Quinolone derivatives or its pharmaceutically acceptable salt

FIELD: chemistry.

SUBSTANCE: present invention is related to new quinolone derivatives of general formula (I) where R1: C3-6cycloalkyl or lower alkylene C3-6cycloalkyl, R2: -H or halogen, R3: -H, halogen, -OR0 or -O-(lower alkylene)-phenyl, R0: are the same or different from each other, and each represents -H or lower alkyl, R4: lower alkyl, halogen(lower alkyl), lower alkyleneC3-6cycloalkyl, C3-7cycloalkyl or a heterocyclic group, where cycloalkyl and the heterocyclic group specified in R4 can be respectively substituted, R5: -NO2, -CN, -L-Ra, -C(O)R0, -O-Rb, -N(R6)2, lower alkylene-N(R6)(Rc), -N(R6)C(O)-Rd, lower alkylene-N(R6)C(O)-Rd, lower alkylene-N(R0)C(O)O-(lower alkyl), -N(R0)C(O)N(R0)-Re, lower alkylene-N(R0)C(O)N(R0)-Re, -N(R0)S(O)2N(R0)C(O)-Rd, -CH=NOH, C3-6cycloalkyl, (2,4-dioxo-1,3-thiazolidin-5-yliden)methyl or (4-oxo-2-tioxo-1,3-thiazolidin-5-yliden)methyl where cycloalkyl specified in R5 can be respectively substituted, R6: H, lower alkyl, lower alkylene-CO2R0 or lower alkylene-P(O)((OPp)2, where lower alkylene specified in R6 can be substituted, L: lower alkylene or lower alkenylene which can be respectively substituted, Ra: -OR0, -O-(lower alkylene)-phenyl, -O-(lower alkylene)-CO2R0, -CO2R0, -C(O)NHOH, -C(O)N(R6)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-phenyl, -C(O)N(R0)-S(O)2-(heterocyclic group), -NH2OH, -OC(O)R0, -OC(O)-(halogen(lower alkyl)), -P(O)(ORp)2, phenyl or the heterocyclic group where phenyl or the heterocyclic group specified in Ra can be substituted, Rp: R0, lower alkylene-OC(O)-(lower alkyl), lower alkylene-OC(O)-C3-6cycloalkyl, lower alkylene-OC(O)O-(lower alkyl), Rb: H, lower alkylene-Rba or lower alkenylene-Rba where lower alkylene or lower alkenylene specified in Rb can be substituted, Rba: -OR0, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-[phenyl, -C(NH2)-NOH, -C(NH2)=NO-C(O)-(lower alkylene)-C(O)R0, -CO2-(lower alkylene)-phenyl, -P(O)(ORp)2, -C(O)R0, -C(O)-phenyl, C3-6cycloalkyl, phenyl or the heterocyclic group where phenyl and the heterocyclic group specified in Rba can be substituted, Rc: H, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-P(O)((OPp)2, phenyl where lower alkylene and phenyl are specified in Rd can be substituted, Rd: C1-7-alkyl, lower alkenyl, halogen(lower alkyl), lower alkylene-Rda, lower alkylenylene-Rda, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where lower alkylene, cycloalkyl, phenyl, naphthyl and the heterocyclic group specified in Rd can be substituted, Rda: -CN, -OR0, -O-(lower alkylene)-CO2R0, -O-naphthyl, -CO2R0, -CO2-(lower alkylene)-N(R0)2, -P(O)(ORp)2, -N(R6)2, -C(O)N(R0)-phenyl, -C(O)N(R0)-(lower alkylene which can be used by -CO2R0)-phenyl, -N(R0)C(O)-phenyl, -N(R0)C(O)-OR0, -N(R0)C(O)-O-(lower alkylene)-phenyl, -N(R0)S(O)2-phenyl, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where phenyl, naphthyl and heterocyclic group specified in Ra can be substituted, Re: lower alkylene-CO2R0, phenyl, -S(O)2-phenyl or -S(O)2-(heterocyclic group), where phenyl and the heterocyclic group specified in Re can be substituted, X: CH, A: C(R7), R7: -H, or R4 and R7 together can form lower alkylene, where the substituted groups have the substituted specified in cl.1, and provided 7-(cyclohexylamino)-1-ethyl-6-fluor-4-oxo-1,4-dohydroquinoline-3-carbonitryl is excluded. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I) and application of formula (I) for preparing a thrombocyte aggregation inhibitor or a P2Y12 inhibitor.

EFFECT: there are produced new quinol-4-one derivatives showing effective biological properties.

11 cl, 83 tbl, 71 ex

 

Description

The technical field

The present invention relates to a pharmaceutical agent, in particular a new quinolone derivative or its pharmaceutically acceptable salts, which are applicable as platelet aggregation inhibitors or inhibitors of P2Y12.

Background of invention

Platelets after opening their Donne et al. in 1842 a long time regarded as a component of blood necessary for hemostasis. Currently, it is shown that platelets not only play a leading role in the mechanism of hemostasis, but also are noteworthy in terms of the clinical application of multi-functional properties, such as associated with the manifestation of arteriosclerosis, diseases of the circulatory system, including thrombotic diseases, metastasis, inflammation, rejection after transplantation and immune response.

As a rule, therapy for reperfusion of blood with a pharmaceutical or physical methods is carried out in case of thrombotic diseases and ischemic diseases. However, recently discovered causing clinical problems is the phenomenon in which the activation, adhesion and aggregation of platelets accelerated after the implementation of revascularization due to the destruction of the tissues of the blood vessels, including endothelial cells, or the collapse of the equilibrium fibrinolysis-coagulation, caused by the medicinal product. For example, it is shown that the recirculated through the treatment of thrombolytic agents with the use of t-PA or similar means are activated ability to fibrinolysis and the ability to cut and disrupted the balance of the fibrinolysis-coagulation. Clinically, this leads to re-obstruction, which is a major therapeutic problem (non-patent reference 1).

On the other hand, RTS therapy or method of a permanent stent quickly promoted and achieve certain results in the case of treatment of diseases which are based on angina, myocardial infarction, and such as stricture of the coronary artery and stricture of the aorta. However, since these treatments damage the tissue of the blood vessels, including endothelial cells, there are problems of acute coronary obstruction and other restructure that occurs in the chronic phase. Platelets play an important role in various thrombolytic side effects (reabstraction etc.) after revascularization. Thus, despite the expected effectiveness of antithrombotic agents, a sufficient effect of conventional antithrombotic funds is not confirmed.

As preventive or therapeutic agents for such diseases of the circulatory system IP is resultsa aspirin, Cilostazol, prostaglandin I2, prostaglandin E1, ticlopidine, clopidogrel, dipyridamole and similar inhibitors of platelet aggregation. Also recently developed antagonist GPIIb/IIIa, which inhibits the final stage of platelet aggregation and has a strong activity of inhibiting platelet aggregation, but its application is limited to intravenous drip infusion in acute phase of thrombosis (non-patent reference 2).

In recent years shows that in respect of ticlopidine and clopidogrel, which is used as antithrombotic funds, such funds are active inhibition of platelet aggregation through inhibition as P2Y12 receptor ADP (ADP) due to their active metabolites. Further, there are reports derived triazolo[4,5-D]pyrimidine (patent reference 1), a derivative of piperazine and/or homopiperazine (patent reference 2 and patent reference 3), derived pyrazolidinone (patent reference 4), derived athinaikon (patent reference 5) and similar compounds as compounds having activity of inhibiting P2Y12.

On the other hand, patent references 6 and 7 known quinolone derivatives.

Patent reference 6 know the compound represented by formula (A)which have an antimicrobial effect, but information about its activity Engibarov what I platelet aggregation are not given. In addition, its structure differs from the structure of the compounds of the present invention in the sense that the group, which corresponds to R5in the compound of the present invention, represents a carboxyl group, ester group or carbarnoyl

(In the formula, R1represents-OR9the amino group or a lower alkylamino and R9represents a hydrogen atom or carboxyamide group. The value of the other characters see in this message.)

In patent reference 7 it is reported that a compound represented by the formula (V), has the activity of inhibiting P2Y12. However, its structure differs from the structure of the compounds of the present invention in the sense that the group, which corresponds to R5in the compound of the present invention, is a carbarnoyl

(The meaning of the symbols in the above formula, see this message.)

In the patent reference 8 it is reported that a compound represented by the formula (C), has the activity of inhibiting P2Y12. However, its structure differs from the structure of the compounds of the present invention in the sense that the group, which corresponds to R5in the compound of the present invention, is a carbarnoyl

(The meaning of the symbols in the above formula, see this message.)

Non-patent reference 1: “Journal of American College of Cardiology”, 1998, vol.12, p. 616-623.

Non-patent reference 2: “Sogo Rinsho (Synthetic Clinic)”, 2003, vol.52, p. 1516-1521.

Patent reference 1: international publication WO 00/34283.

Patent reference 2: international publication WO 02/098856.

Patent reference 3: international publication WO 03/022214.

Patent reference 4: international publication WO 05/000281.

Patent reference 5: international publication WO 05/035520.

Patent reference 6: international publication WO 98/23592.

Patent reference 7: international publication WO 05/009971.

Patent reference 8: international publication WO 06/077851.

Disclosure of invention

Problems are addressed invention

In such a situation is highly desirable development of antithrombotic agents with high profile security weakened unwanted effect bleeding and with a distinct pharmaceutical efficiency not only in the acute phase, but also in the chronic phase. Thus, the objective of the invention is to develop an inhibitor of platelet aggregation or P2Y12 inhibitor with strong pharmacological action and a good balance between pharmacological effect and safety profile.

Solutions to problems

For the NGOs, the authors of the present invention conducted intensive studies to overcome the above problems and as a result discovered that a new quinolone derivative has excellent activity of inhibiting platelet aggregation or activity inhibition of P2Y12 and has excellent pharmacokinetics, and thus have accomplished the present invention.

In other words, the present invention relates to quinolone derivative represented by the following General formula (I)or its pharmaceutically acceptable salt

[Symbols in the formula have the meanings specified below.]

R1: cycloalkyl or lower alkyltrimethyl where cycloalkyl in R1may be substituted,

R2: -H or halogen,

R3: -H, halogen, -OR0or-O-(lower alkylene)-aryl,

R0: the same or different from one another and each represents-H or lower alkyl,

R4: lower alkyl, halogen(lower alkyl), lower alkylbenzoates, cycloalkyl or heterocyclic group,

where specified in R4cycloalkyl and heterocyclic group may be respectively substituted,

R5: -NO2, -CN, lower alkyl, lower alkenyl, halogen(lower alkenyl), -L-Ra, -C(O)R0, -O-Rb, -N(R6)2lowest Alki the EN-N(R 6)(Rc), -N(R6)C(O)-Rdlowest alkylene-N(R6)C(O)-Rdlowest alkylene-N(R0)C(O)O-(lower alkyl), -N(R0)C(O)N(R0)-Relowest alkylene-N(R0)C(O)N(R0)-Re, -N(R0)S(O)2N(R0)C(O)-Rd, -CH=NOH, cycloalkyl, heterocyclic group, (2,4-dioxo-1,3-thiazolidin-5-ilidene)methyl or (4-oxo-2-thioxo-1,3-thiazolidin-5-ilidene)methyl,

where specified in R5cycloalkyl and heterocyclic group may be respectively substituted,

R6: H, lower alkyl, lower alkylene-CO2R0or lower alkylene-P(O)(ORp)2,

where specified in R6lowest alkylene may be substituted,

L: low alkylene or lower albaniles, which may be respectively substituted,

Rand: -OR0, -CN, -O-(lower alkylene)-aryl, -O-(lower alkylene)-CO2R0, -C(O)R0, -CO2R0, -C(O)NHOH, -C(O)N(R6)2, -C(O)N(R0)-aryl, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-aryl, -C(O)N(R0)-S(O)2-(heterocyclic group), -NH2OH, -OC(O)R0, -OC(O)-halo(lower alkyl), -P(O)(ORp)2, aryl or heterocyclic group,

where specified in Randthe aryl and heterocyclic group may be substituted,

RR: R0lowest alkylene-OC(O)-(lower alkyl), lower alkylene-OC(O)-cyclea the keel, lowest alkylene-OC(O)O-(lower alkyl), lower alkylene-OC(O)O-cycloalkyl or lower alkylene-(heterocyclic group),

where specified in RRheterocyclic group may be substituted,

Rb: N, cycloalkyl, aryl, heterocyclic group, lower alkylene-Rbor lower albaniles-Rb,

where specified in Rblowest alkylene, lower albaniles, cycloalkyl, aryl and heterocyclic group may be substituted,

Rba: -OR0, -O-Si(lower alkyl)3, -CO2R0, -C(O)NHOH, -C(O)N(R0)2-C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-aryl, -C(NH2)=NOH, -C(NH2)=NO-C(O)R0, -C(NH2)=NO-C(O)-(lower alkylene)-C(O)R0, -CO2-(lower alkylene)-aryl, -P(O)(ORp)2, -C(O)R0-C(O)-aryl, cycloalkyl, aryl or heterocyclic group,

where specified in Rbathe aryl and heterocyclic group may be substituted,

Rwith: H, lower alkyl, lower alkylene-OR0lowest alkylene-CO2R0lowest alkylen-C(O)NHOH, lower alkylene-C(O)N(R0)2lowest alkylene-P(O)(ORp)2lowest alkylaryl, lower alkylene-(heterocyclic group), aryl or heterocyclic group,

where specified in Rwithlowest alkylene, aryl and heterocyclic group may be substituted,

Rd: C1-7 -alkyl, lower alkenyl, halogen(lower alkyl), lower alkylene-Rdalowest albaniles-Rdacycloalkyl, aryl or heterocyclic group,

where specified in Rdlowest alkylene, lower albaniles, cycloalkyl, aryl and heterocyclic group may be substituted,

Rda: -CN, -OR0, -OC(O)R0, -O-(lower alkylene)-CO2R0, -O-aryl, -CO2R0, -C(O)NHOH, -C(O)N(R0)2, -CO2-(lower alkylene)-N(R0)2, -P(O)(ORp)2, -N(R6)2, -N(R0)C(O)R0-C(O)N(R0)-aryl, -C(O)N(R0)-(lower alkylene, which may be substituted by-CO2R0)-aryl, -N(R0)C(O)-aryl, -N(R0)C(O)-or SIG0, -N(R0)C(O)-O-(lower alkylene)-aryl, -N(R0)S(O)2-aryl, -S-heterocyclic group, -C(O)N(R0)-(heterocyclic group), -N(R0)C(O)-(heterocyclic group), cycloalkyl, aryl or heterocyclic group,

where specified in Rdacycloalkyl, aryl and heterocyclic group may be substituted,

Re: lower alkylene-CO2R0lowest alkylen-C(O)NHOH, lower alkylene-C(O)N(R0)2lowest alkylen-(heterocyclic group), aryl, heterocyclic group, -S(O)2-aryl or-S(O)2-(heterocyclic group),

where specified in Rethe aryl and heterocyclic group may be substituted is,

X: CH or N,

A: C(R7or N,

R7: -H, lower alkyl,

or R4and R7together may form a lower alkylene, which may be substituted,

provided that

excluded 7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbonitrile. The same will be true in this description later.]

