according to claims 1, 3 or 4, where halogencyclopropanes group in the formula (I) is 1,2-cingularringtonelnl group.

6. Connection, its salts and hydrates according to claim 5, where halogencyclopropanes group in the formula (I) is pure stereochemical Deputy.

7. Connection, its salts and hydrates of claim 6, where halogencyclopropanes group in the formula (I) is (1R,2S)-2-halogencontaining group.

8. Connection, its salts and hydrates according to claim 7, where the halogen atom in halogencontaining group in the formula (I) represents a fluorine atom.

9. Connection, its salts and hydrates of claim 8 where the compound of formula (I) is the stereochemical net connection.

10. Connection, its salts and hydrates of claim 1, 2, 3, 4, 5, 6, 7, 8 or 9, where n in the formula (I) is 1.

11. Connection, its salts and hydrates of claim 10 where the compound of formula (I) is the stereochemical net connection.

12. The compound according to claim 1, which is what I 7-[3-[1-(S)-amino-1-cyclopropyl]methylpyrrolidine-1-yl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoindole-3-carboxylic acid, its salts and hydrates.

13. The compound according to claim 1 which is 5-amino-7-[3-[1-(S)-amino-1-cyclopropyl]methylpyrrolidine-1-yl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoindole-3-carboxylic acid, its salts and hydrates.

14. The compound according to claim 1 which is 5-amino-7-[3-[1-(S)-amino-1-cyclopropyl]methylpyrrolidine-1-yl]-6,8-debtor-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid, its salts and hydrates.

15. Antibacterial agent containing an effective amount of a compound, its salt or hydrate according to any one of claims 1 to 14 as an active ingredient and a pharmaceutically acceptable carrier.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 1-arenesulfonyl-2-arylpyrrolidine and piperidine of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C7)-alkyl; R2 means furyl, thienyl, pyridyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, cyano-group, CF3 or -N(R4)2; R3 means naphthyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, acetyl, cyano-group, hydroxy-(C1-C7)-alkyl, -CH2-morpholine-4-yl, (C1-C7)-alkyloxy-(C1-C7)-alkyl, (C1-C7)-alkyl-N(R4)2 or CF3; R4 means independently of one another hydrogen atom (H), (C1-C7)-alkyl with exception for (RS)-2-phenyl-1-(toluene-4-sulfonyl)pyrrolidine, (RS)-1-(toluene-4-sulfonyl)-2-p-tolylpyrrolidine, N-tosyl-cis-3-methyl-2-phenylpyrrolidine, 3-[1-(toluene-4-sulfonyl)pyrrolidine-2-yl]pyridine and N-tosyl-2-(3,4-dimethoxyphenyl)pyrrolidine, and their pharmaceutically acceptable salts also. Compounds of the formula (I) elicit the effect of agonists or antagonists of metabotropic glutamate receptors that allows their using in pharmaceutical agent useful for treatment or prophylaxis of acute and/or chronic neurological disturbances.

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 3 sch, 94 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

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

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 5-phenylpyrimidine or their pharmaceutically acceptable acid-additive salts that elicit properties of antagonists of neuropeptide receptor neurokinin-1 (NK-1). This allows their applying for treatment of such diseases as Alzheimer's disease, cerebrospinal sclerosis, attenuating syndrome in morphine withdrawal, cardiovascular alterations and so on. Compounds of invention correspond to the general formula (I):

wherein R1 means hydrogen or halogen; R2 means hydrogen, halogen atom, (lower)-alkyl or (lower)-alkoxy-group; R3 means halogen atom, trifluoromethyl group, (lower)-alkoxy-group or (lower)-alkyl; R4/R4' mean independently hydrogen atom or (lower)-alkyl; R5 means (lower)-alkyl, (lower)-alkoxy-group, amino-group, hydroxyl group, hydroxy-(lower)-alkyl, -(CH2)n-piperazinyl substituted optionally with lower alkyl, -(CH)n-morpholinyl, -(CH2)n+1-imidazolyl, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl, (lower)-alkylsulfanyl, (lower)-alkylsulfonyl, benzylamino-group, -NH-(CH2)n+1N(R4'')2, -(CH2)n-NH-(CH2)n+1N(R4'')2, -(CH2)n+1N(R4'')2 or -O-(CH2)n+1N(R4'')2 wherein R4'' means hydrogen atom or (lower)-alkyl; R6 means hydrogen atom; R2 and R6 or R1 and R6 in common with two ring carbon atoms can represent -CH=CH-CH=CH- under condition that n for R1 is 1; n means independently 0-2; X means -C(O)N(R4'')- or -N(R4'')C(O)-. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds.