In addition, this application relates to a pharmaceutical agent, in particular an inhibitor of the P2Y12 receptor and/or an inhibitor of platelet aggregation, which includes a quinolone derivative represented by the General formula (I)or its salt as an active ingredient.

In addition, this application also relates to the use of compounds represented by the General formula (I)or its pharmaceutically acceptable salt to obtain inhibitor of the P2Y12 receptor and/or inhibitor of platelet aggregation and to a method of treatment of diseases of the circulatory system, closely associated with thrombus formation by platelet aggregation, which includes an introduction to the patient an effective amount of the compound represented by the General formula (I)or its pharmaceutically acceptable salt. In other words, the invention also relates to (1) pharmaceutical compositions comprising a compound described by the General formula (I)or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier

(2) the pharmaceutical composition according to (1), which is an inhibitor of platelet aggregation;

(3) the pharmaceutical composition according to (1), which is a P2Y12 inhibitor;

(4) the use of compounds described by the General formula (I)or its pharmaceutically acceptable salt to obtain an inhibitor of platelet aggregation or P2Y12 inhibitor.

Action inventions

Since the compound of the present invention has excellent activity of inhibiting platelet aggregation or activity inhibition of P2Y12, it is applicable as pharmaceuticals, in particular inhibitor of platelet aggregation or P2Y12 inhibitor. Accordingly, the connection according to the present invention is applicable as a tool for prevention and/or treatment of diseases of the circulatory system, closely associated with thrombus formation by platelet aggregation, such as unstable angina and acute myocardial infarction, and to prevent its recurrence, re-obstruction and restricture after bypass surgery coronary artery surgery RTSA or surgery stent placement, acceleration of thrombolysis in coronary artery and prevent re-obstruction and similar ischemic diseases such as cerebral infarction with transient ischemic violation of the Ministry of health the new blood (TIA), subarachnoid hemorrhage (vasospasm) and a similar stroke; chronic occlusion of arteries and such peripheral artery disease; and similar diseases; and as an aid in heart surgery or surgery on the blood vessels.

The best way of carrying out the invention

Further, the present invention is described in detail.

In this specification, "lower alkyl", "lower alkenyl", "lower alkylene" and "lower albaniles" indicate, respectively, the hydrocarbon chain with 1-6 carbon atoms which may be straight or branched, unless otherwise specified.

Accordingly, the "lower alkyl" denotes a1-6-alkyl, and its illustrative examples include methyl, ethyl, propyl, butyl, pentyl or hexyl or their structural isomers such as isopropyl, tert-butyl or the like, preferably1-5-alkyl, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or 3-pentyl.

"Lower alkenyl" means2-6alkenyl, and it may contain two or more double bonds. Its illustrative examples include ethynyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl and the like, of which the preferred is2-3alkenyl, and more preferred is ethynyl or propenyl.

"Lower alkylene" means dvuhvalenten the th group, formed by removing one hydrogen atom from any position "lower alkyl", and is, as a clarification, methylene METROTILE, ethylene, propylene, butylene, or similar group, preferably1-4-alkylene, preferably methylene METROTILE, ethylene or propylene.

"Lower albaniles" denotes a divalent group formed by removing one hydrogen atom from any position "lower alkenyl", and is, as a clarification, vinile, propylen, butylen or similar group, preferably2-3-albaniles preferred vinile, propylen.

"Halogen" denotes a monovalent group formed by halogen atom, and as a clarification, you can call the group of fluorine, chlorine, bromine, iodine or the like, of which the preferred fluorine or chlorine.

"Halo(lower alkyl)" refers to a group in which at least one of any of a hydrogen atom of the above "lower alkyl" substituted by the above-mentioned "halogen", and its illustrative examples include trifluoromethyl, triptorelin or similar group of which the preferred is trifluoromethyl.

"Halogen(lower alkenyl)" refers to a group in which at least one of any of a hydrogen atom of the above "lower alkenyl" substituted by the above-mentioned "halogen", and his belt is sustained fashion examples include torvinen, the chloride or a similar group.

"Cycloalkyl" means nonaromatic3-10is a hydrocarbon cycle, and it can form a bridge loop or spirits, partially contain an unsaturated bond or be condensed with a benzene cycle. However, when cycloalkyl" condensed with the benzene ring cycle, the position of the join is on the non-aromatic cycle. Illustrative examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclohexenyl, cyclooctadiene, substituted, norbornyl, indanyl with the place of attachment in position 1-3, etc. are Preferred cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and more preferred cyclopentyl or cyclohexyl.

"Aryl" means a monocyclic-tricyclic aromatic With6-14is a hydrocarbon cycle, and its illustrative examples include phenyl, naphthyl, or similar group of which the preferred phenyl. In addition, the "aryl" may condense With5-8-cycloalkyl. However, when the "aryl" of condensed with cycloalkyl, the position of the join is on the aromatic cycle. For example, "aryl" may form indanyl with the place of connection in positions 4-7 or tetrahydronaphthalen with the place of connection in positions 5-8.

"Heterocycle" is a common name, which is includes "aromatic heterocycle" and "the non-aromatic heterocycle". "Aromatic heterocycle" denotes a monocyclic aromatic heterocycle, which is a monocyclic 5-7-membered aromatic group containing from 1 to 4 identical or different heteroatoms selected from the group consisting of nitrogen atoms, oxygen, and sulfur, a bicyclic aromatic heterocycle, in which the condensed monocyclic aromatic heterocycle or monocyclic aromatic heterocycle condensed with the benzene ring cycle, or tricyclic aromatic heterocycle, in which the bicyclic aromatic heterocycle condensed with a monocyclic aromatic heterocycle or a benzene cycle. Its illustrative examples include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furutani, pyridyl, pyranyl, tiopronin, pyridazinyl, pyrimidinyl, Persil, indolyl, isoindolyl, indolizinyl, benzofuran, benzothiazyl, benzoimidazolyl, indazoles, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzoxazolyl, hinely, ethanolic, bromanil, benzothiophene, phthalazine, naphthyridine, honokalani, hintline, cinnoline, benzodioxolyl, benzodioxolyl, benzodioxepine, carbazolyl and similar groups, and the nitrogen atom and/or sulfur atom contained in such cycles can to be oxidized. Moreover, these cycles can is to be partially saturated. Preferred are pyridyl, furyl, thienyl, indolyl or chinosol.

"The non-aromatic heterocycle" means a saturated or partially saturated monocyclic 3 to 10-membered, preferably 5 to 7-membered monocyclic nonaromatic a heterocycle, which contains 1 to 4 heteroatoms selected from O, S and N, bicyclic nonaromatic a heterocycle, in which the condensed monocyclic nonaromatic heterocycle or monocyclic nonaromatic a heterocycle condensed with a monocyclic nonaromatic a heterocycle, With5-8-cycloalkyl, benzene cycle or aromatic heterocycle or tricyclic nonaromatic a heterocycle, in which the bicyclic nonaromatic a heterocycle condensed with C5-8-cycloalkyl, benzene cycle or aromatic heterocycle. These heterocycles can form the oxide or dioxide through oxidation of S or N as cyclic atom or may form a bridging loop or spirits. Their illustrative examples include hydropyridine, dihydropyrrole, dihydrooxazolo, dihydrothiazolo, dihydroimidazole, piperidyl, morpholinyl, thiomorpholine, piperazinil, pyrazolidine, imidazolidine, pyrrolidinyl, oxazolidinyl, diazolidinyl, azepane, homopiperazine, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrimidines, Romanel, DIOXOLANYL, homomorpholine and similar groups. Preferred are pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholine or piperazinil.

The term "may be substituted" means unsubstituted or substituted by same or different 1 to 5 substituents".

In the description of the substituents, are acceptable as substitutes in case of the expression "which may be substituted", it is enough to include the substituents commonly used in the technique as a substitute for specific groups. In addition, when there are two groups or more, as in the case for R0in-N(R0)2corresponding groups can be the same or different from each other.

As the acceptable substituent for the "lowest alkylene", which can be substituted in the case of R6you can mention preferably halogen.

Preferably a group selected from the following group G1you can mention as an acceptable substitute for "lower alkylene" and "lower Alcanena", which can be substituted in the case of L; "lower alkylene" and "lower Alcanena", which can be substituted in the case of Rb; "lower alkylene", which can be substituted in the case of Rc; "lower alkylene" and "lower Alcanena", which can be substituted in the case of Rd; and educated R4and R7 "lower alkylene", which can be overridden.

Group G1: halogen, -OR0, -CO2R0and-CO2-(lower alkylene)-aryl.

Preferably a group selected from the following group G2you can mention as an acceptable substitute for "cycloalkyl", which can be substituted in the case of R1; "cycloalkyl", which can be substituted in the case of R4; "cycloalkyl", which can be substituted in the case of R5; "cycloalkyl", which can be substituted in the case of Rb; "cycloalkyl", which can be substituted in the case of Rd; and "cycloalkyl", which can be substituted in the case of Rda.

Group G2: halogen, lower alkyl, -OR0, -CO2R0and-C(O)-aryl.

Preferably a group selected from the following group G3you can mention as an acceptable substitute for "aryl"which may be substituted in the case of Rand; "aryl"which may be substituted in the case of Rb; "aryl"which may be substituted in Rb; "aryl"which may be substituted in the case of Rwith; "aryl"which may be substituted in the case of Rda; and the "aryl"which may be substituted in the case of Re.

Group G3: halogen, -CN, lower alkyl, halo(lower alkyl), -OR0, -O-(halo(lower alkyl)), -CO R0and-O-(lower alkylene)-CO2R0.

Preferably a group selected from the following group G4you can mention as an acceptable substitute for "aryl"which may be substituted in Rd.

Group G4: halogen, -CN, -NO2, lower alkyl, halo(lower alkyl), -OR0, -O-(halo(lower alkyl)), -C(O)R0, -CO2R0lowest alkylene-CO2R0, -O-(lower alkylene)-CO2R0, -OC(O)R0, -N(R0)2, -S(O)2-(lower alkyl), aryl and heterocyclic group. However, the aryl and heterocyclic group in the group G4may be substituted by a group Q.

Group Q: halogen, lower alkyl, halo(lower alkyl), -OR0, -O-(halo(lower alkyl)), oxo and-CO2R0.

Preferably a group selected from the following group G5you can mention as an acceptable substitute for "heterocyclic group"which may be substituted in the case of R4; "heterocyclic group"which may be substituted in the case of R5; "heterocyclic group"which may be substituted in the case of Rand; "heterocyclic group"which may be substituted in the case of Rb; "heterocyclic group"which may be substituted in the case of RR; "heterocyclic group"which may be substituted in case the e R b; and "heterocyclic group"which may be substituted in the case of Re.

Group G5: halogen, lower alkyl, halo(lower alkyl), -OR0, -O-(halo(lower alkyl)), oxo, -CO2R0lowest alkylene-CO2R0and-S(O)2-(lower alkyl).

Preferably a group selected from the following group G6you can mention as an acceptable substitute for "heterocyclic group"which may be substituted in the case of Rwith; and "heterocyclic group"which may be substituted in the case of Rda.

Group G6: halogen, lower alkyl, halo(lower alkyl), -OR0, -O-(halo(lower alkyl)), oxo, -CO2R0lowest alkylen-C(O)2R0, -S(O)2-(lower alkyl), aryl, -S-(lower alkylene)-aryl and a heterocyclic group.

In this regard, the aryl and heterocyclic group in the group G6may be substituted by a group selected from the above group Q.

Preferably a group selected from the following group G7you can mention as an acceptable substitute for "heterocyclic group"which may be substituted in the case of Rd.

Group G7: halogen, nitro, lower alkyl, halo(lower alkyl), -OR0, -O-(halo(lower alkyl)), oxo, -CO2R0lowest alkylene-CO2R0, -N(R0) , -S(O)2-(lower alkyl), -S(O)2-aryl, aryl, lower alkylaryl, heterocyclic group, (lower alkylene)-(heterocyclic group),- S-(lower alkylene)-CO2R0.

In this regard, the aryl and heterocyclic group in the group G7may be substituted by a group selected from the above group Q.

The preferred embodiment of the present invention shown next.

(a) Preferred R1is cyclohexyl or cyclopropylmethyl, preferably cyclohexyl.

(b) Preferred R2is-F.

(C) Preferred R3is-H, -HE or-F, is preferred.

(d) Preferred R4is lower alkyl or cycloalkyl, preferably isopropyl, 3-pentyl or cyclopentyl, even more preferred is isopropyl, 3-pentyl or cyclopentyl.

(e) Preferred R5is-N(R0)C(O)-(lower alkylene)-CO2R0, -N(R0)C(O)-(lower albaniles)-CO2R0lowest alkylene-CO2R0lowest albaniles-CO2R0, -O-(lower albaniles)-CO2R0, -O-(lower alkylene, which may be substituted by-CO2R0)-aryl, -O-(lower albaniles)-CO2R0, -O-(lower albaniles, which may be substituted by-CO2R0)-aryl or-O-(lower albaniles)tetrazolyl, prefer the INEE-N(R 0)C(O)-(lower alkylene)-CO2R0lowest alkylene-CO2R0lowest albaniles-CO2R0, -O-(lower alkylene)-CO2R0, -O-(lower alkylene, which may be substituted by-CO2R0)-aryl or-O-(lower albaniles)-CO2R0even more preferred lower albaniles-CO2R0or-O-(lower alkylene)-CO2R0.

(f) Preferred X is CH.

(g) is Preferred And is SN.

Also more preferred is a compound that includes a combination of the above preferred groups (a)-(g).

Also the following shows another preferred embodiment of the compounds of the present invention represented by the General formula (I).

(1) the Compound described General formula (I), where X represents CH.

(2) the Compound described in (1), where R3represents-H, -HE or-F.

(3) the Compound described in (2), where a represents CH.

(4) the Compound described in (3), where R1represents a cyclohexyl or cyclopropylmethyl.

(5) the Compound described in (4), where R2is a-F.

(6) the Compound described in (5), where R4represents a lower alkyl or cycloalkyl.

(7) the Compound described in (6), where R5represents-N(R0)C(O)-(lower alkylene)-CO2R0lowest alkylene-CO2/sub> R0lowest albaniles-CO2R0, -O-(lower alkylene)-CO2R0, -O-(lower alkylene, which may be substituted by-CO2R0)-aryl or-O-(lower albaniles)-CO2R0.

(8) the Compound described by the General formula (I), which is selected from the group which consists of

4-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]amino}-4-oxobutanoic acid,

5-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]amino}-5-oxopentanoic acid,

(2E)-3-[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]acrylic acid,

(2S)-2-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]oxy}-3-phenylpropane acid,

(2E)-3-[7-(cyclohexylamino)-6-fluoro-1-isopropyl-4-oxo-1,4-dihydroquinoline-3-yl]acrylic acid,

(2S)-2-{[7-(cyclohexylamino)-6-fluoro-1-isopropyl-4-oxo-1,4-dihydroquinoline-3-yl]oxy}-3-phenylpropane acid,

(2S)-2-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]oxy}propanoic acid and

(2S)-2-{[7-(cyclohexylamino)-6-fluoro-1-isopropyl-4-oxo-1,4-dihydroquinoline-3-yl]oxy}propanoic acid,

or its pharmaceutically acceptable salt.

Also compounds of the present invention may form salts, and such salts are included in the compounds of the present invention, if they are farmaci is almost acceptable salts. Their illustrative examples include acid additive salts formed with inorganic acids (e.g. hydrochloric acid, Hydrobromic acid, itestosterone acid, sulfuric acid, nitric acid, phosphoric acid, etc. or organic acids (e.g. formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, econsultancy acid, p-toluensulfonate acid, aspartic acid, glutamic acid and the like), salts with inorganic bases, including metal salts (e.g. sodium, potassium, calcium, magnesium and the like), or salts of metals of the main character (for example, methylamine, ethylamine, ethanolamine, lysine, ornithine and the like), ammonium salts and such salts.

In addition, in some cases, depending on the type of substituents of the compounds of the present invention may contain an asymmetric carbon atom, and in this regard may be optical isomers. The present invention includes all mixtures and isolated forms of these optical isomers. The compounds of the present invention in some cases can be tauto the career, and the present invention includes separate forms of these isomers or a mixture thereof. In addition, the labeled substance, namely, a compound in which at least one atom of the compounds according to the present invention is replaced with a radioactive or non-radioactive isotope, is also in the scope of the present invention.

In addition, the invention also includes various types of hydrate and solvate or polymorph of the compound of the present invention. In this regard, as discussed, the compounds of the present invention is not limited to the compounds described in the examples which follow, and includes all derivative represented by the formula (I)and their pharmaceutically acceptable salts.

In this connection, all connections, which in vivo into the compounds of the present invention represented by the above General formula (I), so-called prodrugs, are also included in the compounds of the present invention. As examples of groups that can form prodrugs of the compounds of the present invention, include groups described in Prog. Med., 5: 2157-2161 (1985), and the groups described in “Iyakuhin no Kaihatsu (Development of Medicines)”, vol.7, Bunshi Sekkei (Molecular Design), pp. 163-198, publication Hirokawa Shoten, 1990.

Ways to get

The compound of the present invention and its pharmaceutically PR is acceptable salt can be obtained by using various known synthesis methods using features based on its primary structure or the form of substituents. Examples of typical methods of obtaining follow. In this regard, depending on the type of functional group, effectively, from the point of view of technology, to replace the specified functional group suitable protective group, namely a group which can easily turn into a specified functional group at the stage of initial substance - intermediate substance. Then the desired compound can be obtained by removing the protective group as required by the situation. Examples of functional groups include hydroxyl group, carboxyl group, amino group and similar groups, as well as their protective groups can be called protective groups described in “Protective Groups in Organic Synthesis (third edition)”, editors Greene and Wuts, which can optionally be used in accordance with the reaction conditions.

The first method of obtaining

(In the above formulas, L1represents a removable group, such as halogen, -O-methanesulfonyl, -O-para-toluensulfonyl or similar. The same is true for the description below.)

Stage And

This stage is the stage at which the compound (I-a) according to the present invention is obtained by reduction of compound (1).

In response recovery at this stage m is tenderly to use the reaction for reduction of carboxylic acids or ether complex, usually used by experts in the field of technology. For example, the reaction can be performed under cooling and boiling under reflux using equimolar or excess amount of a reducing agent, such as alumalite lithium hydride diisobutylaluminum, borohydride sodium or the like, when interacting in an inert solvent, for example aromatic hydrocarbons such as benzene, toluene, xylene, ethers, such as diethyl ether, tetrahydrofuran (THF), dioxane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-the organic (NMP), dimethyl sulfoxide (DMSO), acetonitrile, alcohols, such as methanol, ethanol, and water. In addition, when the compound (1) is a carboxylic acid, where R0represents-H, a carboxylic acid can also be recovered after turning it on Riccione-able derivative. As a reactive carboxylic acid derivative can be called allmydata obtained by the interaction with 1,1'-carbonyl diimidazol (CDI), a mixed anhydride obtained by the interaction with isobutylparaben, etc. and similar derivatives.

Stage

This stage is the stage at which the compound (I-b) this image is meniu obtained by oxidation of compound (I-a) according to the present invention.

In oxidation reactions at this stage you can use the oxidation reaction of alcohols typically used by experts in the field of technology. For example, the reaction can be performed at a temperature of from room temperature to heating using an equivalent to excess amount of manganese dioxide as an oxidizing agent, in a solvent such as the aforementioned aromatic hydrocarbons, halogenated hydrocarbons or similar.

Stage

This stage is the stage at which the compound (I-C) according to the present invention receives, by subjecting compound (I-b) according to the present invention the reaction of oxidative rearrangement (Bayer-Villiger) and then hydrolysis.

The reaction of oxidative rearrangement at this stage can be performed at a temperature of from room temperature to heating using an equivalent to excess amount of m-chloroperbenzoic acid, peracetic acid, aqueous hydrogen peroxide or similar compound as an oxidizing agent in a solvent inert to the reaction, such as the aforementioned aromatic hydrocarbons, halogenated hydrocarbons, acetic acid, water or a similar solvent.

The hydrolysis reaction at this stage can be done using the hydrolysis of esters commonly used is the illusion in the art. For example, the reaction can be carried out during cooling and during heating in an inert reaction solvent such as the aforementioned aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols, DMF, DMA, NMP, DMSO, pyridine, water or similar solvent, in the presence of a mineral acid, such as sulfuric acid, hydrochloric acid, Hydrobromic acid or the like acid, or organic acids such as formic acid, acetic acid or a similar acid, or in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, or ammonia, or similar grounds.

Depending on the form of compounds, the compound (I-c) can be obtained in some cases by hydrolysis during the reaction of oxidative rearrangement.

Stage D

This stage is the stage at which the compound (I-d) according to the present invention receives, by subjecting compound (I-C) according to the present invention the reaction of nucleophilic substitution.

The reaction of nucleophilic substitution at this stage can be done using an equivalent to excess amount of compound (2) from room temperature to heating in a solvent such as the aforementioned aromatic hydrocarbons, simple is Fira, halogenated hydrocarbons, DMF, DMA, NMP, DMSO or a similar solvent, in the presence of a base such as potassium carbonate, tert-piperonyl potassium, sodium hydride, triethylamine or similar basis.

The second way to obtain

(In the above formulas, R10and R11denote-H, halogen, -CO2R0or lower alkyl or aryl, which may be respectively substituted, and R20denotes the remainder of the reagent Horner-Emmons (4), R21denotes the rest of the phosphonium salts of (5), Xand-denotes Cl-, Br-or similar counterion and R22denotes the rest of the ylides connection (6)).

Stage E

This stage is the stage at which the compound (I-e) according to the present invention receives, by subjecting compound (I-b) according to the present invention the reaction of reductive alkylation.

As the reaction of the reductive alkylation at this stage you can use the reaction of reductive alkylation, usually used by experts in the field of technology. For example, we can mention the method described in “Jikken Called Koza (Experimental Chemistry Course)”, the editors of the Chemical Society of Japan, Vol.20 (1992) (Maruzen), or similar methods. Interaction is desirable to carry out when cooling and up to boiling with a reverse holodilniki using a reducing agent, such as sodium borohydride, triacetoxyborohydride sodium, or similar reducing agent in the absence of solvent or in an inert reaction solvent such as the aforementioned aromatic hydrocarbons, ethers, alcohols, esters, including ethyl acetate or similar esters, acetic acid or a similar solvent. Depending on the connection in some cases it is advantageous to carry out interaction in the presence of organic acids, such as sulfuric acid, hydrochloric acid, Hydrobromic acid or similar mineral acid, formic acid, acetic acid or like organic acid or a Lewis acid such as titanium chloride(IV), tetraisopropyldisiloxane or similar acid. In addition, the interaction can also be carried out at room temperature and heated in a hydrogen atmosphere at normal pressure and at high pressure using a catalyst, for example palladium-on-charcoal, rhodium-on-charcoal, Raney Nickel, platinum or the like, in an inert reaction solvent such as the aforementioned aromatic hydrocarbons, esters, ethers, halogenated hydrocarbons, DMF, DMA, NMP, acetonitrile, acetic acid or a similar solvent. Depending on the connection in some cases for the smooth PR is takane reaction it is advantageous to carry out interaction in the presence of an acid (preferably hydrochloric acid, acetic acid or similar acid).

Stage F

This stage is the stage at which the compound (I-f) according to the present invention receives, by subjecting compound (I-b) according to the present invention the reaction Horner-Emmons or Wittig.

For the reaction Horner-Emmons or Wittig at this stage you can use the method commonly used by experts in the field of technology. For example, when using a reagent Horner-Emmons (4) or phosphonium salt of (5), the interaction can be performed during cooling and during heating using potassium carbonate, tert-butoxide potassium, sodium hydride, n-utility or similar alkylate or similar compound as the base, in a solvent such as the aforementioned aromatic hydrocarbons, ethers, halogenated hydrocarbons, DMF, DMA, NMP, DMSO, acetonitrile or a similar solvent. Also, when using ylides connection (6), the interaction can be performed during cooling and during heating in a solvent such as the aforementioned aromatic hydrocarbons, ethers, halogenated hydrocarbons, DMF, DMA, NMP, DMSO, acetonitrile or a similar solvent.

Stage G

This stage is the stage at which the compound (I-g) according to the present invention is obtained by restoring the double bond of the compound (I-f) on us is oedema invention.

For the reaction of recovery at this stage you can use the method commonly used by experts in the field of technology. For example, the reaction can also be carried out from room temperature to heating in a hydrogen atmosphere at normal pressure and high pressure using a catalyst of palladium-on-charcoal, Raney Nickel, platinum or similar compound, in an inert reaction solvent such as the aforementioned aromatic hydrocarbons, esters, ethers, halogenated hydrocarbons, DMF, DMA, NMP, acetic acid or a similar solvent. Depending on the connection in some cases for the smooth progress of the reaction it is advantageous to carry out the reaction in the presence of an acid (preferably hydrochloric acid, acetic acid or similar acid).

The third way to obtain

(In the above formulas, L2represents a removable group, such as halogen, -O-methanesulfonyl, -O-para-toluensulfonyl or similar. The same applies to the description below.)