15 cl, 4 sch, 86 ex

The invention relates to new derivatives of 4-phenylpyrimidine and their pharmaceutically acceptable acid additive salts, which possess the properties of receptor antagonists neirokinina(NK-1), and can be used to treat diseases, oposredstvovanii NK-1 receptor, for example, headache, Alzheimer's disease, multiple sclerosis, cardiovascular changes, oedema, chronic inflammatory diseases and so on

The invention relates to new monoethanol and hemiethanolate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine, to crystalline forms of these Atanasov, methods for producing Atanasov, methods of treatment using Atanassov and mutilates salts obtained using Atanassov

The invention relates to organic chemistry and can find application in medicine

The invention relates to pharmaceutical industry and AA derivatives of N-(aryloxyalkyl)-heteroarylboronic and-heteroarylboronic General formula (I) used to obtain drugs with antipsychotic or analgesic activity, and a method of treating psychoses by using these derivatives

The invention relates to crystalline polyhydroxylated 8-cyan-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid of formula (VI)

The invention relates to 4-hydroxy-3-chinainternational and hydrazides of General formula (I), where a represents a-CH2- or-NH-, a R1, R2, R3and R4such as defined in the claims

The invention relates to a method of obtaining the ethyl ester of 6-fluoro-7-chloro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid, which consists in the reaction of cyclization of diethyl ether 3-chloro-4-pornisinmyblood acid in the presence of, as a solvent, summer diesel fuel at a temperature of 230-245oWith

The invention relates to new proizvodnim quinoline of formula (I), where R is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and allyl; R4is hydrogen and pharmaceutically acceptable inorganic or organic anion; R5is methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, chlorine, bromine, CF3and coxFywhere x=0-2, y=1-3, provided that x+y=3; R6is hydrogen; R5and R6taken together, constitute methylendioxy

The invention relates to new compounds of General formula (I), where R1is hydrogen, alkyl with 1 to 4 carbon atoms, R2hydrogen, (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, residues of formula-CH=CH-COOR3CH2CH2COOR3, -CH2CH2CN, -CH2CH2COCH3, -CH2PINES3where R3means methyl or ethyl, or a residue of the General formula R4- NH-CHR5-CO-, where R4denotes hydrogen, alkyl with 1 to 3 atoms wereda R5denotes hydrogen, alkyl with 1 to 4 carbon atoms, or benzyl, the Invention also concerns a pharmaceutical composition having antibacterial activity, containing the compounds of formula (I)

The invention relates to new antimicrobial 5-(N-heterosomata amino) quinolone compounds of General formula I

< / BR>
where R1, R2and R3form any of a variety of quinolones and friends heterocyclic structures similar to those known socialists as having antimicrobial activity, and (2) (a) R4and R5are, independently, hydrogen, lower alkyl, cycloalkyl, heteroalkyl, or-C(=O)-X-R8where X is a covalent bond, N, O or S and R8is lower alkyl, lower alkenyl, arylalkyl, carbocyclic ring, heterocyclic ring, or (b) R4and R5together form a heterocyclic ring that includes the nitrogen to which they are attached, and their pharmaceutically acceptable salts and biokerosene esters and solvate

FIELD: medicine, antibiotics.

SUBSTANCE: invention relates to cephalosporin antibiotic - cefuroximaxetil that is used in treatment of bacterial infections. Invention proposes a new form of cefuroximaxetil not forming gel in contact with an aqueous solution. New form represents a solid solution of cefuroximaxetil in polymer and/or solid dispersion on adsorbent. New form of cefuroximaxetil can be used for preparing a granulate that can be used in oral pharmaceutical compositions as tablets or powder. Exclusion of gel-formation allows improving solubility of cefuroximaxetil that results to enhancing absorption of cefuroximaxetil in digestive tract.

EFFECT: improved pharmaceutical properties of combinations.

23 cl, 3 dwg, 8 tbl, 19 ex

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