Stage N

This stage is the stage at which the compound (I-h) according to the present invention receives, subjecting the compound (7) reactions of nucleophilic substitution.

The reaction of nucleophilic substitution on this stud and can be accomplished with the use of the compounds (7) and compound (8) in equimolar amounts or one of them in excess amount in the temperature range from room temperature to heating in the absence of solvent or in a solvent such as the aforementioned aromatic hydrocarbons, ethers, halogenated hydrocarbons, DMF, DMSO, esters including ethyl acetate and like esters, acetonitrile, alcohol or similar solvent. Depending on the compounds, in some cases to carry out the reaction advantageously in the presence of an organic base (suitable is triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine or a similar basis, or Foundation, formed metal salt (potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, tert-butoxy potassium and others).

Stage I

This stage is the stage at which the compound (I-i) of the present invention is obtained by reduction of compound (I-h) according to the present invention.

For the reduction reaction of the nitro group at this stage you can use the method commonly used by experts in the field of technology. For example, the reaction can also be carried out in the temperature range from room temperature to heating in a hydrogen atmosphere at normal pressure and high pressure using a catalyst of palladium-on-charcoal, Raney Nickel, platinum or similar compound, in an inert reaction solvent such as the aforementioned aromatic coal is hydrogens, esters, ethers, halogenated hydrocarbons, DMF, DMA, NMP, acetic acid or a similar solvent. Depending on the connection in some cases for the smooth progress of the reaction it is advantageous to carry out the reaction in the presence of an acid (preferably hydrochloric acid, acetic acid or similar acid).

The fourth way to obtain

Stage J

This stage is the stage at which the compound (I-j) according to the present invention is produced by dehydration of the compound (9).

For the reaction of dehydration at this stage you can use the method commonly used by experts in the field of technology. For example, the reaction can be carried out in the temperature range from room temperature to heating using as a dehydrating agent pentoxide Diaspora, phosphorus oxychloride, triperoxonane anhydride or similar compound, in the absence of solvent or in an inert reaction solvent such as aromatic hydrocarbons, halogenated hydrocarbons, ethers, or similar solvents. However, when a dehydrating agent is used triperoxonane anhydride, an amino group in position 7 quinolone in some cases will triptoreline, depending on the type of connection the Oia, and this is the case when further processing is required hydrolysis. The hydrolysis can be used the way that specialists in this field of technology is usually used in the hydrolysis of amides.

Stage

This stage is the stage at which the compound (I-k) according to the present invention is obtained by reduction of compound (I-j) according to the present invention.

The reaction for reduction of the nitrile group at this stage can also be carried out in the temperature range from room temperature to heating in a hydrogen atmosphere at normal pressure and high pressure using a catalyst of palladium-on-charcoal, Raney Nickel, platinum or similar compound, in an inert reaction solvent such as the aforementioned aromatic hydrocarbons, esters, ethers, halogenated hydrocarbons, DMF, DMA, NMP, acetic acid or a similar solvent. Depending on the connection in some cases for the smooth progress of the reaction it is advantageous to carry out the reaction in the presence of an acid (preferably hydrochloric acid, acetic acid or similar acid).

The fifth way to obtain

(In the above formula, J represents a simple bond or a lower alkylene and R12is an R or Rc. The same shall apply in this specification, hereinafter.)

Stage L

This stage is the stage at which the compound (I-m) according to the present invention receives, by subjecting compound (I-l) according to the present invention the nucleophilic substitution reaction or the reaction of reductive alkylation.

The nucleophilic substitution reaction and the reaction of the reductive alkylation at this stage can be implemented, respectively, in the same way as in stage D and stage E.

Stage M

This stage is the stage at which the compound (I-n) according to the present invention receives, by subjecting compound (I-m) according to the present invention the nucleophilic substitution reaction or the reaction of reductive alkylation.

The nucleophilic substitution reaction and the reaction of the reductive alkylation at this stage can be implemented, respectively, in the same way as in stage D and stage E.

The sixth way to obtain

Stage N

This stage is the stage at which the compound (I-p) according to the present invention receives, by subjecting compound (I-a) according to the present invention the amidation reaction the compound (10) or its reactive derivative.

For the amidation reaction at this stage you can use amadiro is the W, which usually can use the specialists in this field of technology. Particularly suitable is a method in which using a condensing agent, such as carbonyldiimidazole (CDI), the hydrochloride of 1-ethyl-3-(dimethylaminopropyl)carbodiimide (WSC·HCl), dicyclohexylcarbodiimide, diphenylphosphoryl, diethylphosphoramidite or similar connection method, which is carried out using mixed acid anhydride using isobutylphthalate, ethylchloride and the like, and a method, which is carried out using halogentated using thionyl chloride, phosphorus oxychloride or similar connection. Reaction conditions can be chosen randomly depending on the reactive derivative and the condensing agent, and, as a rule, the reaction is carried out with cooling, at temperatures from cooling to room temperature, or from room temperature to heating in an inert reaction solvent such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, DMF, DMSO or a similar solvent. Depending on the reaction in some cases it is advantageous to carry out in the presence of an organic base (suitable is triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine or the like based is (e), formed metal salt (preferred potassium carbonate, cesium carbonate or the like).

The seventh way to obtain

(In the formula, L3represents a removable group such as-O-(lower alkyl), -O-para-nitrophenyl or similar.)

Stage About

This stage is the stage at which the compound (I-r) according to the present invention is obtained by formation of urea from compound (I-q) according to the present invention.

The reaction of formation of urea can be performed from room temperature to heating using equivalent amounts of the compound (I-q) and the compound (11) or excess of one of them, in an inert reaction solvent such as aromatic hydrocarbons, halogenated hydrocarbons, ethers, DMF, DMSO or a similar solvent. Depending on the reaction, in some cases it is advantageous to carry out in the presence of an organic base (suitable is triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, 1,8-diazabicyclo[5.4.0]-7-undecene or similar basis) or metal salt the main character (suitable are potassium carbonate, cesium carbonate or the like salt).

In addition, some compounds represented by formula (I)can also be n in order to obtain compounds received the above-described method, arbitrarily combining stage, such as the widely known alkylation, acylation, substitution reaction, oxidation, reduction, hydrolysis, etc. that could use the specialists in this field of technology. In particular, compound (I-a), (I-b), (I-c), (I-h), (I-i) and (I-j) according to the present invention is also applicable as intermediates for the synthesis of compounds of the present invention.

Synthesis of starting compounds

Starting compound for use in preparation of compounds (I) of the present invention can be synthesized using the following methods, widely known methods or modified methods.

Synthesis of 1 starting substances

The compound (I-a) can be obtained using the method described in patent reference 7, or such a modified method.

Stage P

This stage is the stage at which the compound (9) obtained by amidation of the compound (I-a).

As for the amidation reaction at this stage, it can be done, for example, by the method described in stage N.

Synthesis of 2 of the original substance

Stage Q

This stage is the stage at which the compound (14) obtained by condensation of a connection is possible (12) with a complex ether of orthomorphisms acid and subsequent reaction of the attachment-elimination compound (13).

The reaction of condensation at this stage the ether orthomorphisms acid can be performed in the temperature range from room temperature to heating, using as solvent reagent that captures the alcohols formed from the ether orthomorphisms acid, such as acetic anhydride, or by using a reagent that captures the alcohols formed from the ether orthomorphisms acid, in an inert reaction solvent such as halogenated hydrocarbons, aromatic hydrocarbons, DMF, DMSO, esters, acetonitrile or a similar solvent.

Response attachment-elimination after the above condensation reaction can be performed under cooling, room temperature or heated in an inert reaction solvent such as alcohols, halogenated hydrocarbons, ethers, aromatic hydrocarbons, DMF, DMSO or a similar solvent. In this regard, the reaction can also be carried out using an excess of the compound (13). Depending on the compounds, in some cases the reaction is advantageously carried out in the presence of an organic base (suitable is triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine or a similar base) or base formed metal salt (fittingly, the mi are potassium carbonate, the cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, tert-piperonyl potassium or similar connection).

Stage R

This stage is the stage at which the compound (7) obtained by reaction of intramolecular cyclization of the amino group of compound (14).

The intramolecular cyclization reaction at this stage can be accomplished by cooling, room temperature or heated in an inert reaction solvent such as halogenated hydrocarbons, ethers, aromatic hydrocarbons, DMF, DMSO or a similar solvent. Depending on the compounds, in some cases the reaction is advantageously carried out in the presence of an organic base (suitable is triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, 1,8-diazabicyclo[5.4.0]-7-undecene or similar basis) or metal salt the main character (suitable are potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, tert-piperonyl potassium or similar connection).

The compound of the present invention, thus obtained, extracted and purified directly in free form or in the form of its salts, applying processing for the formation of salts in the usual way. Extraction and purification carried out using conventional chemical operations, that is them as extraction, concentration, evaporation, crystallization, filtration, recrystallization, various types of chromatography, etc.

Different types of isomers can be extracted in the usual way, using the difference in physicochemical properties between the isomers. For example, the racemic mixture can be converted into optically pure isomers in the usual way for the splitting of the racemate, including, for example, the transformation in salt diastereomers with an optically active acid, such as tartaric acid, and the subsequent splitting of optical isomers. The mixture of diastereoisomers can be separated, for example, by fractional recrystallization or various types of chromatography. In addition, the optically active compound can also be obtained using the corresponding optically active compounds as source materials.

Pharmaceutical composition that contains one or more compounds of the present invention or their pharmaceutically acceptable salts as the active ingredient, obtained using carriers and excipients and other additives usually used in the preparation of pharmaceutical products.

To enter the pharmaceutical composition can or oral way with the help of tablets, pills, capsules, granules, powders, solutions and the like, or parenteral method using ADAP who rivenich, intramuscular or similar injections, suppositories, percutaneous preparations, transnasal preparations, inhalations and the like, the Dose of the composition determined arbitrarily with regard to symptoms, age, sex, etc. of the subject, which is treated, in each case, but in the case of oral administration the dose usually ranges from 0.001 mg/kg to 100 mg/kg per day for an adult subject, and such a dose is administered in one portion or sharing for 2-4 servings. Also in the case of intravenous administration, the dose is administered in the range of from 0.0001 mg/kg to 10 mg/kg for an adult subject of one or two or more times per day. In addition, in the case of transnasal the introduction of the injected dose in the range of from 0.0001 mg/kg to 10 mg/kg for an adult subject of one or two or more times per day.

As a solid composition for oral administration according to the present invention using tablets, powders, granules, etc. In such solid compositions one or more active substances are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminosilicate, or similar diluent. According to conventional practice, the composition may contain additives other than the inert diluent, such as a lubricating substance (for example, magnesium stearate or the like is substance), a substance that promotes dispersal (e.g., calcipala cellulose or similar substance), stabilizer, solubilizer and the like, If necessary, tablets or pills may be coated in sugar coating or film gastro - or Intercollege substances, such as sucrose, gelatin, hydroxypropylcellulose, phthalate of hydroxypropylmethylcellulose, or similar substances.

Liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like and contains the most commonly used diluent such as distilled water or ethanol (EtOH). In addition to the inert diluent, this composition may contain a wetting agent, suspendisse substance and such auxiliary substances, as well as sweetening means, corrigentov, flavorings and preservatives.

Injections for parenteral administration include aseptic aqueous or non-aqueous solutions, suspensions and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. In non-aqueous solutions and suspensions are included, for example, propylene glycol, polyethylene glycol, olive oil or similar oil, EtOH or the like alcohols, Polysorbate 80 and the like, the composition may also contain auxiliary substances is STV, such as antiseptics, wetting agent, emulsifier, dispersing agent, stabilizer, solubilizer, or a similar substance. Such compositions are sterilized, for example, filtration through a filter, inhibiting bacteria, adulteration of bactericide or irradiation. You can also use them, receiving sterile solid compositions and then dissolving them in sterile water or a sterile solvent for injection before use.

The pharmacological activity of the compounds of the present invention described later confirmed by tests.

Test method (1). Test with measurement of the activity of inhibition of aggregation of human platelets

In healthy volunteers (adult men) take samples of blood using a syringe containing 1/10 volume of 3.8% solution of sodium citrate, and centrifuged at 160×g for 10 minutes, and thus is separated from the supernatant platelet-rich plasma (PRP). The blood remaining after harvest PRP, centrifuged at 1800×g for 10 minutes to separate the plasma-depleted platelets (PPP). The number of platelets in PRP was measured using an automatic counter blood corpuscles (MEK-6258, Nihon Kodhen Corp.), and then the number of platelets was adjusted to 3×108/ml, adding PPP PRP, and use the following test. The ADP as an inducer of platelet aggregation C is bathed in MS Medical. Platelet aggregation was measured using aggregometry (MSM Hematracer 212; MS Medical). Namely, 80 μl of PRP with 3×108platelets/ml and 10 μl solution of the test compound or solvent (10% DMSO or 10% DMSO-9% hydroxypropyl-β-cyclodextrin-4,5% d-mannitol) incubated at 37°C for 1 minute, then add to the mixture 10 ál of a solution of ATP (50 μm) to induce platelet aggregation, and register the change of the transmitted light for 5 minutes. The degree of inhibition is calculated using as a measure of the area under the curve of platelet aggregation. Results when the concentration of the compounds of the present invention 10 μm (final concentration) are given in table 1.

In this regard, the room SPR represents the number of the reference example, and so forth. - the number of the example. In addition, reference examples 1 and 2 are examples of compounds described in the above patent reference 7, and receive according to the method described in the patent reference.

Reference example 1 (example 467 in the patent reference 7)

4-({[7-(Cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]carbonyl}amino)butane acid

Reference example 2 (example 6 in the patent reference 7)

({[7-(Cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]carbonyl}amino)acetic acid

Table 1
Test connectionInhibition, %
SPR 164
SPR 279
Ave. 293
Ave. 7694
Ave. 8092
Ave. 8289
Ave. 8792
Ave. 11485
Ave. 12591
Ave. 14683
Ave. 20294
Ave. 26197
Ave. 27191
Ave. 29789
Ave. 32193
Ave. 35485
Ave. 38089
Ave. 40784

Test method (2). Test for substitution for binding human P2Y12 2-methylthio-ADP (2-MeS-ADP)

Cells C6-15 inoculant in 10-cm Petri dish to a density of 1×106cells using DMEM medium and cultured for 1 day and then hemotransfusion 8 µg plasmid human P2Y12 pEF-BOS-dfhr and 0.8 μg of pEF-BOS-neo (Nucleic Acid Res., 18, 5322, 1990) using the transfection reagent (LipofectAMINE 2000; projectors. GIBCO BRL).

24 hours after the specified operation transfer hemotransfusion cell extract, suspended in DMEM with addition of 0.6 mg/ml G 418 (projectors. GIBCO BRL) and then serially diluted and again inoculant in 10-cm Petri dish. Colonies that appeared after 2 weeks, get separately and used in the subsequent test cells C6-15 expressing the P2Y12 protein (WO 02/36631, Mol. Pharmacol., 60, 432, 2001).

After culturing cells C6-15 expressing the P2Y12 protein, cell extract. Cells are washed with PBS and then suspended in 20 mm Tris-HCl (pH 7.4)containing 5 mmol/l add and set cocktail of protease inhibitors Complete™ (projectors. Boehringer-Mannheim), and homogenized using a transmitter station. After ultracentrifugation, the precipitate is suspended in 50 mm Tris-HCl (pH 7.4)containing 1 mm etc, 100 mm NaCl, and Complete™, and the resulting mixture is used as the membrane fraction.

Part in 100 ál obtained above me is abusive fraction of cells C6-15, expressing the P2Y12 protein (100 µg/ml), mixed with 1.5 μl solution of the test compound and 50 μl of 0.75 nm [3H]-2-MeS-ADP (80 CI/mmol, projectors. Amersham Pharmacia Biotech) or 0.75 nm [33R]-2-MeS-ADP (2100 CI/mmol, projectors. Perkin Elmer), incubated at room temperature for 1 hour in 50 mm Tris-HCl (pH 7.4)containing 100 mm NaCl and 50 mm MgCl2and then pull on a glass filter using a cell harvester. On a glass filter add microstimulator and measure the radioactivity using a liquid scintillation counter. Samples, where in the above test at the same time add one solvent and 1.5 ál 250-µm ADP, considered as showing the total binding and the nonspecific binding and measure their radioactivity. Taking the total binding and the nonspecific binding for the degree of inhibition of 0% and 100%, respectively, calculate the degree of inhibition (%) for each test compound. Results when the concentration of the compounds of the present invention 30 nm (final concentration) are given in table 2.

Table 2
Test connectionInhibition, %
SPR 176
SPR 286
Ave. 289
Ave. 8089
Ave. 8265
Ave. 8787
Ave. 11492
Ave. 12583
Ave. 14692
Ave. 19686
Ave. 20282
Ave. 26167
Ave. 27180
Ave. 32173
Ave. 32492
Ave. 38096
Ave. 40772
Ave. 48835

Test method (3). Test for inhibition of platelet aggregation in rats and measuring the concentration of the test compound in plasma

Adding an aqueous solution of Hydra is xida sodium to the compound of the present invention, receive an aqueous solution or suspension with 0.5% methylcellulose. Thus obtained liquid is administered orally to male SD rats (aged 5-7 weeks) using a probe through 12 or more hours after feeding. 2 hours after the introduction of the connections take blood samples using a syringe containing 1/10 volume of 3.8% solution of sodium citrate. In the same way as in test method (1), receive PPP and PRP with 3×108platelets/ml Portion of PRP with 3×108platelets/ml in 90 µl incubate at 37°C for 1 minute and then add 10 μl of ATP (50 μm) to induce platelet aggregation, and record changes in transmitted light for 5 minutes. The degree of inhibition is calculated using as a measure of the area under the curve of platelet aggregation.

Concentration in plasma was measured using PPP, obtained above. In order to obtain a standard curve, also provide RRR SD rats, which connection was not introduced, and also get a sample with the compound of the present invention, serially diluted such PPP (from 30 μm to 0,0003 μm in final concentration: selecting random in response to each connection). Portion 100 μl of PPP rats, which were administered the compound of the present invention, and PPP containing a dissolved compound of the present invention, is mixed with the akim of the same volume of distilled water, add to the mix another 5% triperoxonane acid and mix. After maturation on ice for 10 minutes to remove the supernatant by centrifugation operation. The supernatant is neutralized by adding 3 ál of 2 M Tris-base and mixing. Portion 150 μl of the membrane fraction of cells C6-15 expressing the P2Y12 protein (200 μg/ml), mixed with 50 ál of such treated trichloroacetic acid PPP (depending on the connection, use the PPP, diluted with 50 mm Tris-HCl (pH 7.4)containing 100 mm NaCl and 50 mm MgCl2). Then to the mixture is added 50 μl of 0.75 nm [3H]-2-MeS-ADP (80 CI/mmol, projectors. Amersham Pharmacia Biotech) or 0.75 nm [33R]-2-MeS-ADP (2100 CI/mmol, projectors. Perkin Elmer), incubated at room temperature for 1 hour in 50 mm Tris-HCl (pH 7.4)containing 100 mm NaCl and 50 mm MgCl2and then pull on a glass filter using a cell harvester. On a glass filter add microstimulator and measure the radioactivity using a liquid scintillation counter. Using a standard curve of inhibition of binding was calculated from the measurement results obtained with ECD containing serially diluted compound of the present invention, the concentration of the compounds of the present invention in PPP transform of the measurement results obtained in rats, which were injected connected to the e of the present invention.

The results are shown in table 3. The evaluation using the above method get that compounds of the present invention show good activity of inhibiting platelet aggregation in oral introduction and also show a good pharmacokinetics.

30
Table 3
Test connectionDose, mg/kgInhibition, %
SPR 13011
SPR 230-7
Ave. 821075
Ave. 871072
Ave. 114366
Ave. 1253089
Ave. 1463072
Ave. 2713089
Ave. 29748
Ave. 3803074
Ave. 4073054

EXAMPLES

The present invention describes for explanations based on examples, but the present invention is not limited to the given examples. In this regard, as new substances included in the original compounds used in the examples, the methods of obtaining of such starting compounds are described as examples of receipt.

In this regard, the symbols in the examples of the preparation and examples have values below (the same applies to the description below).

Prpol. (Rf): the number of sample receipt, etc: the number of the example, n: number of connections, data: physical data (Sol (the absence of such a designation means that it is free form, and the number before the acid component indicates the proportion in the composition. For example, when written 2HCl, it shows that the connection is a dihydrochloride. Oxa: oxalate, TFK: trifenatate)), NMR: δ (ppm) of characteristic peak in1H-NMR, EI: EI-MS (M+if not otherwise specified), FAB: FAB-MC (position.) (M++ 1, unless otherwise specified), ESI: ESI-MC (position.) (M++ 1, unless otherwise stated)ACPI: ACPI-MS (position.) (M++ 1, unless Ino is), ESI (neg.): ESI-MS (neg.) (M-- 1, unless otherwise specified), FAB (neg.): FAB-MS (neg.) (M-- 1, if not specified otherwise), Me is methyl, Et is ethyl, n-Pr, n - propyl, ISO-Pr is isopropyl, cPr - cyclopropyl, n-Bu is n-butyl, ISO-Bu is isobutyl, tert-Bu tert-butyl, cBu - cyclobutyl, cPen - cyclopentyl, snekh - cyclohexyl, Ph is phenyl, Bn is benzyl, BOC - tert-butoxycarbonyl, AC is acetyl, Bz is benzoyl, TBDMS tert-butyldimethylsilyl. Sint.: the method of obtaining (the figure shows that, like the compound of example, having a number is the same as the number of the example in which it is received, it is carried out by using an appropriate source materials; when the figure added "prpol.", this shows that, like the compound of example, obtain, having the same number as the sample receipt in which it is received, it is carried out by using an appropriate source materials; when written two or more digits, it shows that it is carried out with appropriate ways of getting on the basis of substances under the first digit). Sintra.: the method of obtaining (the figure shows that, like the connection of sample receipt (Prol.), having the number same as the number of sample receipt in which it is received, it is carried out by using an appropriate source materials; when the figure added "PR", it shows that, like the connection p is of iMER, having the same number as that of the example in which it is received, it is carried out by using an appropriate source materials).

Example obtain 1

Add 2.6 g of 1,1'-carbonyldiimidazole to a suspension of 4.0 g of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid in 30 ml of DMF and the mixture is then stirred at 100°C. for 13.5 hours. To the mixture under ice cooling, add 10 ml of 28% aqueous ammonia and the mixture is then stirred under ice cooling for 75 minutes and at room temperature for 5 hours. After evaporation of the solvent under reduced pressure, add ethanol and implement boiling under reflux. After cooling to room temperature, the insoluble matter is collected by filtration and dried, and obtain 3.7 g of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxamide.

Example of getting 2

At 0°C type of 0.87 ml of triethylamine and 0.4 ml of isobutylphthalate to a solution of 1.0 g of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid in 20 ml of dichloromethane and the mixture is then stirred at 0°C for 30 minutes. Then added to the mixture 315 mg of the hydrochloride of N,O-dimethylhydroxylamine and then the mixture is stirred at room temperature for 1 hour. To the reaction mixture chloroform Wodny a saturated solution of ammonium chloride, the layers are separated and washed with aqueous saturated solution of sodium chloride. After drying over anhydrous sodium sulfate and then filtered, the solvent is evaporated under reduced pressure. Purification of the obtained residue column chromatography on silica gel obtain 950 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-N-methoxy-N-methyl-4-oxo-1,4-dihydroquinoline-3-carboxamide.

Example of getting 3

Dissolve 5 g of 2-nitro-1-(2,4,5-tryptophanyl)ethanone in 100 ml of acetic anhydride to the solution at room temperature, add 4.0 ml of triethylorthoformate, then the mixture is stirred at 130°C for 3 hours and concentrated under reduced pressure. The resulting residue is dissolved in 100 ml of dichloromethane, added under ice cooling a solution of 2.5 ml of cyclopentylamine in 50 ml of dichloromethane and the mixture is stirred at room temperature for 3 hours. Then water is added and the mixture is then extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue is dissolved in 80 ml of 1,4-dioxane, is added at room temperature a solution of 3.6 ml of 1,8-diazabicyclo[5.4.0]-7-undecene in 20 ml of dioxane and the mixture is then stirred at room temperature for 3 hours. Pouring the reaction mixture is cooled in ice water and collecting nerest the action of the substance by filtration, obtain 1.8 g of 1-cyclopentyl-6,7-debtor-3-nitroanilin-4(1H)-it.

Example 4

Under ice cooling 11.5g of triacetoxyborohydride sodium is added in small portions to a solution of 4.0 g of 3,4,5-triptorelin and 3.6 ml of Cyclopentanone in 150 ml of dichloroethane and 3.1 ml of acetic acid and after raising the temperature to room the mixture is stirred for 3.5 hours. To the mixture is added aqueous saturated solution of sodium bicarbonate, the mixture is then extracted with chloroform, and then the organic layer is dried over anhydrous sodium sulfate. After filtration the solvent is evaporated under reduced pressure, the obtained residue is purified column chromatography on silica gel and receive a 5.4 g of N-cyclopentyl-3,4,5-triptorelin.

Example of getting 5

Add 3.2 ml diethyl(ethoxymethylene)malonate 3.3 g of N-cyclopentyl-3,4,5-triptorelin and the mixture is then stirred at 130°C for 4 hours. Cleaning column chromatography on silica gel get 2.2 g diethyl{[cyclopentyl(3,4,5-tryptophanyl)amino]methylene}malonate.

An example of obtaining 6

Add 5.7 g polyphosphoric acid to 2.2 g diethyl{[cyclopentyl(3,4,5-tryptophanyl)amino]methylene}malonate and then the mixture was stirred at 140°C for 40 minutes. The reaction mixture was poured into a mixture of ice water and the insoluble matter is collected by filtration. Received ve is estvo dissolved in chloroform, washed with water and aqueous saturated sodium chloride solution and dried over anhydrous sodium sulfate. After filtration the solvent is evaporated and get 1.4 g of ethyl-1-cyclopentyl-5,6,7-Cryptor-4-oxo-1,4-dihydroquinoline-3-carboxylate.

Example of getting 7

Add 42% portorotondo acid to 1.1 g ethyl-1-cyclopentyl-5,6,7-Cryptor-4-oxo-1,4-dihydroquinoline-3-carboxylate and the mixture is then heat at 90°C for 20 hours. To the reaction mixture, water is added, the insoluble matter is collected by filtration and dried, and obtain 1.4 g of boron compounds. To 1.4 g of the thus obtained compounds of boron added 15 ml of DMSO and 0.97 ml of cyclohexylamine and then the mixture is stirred at room temperature for 30 minutes. To the reaction mixture, water is added and the insoluble matter is collected by filtration. After drying, the resulting substance is added 30 ml of ethanol and 15 ml of aqueous 1 M sodium hydroxide solution and the mixture is then stirred at 80°C for 1.5 hours. Upon completion of the reaction nerastvorim substance is removed by filtration, to the filtrate add water and diethyl ether, carry out the separation of the layers and the aqueous layer was added 1 M hydrochloric acid. The resulting precipitated precipitated substance is collected by filtration and dried, and obtain 1.0 g of 7-(cyclohexylamino)-1-cyclopentyl-5,6-debtor-4-oxo-1,4-di is hydrochinon-3-carboxylic acid.

Example obtain 8

While cooling with ice and 3.2 ml of a 1.60 M solution of n-utility in hexane are added to a solution of 0.58 ml of benzyl alcohol in 2.4 ml of THF and the mixture is then stirred for 1 hour. The solvent is evaporated under reduced pressure and then added to 8.0 ml of toluene to obtain a suspension. The resulting suspension is added to the obtained in a separate container a suspension of 400 mg of 7-(cyclohexylamino)-1-cyclopentyl-5,6-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid in toluene and then the mixture is stirred at room temperature for 6 hours. Then to the reaction mixture was added 1 M hydrochloric acid, the mixture is extracted with chloroform and the organic layer was washed with saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate and then filtered, the solvent is evaporated under reduced pressure. By recrystallization of the resulting residue using ethyl acetate receive 400 mg of 5-(benzyloxy)-7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.

Example of getting 9

Dissolve 900 mg of the ethyl-1-cyclopentyl-7-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate 6.4 ml of acetic acid, add 0.8 ml of 6 M hydrochloric acid and then the mixture is stirred overnight at 120°C. the resulting reaction mixture is cooled to room temperature, the ner storymode substance is collected by filtration and washed with water, and obtain 710 mg of 1-cyclopentyl-7-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.

Example 10

Under ice cooling of 1.02 g of the hydrochloride of 1-cyclobutylamine and 1.05 ml of triethylamine are added to a solution of 2.0 g of ethyl-2-(2-chloro-4,5-differentail)-3-ethoxyacrylate in 15 ml of THF, after which the mixture is stirred over night at room temperature. To the obtained reaction mixture, water is added, then the mixture is extracted with ether and the organic layer washed with water and aqueous saturated solution of sodium chloride. After drying over anhydrous magnesium sulfate carry out concentration under reduced pressure. Under ice cooling 315 mg of 55% sodium hydride are added to a solution of the obtained residue in 30 ml of dioxane and the mixture is then stirred over night at 80°C. the Reaction mixture was poured into 1 M hydrochloric acid, then the mixture is extracted with chloroform and the organic layer washed with water and aqueous saturated solution of sodium chloride. After drying over anhydrous sodium sulfate and subsequent concentration under reduced pressure, the obtained residue is purified column chromatography on silica gel and obtain 1.13 g of ethyl-1-(1-cyclobutylmethyl)-6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylate.

In the same way as in the examples of the preparation of 1-10, using the appropriate starting substances get with the organisations examples of obtaining 11-27, listed in tables 4-9. Structure and physico-chemical properties of the compounds of examples of the preparation are given in tables 4-9.

Example 1

Dissolve 250 mg of 3-amino-7-(cyclohexylamino)-1-cyclopentyl-6-ftorhinolon-4(1H)-she and 127 mg of 4-ethoxy-4-oxobutanoic acid in 20 ml of DMF, added 170 mg of the hydrochloride of N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide and 160 mg of 1-hydroxybenzotriazole and then the mixture is stirred over night at room temperature. Adding water to the reaction mixture and then collecting the insoluble substance by filtration, to obtain 220 mg of ethyl-4-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]amino}-4-oxobutanoate.

Example 2

Dissolve 200 mg of ethyl-4-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]amino}-4-oxobutanoate in 2.0 ml THF and 2.0 ml of ethanol, add 1.3 ml of aqueous 1 M sodium hydroxide solution and the mixture is then stirred at room temperature for 4 hours. After adding to the mixture of 1 M hydrochloric acid and water, the insoluble matter is collected by filtration and obtain 180 mg of 4-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]amino}-4-oxobutanoic acid.

Example 3

Dissolve 200 mg of diethyl-{(E)-2-[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]vinyl}phosphonate in 2.0 ml of chloroform, add 0.4 to the l of bromotrimethylsilane and then the mixture is stirred over night at room temperature. To the reaction mixture add the ethanol and the mixture is then concentrated under reduced pressure. To the obtained residue is added ethyl acetate, the insoluble matter is collected by filtration and receive 120 mg hydrobromide {(E)-2-[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]vinyl}phosphonic acid.

Example 4

With stirring 169 mg triacetoxyborohydride sodium to a solution of 142 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde and 66 mg of 4-aminophenol in 10 ml of 1,2-dichloroethane and 0.05 ml of acetic acid and the mixture is then stirred for 24 hours. To the mixture is added aqueous saturated solution of sodium bicarbonate and the mixture is then extracted with chloroform. After drying over anhydrous sodium sulfate and subsequent filtration, concentration under reduced pressure. The resulting residue is purified column chromatography on silica gel and then crystallized from ethyl acetate, and obtain 46 mg of [7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-{[(4-hydroxyphenyl)amino]methyl}quinoline-4(1H)-it.

Example 5

Dissolve 250 mg of the hydrochloride of 3-(aminomethyl)-7-(cyclohexylamino)-1-(1-ethylpropyl)-6-ftorhinolon-4(1H)-she's in 25 ml of THF, add of 0.11 ml of diethyl(2-oxopropyl)phosphonate and 123 mg of triacetoxyborohydride sodium, 0.16 ml of triethylamine and 1.25 ml of acetic acid in asanam order and then the mixture is stirred over night at room temperature. Add water, insoluble matter is collected by filtration and then purified column chromatography on silica gel, and get to 135 mg of diethyl[2-({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]methyl}amino)propyl]phosphonate.

Example 6

Dissolved 170 mg of ethyl-4-({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]methyl}amino)butanoate in 2.0 ml of pyridine, add 0,040 ml of acetic anhydride and the mixture is then stirred overnight at room temperature. After concentrating the reaction mixture under reduced pressure, to the residue water is added and the mixture is then extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate and then filtered and concentrated under reduced pressure. Purification of the obtained residue column chromatography on silica gel obtain 165 mg of ethyl-4-(acetyl - {[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]methyl}amino)butanoate.

Example 7

Dissolved 180 mg of 4-nitrophenylphosphate in 3.0 ml of dichloromethane, added 140 mg of the hydrochloride of ethyl-3-aminopropanoic and 0.15 ml of pyridine and the mixture is then stirred overnight at room temperature. To the reaction mixture, water is added and the mixture is then extracted with chloroform. The organic layer was washed with aqueous saturated solution is m sodium chloride, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. Purification of the obtained residue column chromatography on silica gel get 180 mg of ethyl-3-{[(4-nitrophenoxy)carbonyl]amino}of propanoate. Dissolved 180 mg of ethyl-3-{[(4-nitrophenoxy)carbonyl]amino}of propanoate in 2.0 ml of dichloromethane, added 220 mg of 3-amino-7-(cyclohexylamino)-1-(1-ethylpropyl)-6-ftorhinolon-4(1H)-she and 0.15 ml of pyridine and the mixture is then stirred overnight at room temperature. Add water to the mixture and the mixture is then extracted with chloroform. The organic layer was washed with aqueous saturated solution of sodium chloride, dried over anhydrous sodium sulfate and then filtered and concentrated under reduced pressure. Purification of the obtained residue column chromatography on silica gel get 120 mg ethyl-3-[({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]amino}carbonyl)amino]propanoate.

Example 8

Dissolve 287 mg of ethyl[(5-chloro-2-thienyl)sulfonyl]carbamate in 5.0 ml of toluene, add 250 mg of 3-amino-7-(cyclohexylamino)-6-fluoro-1-isopropylphenyl-4(1H)-she and then the mixture is stirred overnight at 110°C. the Reaction mixture is cooled to room temperature and concentrate under reduced pressure. Then add ethyl acetate and the insoluble matter is collected by filtration and group what this rotary obtain 280 mg of 5-chloro-N-({[7-(cyclohexylamino)-6-fluoro-1-isopropyl-4-oxo-1,4-dihydroquinoline-3-yl]amino}carbonyl)thiophene-2-sulfonamida.

Example 9

Dissolve 224 mg of the hydrochloride of 2-amino-N-[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]ndimethylacetamide in 5.0 ml of DMF, add 228 mg of potassium carbonate and 0.18 ml of ethylbromoacetate and then the mixture is stirred over night at 60°C. the Reaction mixture is cooled to room temperature, water is added, the insoluble matter is collected by filtration and receive 35 mg diethyl-2,2'-[(2-{[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]amino}-2-oxoethyl)imino]diacetate.

Example 10

Dissolve 150 mg of ethyl{[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]amino}acetate in 3.0 ml of THF, add to 0.060 ml of triethylamine and to 0.060 ml ethyl-5-chloro-5-oxopentanoate and then the mixture is stirred over night at room temperature. To the reaction mixture, water is added and the mixture is then extracted with chloroform. The obtained organic layer was washed with aqueous saturated solution of sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Purification of the obtained residue column chromatography on silica gel get 199 mg ethyl-5-[[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl](2-ethoxy-2-oxoethyl)amino]-5-oxopentanoate.

Example 11

Dissolve 200 mg of ethyl-(2E)-3-[7-(cyclohexylamino)-1-cyclopentyl-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]acrylate 4.0 ml of ethanol, add 50 mg of palladium-on-coal, and then the mixture is stirred over night at room temperature in a hydrogen atmosphere. The reaction mixture was filtered using celite and concentrated under reduced pressure and receive 200 mg of ethyl-3-[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]propanoate.

Example 12

At 0°C 213 μl of diisopropylcarbodiimide added to a solution of 263 mg of benzyl-(2R)-2-hydroxy-3-phenylpropanoate and 270 mg of triphenylphosphine in 5.0 ml of dichloromethane and the mixture is then stirred for 15 minutes. Then to the mixture is added 177 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-(hydroxymethyl)quinoline-4(1H)-she and the mixture is then stirred at room temperature for 4 hours. To the reaction mixture, water is added, then the mixture is extracted with EtOAc and the organic layer washed with aqueous saturated solution of sodium chloride. After drying over anhydrous sodium sulfate and subsequent evaporation under reduced pressure the residue is purified column chromatography on silica gel and receive 160 mg of benzyl(2S)-2-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]oxy}-3-phenylpropanoate.

Example 13

Add 690 mg of potassium carbonate and 363 mg of 4-perbenzoate to a solution of 344 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-hydroxyquinolin-4(1H)-it in 10 ml of DMF and then the mixture is peremeshivayte over night at 80°C. After completion of the reaction and subsequent cooling to room temperature, to the reaction mixture is added aqueous saturated solution of ammonium chloride and the mixture is then extracted with ethyl acetate. After drying over anhydrous sodium sulfate and subsequent evaporation under reduced pressure the residue is purified column chromatography on silica gel and receive 100 mg of 4-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]oxy}benzonitrile.

Example 14

Add 5.0 ml of ethanol and 1.5 ml of aqueous 6 M sodium hydroxide solution to 93 mg of 4-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]oxy}benzonitrile and the mixture is then refluxed for 2 days. After cooling the reaction system to neutralize 1 M hydrochloric acid. Add water and the precipitated solid precipitated substance is collected by filtration. Crystallization of the obtained solid from ethyl acetate-hexane obtain 65 mg of 4-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]oxy}benzoic acid.

Example 15

Dissolve 840 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde in 40 ml of chloroform under cooling with ice add to 0.47 ml trimethylsilylacetamide and 0.05 ml of triethylamine and the mixture is then stirred at room temperature for 5,5hours. After stirring at room temperature for 1.5 hours after adding another 0.06 ml of trimethylsilylacetamide to the mixture add 0.06 ml of trimethylsilylacetamide and then the mixture is stirred at room temperature for 2 days. The obtained precipitated precipitated substance is filtered off and washed with chloroform, and get a solid substance. The obtained solid substance was dissolved in 13 ml of concentrated hydrochloric acid and then stirred at 100°C for 2.5 hours. After cooling to room temperature, water is added, then the mixture is extracted with chloroform, and the organic layer is dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue is purified column chromatography on silica gel and get the crude product of the reaction [7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl](hydroxy)acetic acid. The resulting crude product is washed with a mixture of water:methanol (1:2) and ethyl acetate. To the obtained solid substance added ethyl acetate and aqueous saturated sodium hydrogen carbonate solution and perform the operation of separation of the layers. To the aqueous layer was added 1 M hydrochloric acid, then extracted with ethyl acetate and the organic layer concentrated under reduced pressure. To the obtained residue, add a mixed solvent of THF and water, nerastvorimoe substance is collected by filtration and obtain 149 mg of [7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl](hydroxy)acetic acid.

Example 16

Dissolve 52 mg of [7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl](hydroxy)acetic acid in 10 ml of methanol, add 0.4 ml of concentrated sulfuric acid and then the mixture is stirred at room temperature for 1 hour. To the reaction mixture is added aqueous saturated solution of sodium bicarbonate, the mixture is then extracted with ethyl acetate, and the organic layer washed with aqueous saturated solution of sodium chloride, and concentrated under reduced pressure. The obtained residue is recrystallized from aqueous methanol and obtain 53 mg of methyl[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl](hydroxy)acetate.

Example 17

Dissolve 146 mg of methyl[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl](hydroxy)acetate in 10 ml of THF while cooling with ice add 46 mg of 60% sodium hydride and the mixture is then stirred at room temperature for 30 minutes. Then to the reaction mixture 58 μl of ethylbromoacetate and then the mixture is stirred at room temperature for 5 hours. While cooling with ice add another 46 mg of 60% sodium hydride and 10 ml of THF and the mixture is then stirred at room temperature for 2 hours. Then added to the mixture 58 μl of ethylbromoacetate and then the mixture is stirred at room temperature is re for 17 hours. To the reaction mixture is added aqueous saturated solution of sodium bicarbonate and the mixture is then extracted with ethyl acetate. Then the organic layer was washed with aqueous saturated solution of sodium chloride. After drying over anhydrous sodium sulfate carry out concentration under reduced pressure. The resulting residue is purified column chromatography on silica gel and obtain 66 mg of methyl[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl](2-ethoxy-2-oksidoksi)acetate.

Example 18

Dissolve 13 g of diethyl-{(E)-2-[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]vinyl}phosphonate in 150 ml of chloroform, add to 27.2 ml of bromotrimethylsilane and then the mixture is stirred over night at room temperature. To the reaction mixture add the ethanol and the mixture is then concentrated under reduced pressure. To the obtained residue, add water 1 M sodium hydroxide solution and ether and perform the operation of separation of the layers. To the aqueous layer add concentrated hydrochloric acid and the mixture is then stirred at room temperature for 2 hours. Then, the insoluble matter is collected by filtration and washed with water, and get 10,32 g {(E)-2-[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]vinyl}phosphonic acid.

Example 19

Dissolve 48 mg chloride (methoxymethyl)triphenylphosphine in 5 ml of THF, under ice cooling in an argon atmosphere add 1.2 ml of a 1.6 M solution of n-utility in hexane and the mixture is then stirred at the same temperature for 30 minutes. To the mixture while cooling with ice add a solution of 178 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde in 5 ml of THF, the mixture is then stirred at the same temperature for 15 minutes and then stirred at room temperature for 3 hours. The reaction mixture was poured into a mixture of ice water, then extracted with ethyl acetate, and the organic layer is dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue is dissolved in 10 ml of dioxane, add 5 ml of 4 M solution of hydrogen chloride in dioxane and then stirred at room temperature for 2 hours. The reaction mixture was poured into cooled with ice water saturated solution of sodium bicarbonate, then extracted with ethyl acetate, and the organic layer is dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Purification of the obtained residue column chromatography on silica gel get 239 mg of a crude product of the reaction [7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]acetaldehyde. The resulting crude product is dissolved in 10 ml of ethanol, add 75 mg of borohydride into three and then the mixture is stirred at room temperature for 1 hour. To the reaction mixture, water is added, then extracted with ethyl acetate, the organic layer is dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography on silica gel and crystallized from ethyl acetate, and get 18 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-(2-hydroxyethyl)quinoline-4(1H)-it.

Example 20

Dissolve 856 mg chloride (methoxymethyl)triphenylphosphane 10 mg THF under ice cooling in an argon atmosphere add 1.8 ml of 1.6 M solution of n-utility in hexane and the mixture is then stirred at the same temperature for 30 minutes. To the mixture while cooling with ice add a solution of 356 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde in 10 ml of THF and the mixture is then stirred at room temperature for 3 hours. The reaction mixture was poured into a mixture of ice water, then extracted with ethyl acetate, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography on silica gel and receive 552 mg of crude reaction product 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-[2-methoxyphenyl]quinoline-4(1H)-she. Dissolve 159 mg of the obtained crude product in 14 ml of dioxane, add 7 ml of 4 M solution of hydrogen chloride in dioxane, and then the mixture is peremeshivayte at room temperature for 0.5 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue is dissolved in 6 ml of 2-methyl-2-propanol, 1 ml of acetonitrile and 2 ml of water. Then, with ice cooling type of 0.26 ml of 2-methyl-2-butene, 78 mg of the dihydrate of sodium dihydrophosphate and 228 mg, 79% aqueous solution of sodium chlorite and the mixture is then stirred at room temperature for 14 hours. To the reaction mixture, water is added, then the mixture is extracted with chloroform, and the organic layer is dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue is purified column chromatography on silica gel and crystallized from ethyl acetate, and receive 5 mg of [7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]acetic acid.

Example 21

Dissolve 199 mg of 7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-3-(4-hydroxybutyl)quinoline-4(1H)-she's in 11 ml of 1,2-dichloroethane, add at room temperature 257 mg of triphenylphosphine and 405 mg tetrabromide carbon and the mixture is then stirred for 15 minutes. To the reaction mixture is added aqueous saturated solution of sodium bicarbonate, the mixture is then extracted with chloroform, the organic layer was washed with aqueous saturated solution of sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue is purified the chromatography and obtain 78 mg of 3-(4-bromobutyl)-7-(cyclohexylamino)-1-(1-ethylpropyl)-6-ftorhinolon-4(1H)-it.

Example 22

To 557 g of 3-(4-bromobutyl)-7-(cyclohexylamino)-1-(1-ethylpropyl)-6-ftorhinolon-4(1H)-it add 5 ml of triethylphosphite and then the mixture was stirred at 160°C for 4 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue is purified column chromatography and receive 240 mg of diethyl-{4-[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]butyl}phosphonate.

Example 23

To 2 ml of 2 M solution of isopropylacrylamide in THF at -78°C. add 2 ml of THF and 0.71 ml of diethyl[bromo(debtor)methyl]phosphonate and then the mixture is stirred at the same temperature for 5 minutes. To the reaction mixture is added dropwise a solution of 358 mg of 7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde in 10 ml of THF and after a gradual temperature increase to room temperature the resulting mixture was stirred for 2.5 hours. To the reaction mixture is added aqueous saturated solution of sodium chloride and then the mixture is extracted with chloroform and ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To the residue add the methanol, the insoluble substance is filtered off and the resulting filtrate evaporated under reduced pressure. Purification of the obtained residue column chromatography obtain 257 mg diety is-{2-[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]-1,1-debtor-2-hydroxyethyl}phosphonate.

Example 24

Dissolve 1.0 g of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde in 20 ml of DMF, add 2.0 g of potassium carbonate and 2.8 ml of ethyl(diethoxyphosphoryl)acetate and then the mixture is stirred over night at 60°C. the resulting reaction mixture is cooled to room temperature, add water, and then the insoluble matter is collected by filtration and obtain 1.2 g of ethyl-(2E)-3-[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]acrylate.

Example 25 and example 26

Dissolve 500 mg of {(E)-2-[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]vinyl}phosphonic acid in 10 ml of acetonitrile, added 86 mg of sodium iodide, 0.51 ml of 1,8-diazabicyclo[5.4.0]-7-undecene, 194 mg of tetrabutylammonium hydrosulfate and of 0.53 ml climaterealists in the order specified, and then the mixture is stirred over night at 80°C. To the reaction mixture is added aqueous saturated solution of ammonium chloride and then the mixture is extracted with chloroform. The organic layer was washed with aqueous saturated solution of sodium chloride, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. Purification of the obtained residue column chromatography on silica gel get 400 mg of bis{[(2,2-dimethylpropanoyl)oxy]methyl}{(E)-2-[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydropyri the-3-yl]vinyl}phosphonate (example 25) and 190 mg of {[{(E)-2-[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydro-3-chinoline]vinyl}(hydroxy)phosphoryl]oxy}methylphenidate (example 26).

Example 27

To a solution of 144 mg of 7-(cyclohexylamino)-6-fluoro-3-hydroxy-1-isopropylphenyl-4(1H)-it in 5.0 ml DMF add 313 mg of potassium carbonate and 100 μl of ethylbromoacetate in the order specified, and then the mixture is stirred over night at room temperature. To the reaction mixture is added aqueous saturated solution of ammonium chloride and the mixture is then extracted with ethyl acetate. After drying over anhydrous sodium sulfate and subsequent evaporation under reduced pressure the residue is purified column chromatography on silica gel and obtain 159 mg of ethyl {[7-(cyclohexylamino)-6-fluoro-1-isopropyl-4-oxo-1,4-dihydroquinoline-3-yl]oxy}acetate.

Example 28

To 2,9 ml solution of tert-butyl(2-{[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]amino}-2-oxoethyl)carbamate in dioxane add 3.0 ml of 4 M solution of hydrogen chloride in dioxane, and then the mixture is stirred over night at room temperature. The insoluble matter is collected by filtration and obtain 550 mg of the hydrochloride of 2-amino-N-[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]ndimethylacetamide.

Example 29

To a solution of 15.0 g of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid in 90 ml of DMF added to 9.9 g of 1,1'-carbonyldiimidazole and then the mixture was stirred at 80°C for 24 hours. After the OHL is being introduced, the reaction mixture was poured into a mixture of ice water and the precipitated precipitated solid is collected by filtration. Then at 0°C is added to 1.9 g of sodium borohydride to a solution of the obtained solid in a mixture of 200 ml of THF and 100 ml of water and then the mixture is stirred at the same temperature for 2 hours. Add water, the solvent is evaporated under reduced pressure, the insoluble matter is collected by filtration and obtain 13.8 g of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-(hydroxymethyl)quinoline-4(1H)-it.

Example 30

After you have added at -78°From 0.32 ml DMSO to a solution of 0.20 ml of oxalicacid 7.0 ml of dichloromethane and stirring for 30 minutes added at -78°C a solution of 330 mg of N-[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]-2-(hydroxymethyl)butanamide in dichloromethane and the mixture is then stirred for 30 minutes. Then to the mixture is added 1.2 ml of triethylamine and increase the temperature from -78°C to room temperature for 2 hours. To the reaction mixture is added aqueous saturated solution of sodium chloride, the mixture is then extracted with ethyl acetate, the organic layer is dried over anhydrous sodium sulfate and evaporated under reduced pressure, and get through this 320 mg of crude reaction product N-[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]-2-formylmethylene. To a solution of 320 g of the obtained crude product 6.4 ml dichloromethane added 290 mg of methyl(triphenylphosphonium)acetate and then the mixture is stirred over night at room temperature. By evaporation of the reaction mixture under reduced pressure and purification of the mixture column chromatography on silica gel obtain 220 mg of methyl-(2E)-4-({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]amino}carbonyl)Gex-2-enoate.

Example 31

To a solution of 400 mg of ethyl-3-[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]propanoate in 8 ml of THF at 0°C. add 40 mg of lithium aluminum hydride and the mixture is then stirred for 2 hours. To the reaction mixture, water is added and then filtered through celite. After evaporation under reduced pressure, the obtained residue is purified column chromatography on silica gel and get 288 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-(3-hydroxypropyl)quinoline-4(1H)-it.

Example 32

To a solution of 300 mg of {[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]oxy}acetonitrile in 5 ml of 1,4-dioxane add 0.8 ml azide presence of TBT and the mixture is then refluxed for 2 days. After cooling to room temperature, add aqueous 1 M sodium hydroxide solution and ether, and then the operation is carried out separation of layers. To the aqueous layer was added 1 M hydrochloric acid, then extracted with chloroform and the organic layer washed with aqueous saturated solution of sodium chloride. After drying over anhydrous sulfate is the atrium, the solvent is evaporated under reduced pressure. Adding ether to the resulting residue and collecting the insoluble substance by filtration, receive 70 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-(1H-tetrazol-5-ylethoxy)quinoline-4(1H)-it.

Example 33

To a suspension of 3.69 g of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxamide in 30 ml of dichloromethane at -78°C is added to 7.0 ml of triethylamine and a solution of 4.0 ml triperoxonane anhydride in 10 ml of dichloromethane. After a gradual increase in temperature, the mixture was stirred at room temperature for 2 days. After addition of water the mixture is extracted with chloroform and then the organic layer is dried over anhydrous sodium sulfate. After filtration the solvent is evaporated under reduced pressure and the resulting residue is purified column chromatography on silica gel. Once added to the obtained solid substance mixed solvent of 30 ml of THF, 30 ml of methanol and 10 ml of water to the mixture while cooling with ice add 2.3 g of potassium carbonate. After stirring at room temperature for 15 hours to a mixture of 1.0 g of potassium carbonate and stirred at room temperature for 4 days. After evaporation of the solvent under reduced pressure, water is added and then the extraction is carried out with chloroform. After drying over anhydrous sodium sulfate and then filtered, the solvent is pariwat under reduced pressure. After washing the obtained residue with ethyl acetate receive 2,62 g of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbonitrile.

Example 34

Washed with 10 ml of Raney Nickel ethanol three times. Add 30 ml of ethanol, 3 ml of aqueous ammonia and 2.5 g of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbonitrile and then the mixture is stirred overnight in a hydrogen atmosphere. After adding chloroform and subsequent filtration using celite the solvent is evaporated under reduced pressure. The resulting residue is dissolved in 20 ml THF, added under ice cooling a solution of 1.8 g of di-tert-BUTYLCARBAMATE in 10 ml of THF and then the mixture is stirred over night at room temperature. To the mixture while cooling with ice add a solution of 1.0 g of di-tert-BUTYLCARBAMATE in 10 ml of THF and then the mixture is stirred at room temperature for 3 days. To the mixture while cooling with ice add a solution of 1.0 g of di-tert-BUTYLCARBAMATE in 10 ml of THF and then stirred over night at room temperature. After evaporation of the solvent under reduced pressure and subsequent purification column chromatography on silica gel obtained solid is recrystallized from hexane-ethyl acetate and obtain 1.22 g of tert-butyl {[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-d is hydrochinon-3-yl]methyl}carbamate.

Example 35

To 5.50 g of 7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbonitrile add 50 ml of ethanol, 3.0 ml of concentrated hydrochloric acid and of 0.60 g of platinum oxide and the mixture is then stirred overnight in a hydrogen atmosphere. After adding water will filter through celite and the solvent evaporated under reduced pressure. The obtained residue was dissolved by adding 30 ml of water and 20 ml of THF, added under ice cooling 4.0 g of sodium bicarbonate and 4.5 g of di-tert-BUTYLCARBAMATE and then the mixture is stirred under ice cooling for 1 hour and overnight at room temperature. After evaporation of the solvent under reduced pressure, water is added, then the mixture is extracted with chloroform and the organic layer is dried over anhydrous sodium sulfate. After filtration the solvent is evaporated under reduced pressure, the obtained residue is purified column chromatography on silica gel and get 5,72 g of tert-butyl{[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]methyl}carbamate.

Example 36

To 0.31 g of the hydrochloride of 7-(cyclohexylamino)-6-fluoro-4-oxo-1-(pyrrolidin-3-yl)-1,4-dihydroquinoline-3-carbonitrile add 5 ml of ethanol, 0.2 ml of concentrated hydrochloric acid and 0.10 g of platinum oxide and the mixture is then stirred overnight in an atmosphere in which Orada. After adding water will filter through celite and the solvent evaporated under reduced pressure. Purification of the obtained residue column chromatography on ODS obtain 256 mg of the hydrochloride of 3-(aminomethyl)-7-(cyclohexylamino)-6-fluoro-1-pyrrolidin-3-rhinolin-4(1H)-it.

Example 37

To a solution of 2.0 g of 1-cyclopentyl-6,7-debtor-3-nitroanilin-4(1H)-she's in 40 ml of DMSO added to 2.3 ml of cyclohexylamine and then the mixture is stirred overnight at 90°C. the Reaction mixture is cooled to room temperature and poured into water, cooled with ice, and then the insoluble matter is collected by filtration. By recrystallization of the obtained solid from ethanol 2.5 g of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-nitroanilin-4(1H)-it.

Example 38

To a solution of 220 mg of 3-amino-7-(cyclohexylamino)-1-(1-ethylpropyl)-6-ftorhinolon-4(1H)-she's in 4 ml of ethanol is added 105 mg of 1H-1,2,3-benzotriazol-1-ylmethanol and then the mixture is stirred over night at room temperature. Then to the reaction mixture are added 48 mg of sodium borohydride and the mixture is then stirred for 3 hours. Adding water to the obtained reaction mixture and collecting the insoluble substance by filtration, receive 100 mg of 7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-3-(methylamino)quinoline-4(1H)-it.

Example 39

To a solution of 13.8 g of 7-(cyclohexylamino)-1-qi is lipantil-6-fluoro-3-(hydroxymethyl)quinoline-4(1H)-she's in 100 ml dichloromethane at room temperature add 67,0 g of manganese dioxide and the mixture is then stirred overnight. After completion of the reaction and subsequent filtration using celite the filtrate evaporated under reduced pressure. Crystallization of the obtained solid from ethyl acetate receive 13,0 g of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde.

Example 40

To a solution of 8.0 g of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde in 100 ml of dichloromethane at room temperature gradually add 6,1 g metallocarboranes acid and the mixture is then stirred for 2 hours. To the reaction mixture is added aqueous saturated solution of sodium bicarbonate and an aqueous solution of hydrocyanate sodium, the mixture is stirred for 30 minutes and then extracted with chloroform. After drying over anhydrous sodium sulfate and subsequent evaporation under reduced pressure the residue is purified column chromatography on silica gel and get to 7.7 g of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-hydroxyquinolin-4(1H)-it.

Example 41

To a solution of 150 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde in 2.0 ml acetic acid is added 60 mg of 2-thioxo-1,3-thiazolin-4-she and 40 mg of sodium acetate in this order and then the mixture is stirred over night at 100°C. the Reaction mixture is cooled to room temperature and uprivate reduced pressure. Add ethyl acetate, the insoluble matter is collected by filtration and obtain 173 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-[(Z)-(4-oxo-2-thioxo-1,3-thiazolidin-5-ilidene)methyl]quinoline-4(1H)-it.

Example 42

To a solution of 762 mg of 3-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-7-(cyclohexylamino)-1-cyclopentyl-6-ftorhinolon-4(1H)-she's in 15 ml of THF at room temperature, add 1.5 ml of 1 M solution of tetrabutylammonium fluoride in THF and the mixture is then stirred for 2 hours. To the reaction mixture, water is added, then the mixture is extracted with ethyl acetate and washed with aqueous saturated solution of sodium chloride. After drying over anhydrous sodium sulfate carry out the evaporation under reduced pressure. Purification of the residue column chromatography on silica gel get 273 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-(3-hydroxypropoxy)quinoline-4(1H)-it.

Example 43

To a solution of 500 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-N-methoxy-N-methyl-4-oxo-1,4-dihydroquinoline-3-carboxamide in 10 ml of THF, add 1.2 ml of 1 M solution metallice in THF and then the mixture is stirred at room temperature for 3 days. To the reaction mixture, water is added and will filter through celite. After evaporation under reduced pressure, the obtained residue is purified column chromatography on silica gel and receive 150 mg of 3-acetyl--(cyclohexylamino)-1-cyclopentyl-6-ftorhinolon-4(1H)-it.

Example 44

To a solution of 500 mg of 7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde in 5.0 ml of dichloromethane at -40°C add 0,23 ml diethylphosphate and 0.22 ml of 1,8-diazabicyclo[5.4.0]-7-undecene and then the mixture is stirred over night at room temperature. To the reaction mixture is added aqueous saturated solution of ammonium chloride, the mixture is extracted with chloroform and then washed with aqueous saturated solution of sodium chloride. After drying over anhydrous sodium sulfate and subsequent evaporation under reduced pressure, the obtained residue is purified column chromatography on silica gel and receive 400 mg of diethyl[[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl](hydroxy)methyl]phosphonate.

Example 45

To a solution of 160 mg of ethyl{[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]amino}acetate in 3.2 ml of DMF, add 0.05 ml of benzylbromide and 75 mg of potassium carbonate and the mixture is then stirred overnight at room temperature. Adding water to the reaction mixture and collecting the insoluble substance by filtration, receive 200 mg of ethyl{benzyl[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]amino}acetate.

Example 46

To a solution of 210 mg of (2E)-3-{7-[(cyclopropylmethyl)amino]-6-fluoro-1-isopropyl-4-oxo-1,4-dihydroquinoline-3-yl}acrylic is th acid in 4.2 ml of THF added 120 mg of 1,1'-carbonyldiimidazole and then the mixture is stirred over night at room temperature. To the reaction mixture, water is added and the insoluble matter is collected by filtration. The obtained solid substance was dissolved in 4.2 ml of DMF, add of 0.11 ml of 1,8-diazabicyclo[5.4.0]-7-undecene and 150 mg of 5-chlorothiophene-2-sulfonamida and then the mixture is stirred over night at 80°C. Adding water to the obtained reaction mixture and collecting the insoluble substance by filtration, to obtain 145 mg of (2E)-N-[(5-chloro-2-thienyl)sulfonyl]-3-{7-[(cyclopropylmethyl)amino]-6-fluoro-1-isopropyl-4-oxo 1,4-dihydroquinoline-3-yl}acrylamide.

Example 47

Under ice cooling, 2.0 ml triperoxonane acid are added to a solution of 0.20 g of tert-butyl{[7-(cyclohexylamino)-6-fluoro-4-oxo-1-(tetrahydrofuran-3-yl)-1,4-dihydroquinoline-3-yl]methyl}carbamate in 5 ml of dichloromethane. After stirring for 1.5 hours under ice cooling and at room temperature overnight the solvent is evaporated under reduced pressure. Purification of the obtained residue column chromatography on ODS obtain 184 mg of triptoreline 3-(aminomethyl)-7-(cyclohexylamino)-6-fluoro-1-(tetrahydrofuran-3-yl)quinoline-4(1H)-it.

Example 48

To a solution of 240 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-(3-hydroxypropyl)quinoline-4(1H)-she 4.8 ml of DMSO added 300 mg of a complex of sulfur trioxide and pyridine and 0.8 ml of triethylamine and the mixture is then stirred overnight at room temperature. To react the Onna mixture is added water, the mixture is then extracted with chloroform, and then the organic layer was washed with aqueous saturated solution of sodium chloride. After drying over anhydrous sodium sulfate and subsequent evaporation under reduced pressure, the obtained residue is purified column chromatography on silica gel and obtain 140 mg of the aldehyde. To a solution of 140 mg of aldehyde 2.8 ml DMF added 141 mg of potassium carbonate and 414 mg of ethyl(diethoxyphosphoryl)acetate and then the mixture is stirred over night at 60°C. the Reaction mixture is cooled to room temperature, water is added and the insoluble matter is collected by filtration. Purification of insoluble substances column chromatography on silica gel obtain 57 mg of ethyl-(2E)-5-[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]Penta-2-enoate.

Example 49

Add 3 ml of ethyl acetate and 0.35 ml of 1 M solution of hydrogen chloride in ethyl acetate to of 0.13 g of ethyl({[7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]methyl}amino)acetate obtained in the same manner as in example 9. After evaporation of the solvent under reduced pressure and then adding ether, the insoluble matter is collected by filtration and obtain 97 mg of the hydrochloride of ethyl({[7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]methyl}amino)acetate.

Example 50

Add 10 ml of the of tracedata, 45 mg of oxalic acid and 10 ml of ethanol to 440 mg of ethyl({[7-(cyclohexylamino)-6-fluoro-4-oxo-1-(tetrahydrofuran-3-yl)-1,4-dihydroquinoline-3-yl]methyl}amino)acetate obtained in the same manner as in example 4. After evaporation of the solvent under reduced pressure and then adding ethyl acetate, the insoluble matter is collected by filtration and obtain 349 mg of oxalate ethyl({[7-(cyclohexylamino)-6-fluoro-4-oxo-1-(tetrahydrofuran-3-yl)-1,4-dihydroquinoline-3-yl]methyl}amino)acetate.

Example 51

To 0.25 g of the oxalate ethyl({[7-(cyclohexylamino)-6-fluoro-4-oxo-1-(tetrahydrofuran-3-yl)-1,4-dihydroquinoline-3-yl]methyl}amino)acetate, water is added and the potassium carbonate and the mixture is then extracted with chloroform. After drying over anhydrous sodium sulfate and then filtered, the solvent is evaporated under reduced pressure. To a solution of the obtained residue in 10 ml of ethanol under cooling with ice add to 0.60 ml aqueous 1 M sodium hydroxide solution and then the mixture is stirred under ice cooling for 1 hour and at room temperature over night. After evaporation of the solvent under reduced pressure, water is added and triperoxonane acid. Cleaning column chromatography on ODS obtain 251 mg trifenatate ({[7-(cyclohexylamino)-6-fluoro-4-oxo-1-(tetrahydrofuran-3-yl)-1,4-dihydroquinoline-3-yl]methyl}amino)acetic acid.

Example 52

To a solution of 155 mg of diethyl[2-(acetyl - {[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]methyl}amino)-1,1-dottorati]phosphonate in 2.0 ml of chloroform, add 0,27 ml of bromotrimethylsilane and then the mixture is stirred over night at room temperature. The reaction mixture is evaporated under reduced pressure, to the obtained residue, add water 1 M sodium hydroxide solution, and then purified column chromatography on ODS, washed with ethyl acetate and receive 100 mg of disodium[2-(acetyl - {[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]methyl}amino)-1,1-dottorati]phosphonate.

Example 53

To a solution of 280 mg of ethyl-(2E)-4-{[7-(cyclohexylamino)-6-fluoro-1-isopropyl-4-oxo-1,4-dihydroquinoline-3-yl]oxy}but-2-enoate 8.0 ml of ethanol at room temperature added 28 mg of rhodium-on-coal (10%) and the mixture is then stirred for 2 hours in hydrogen atmosphere. After filtration using celite the filtrate evaporated under reduced pressure, the residue is purified column chromatography on silica gel and obtain 202 mg of ethyl 4-{[7-(cyclohexylamino)-6-fluoro-1-isopropyl-4-oxo-1,4-dihydroquinoline-3-yl]oxy}butanoate.

Example 54

To a solution of 130 mg of N-[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]-2-[(4R)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-yl]ndimethylacetamide in mixed solvents is e (1.0 ml THF and 1.0 ml of methanol) is added 0.3 ml of 1 M hydrochloric acid and then the mixture is stirred over night at room temperature. Then add 0.8 ml of aqueous 1 M sodium hydroxide solution and the mixture is stirred over night at room temperature. The reaction mixture is neutralized 1 M hydrochloric acid, and then the insoluble matter is collected by filtration and purified column chromatography on silica gel, and get 11 mg of (2R)-4-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]amino}-2-hydroxy-4-oxobutanoic acid.

Example 55

To a solution of 100 mg of (2E)-3-[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]acrylic acid in 2.0 ml of THF added 60 mg of 1,1'-carbonyldiimidazole and then the mixture is stirred over night at room temperature. Adding water to the obtained reaction mixture and collecting the insoluble substance by filtration, get allmydata. To a solution of the obtained elliminate in 2.0 ml DMF added 0.5 ml of aqueous ammonia and the mixture is then stirred overnight at 60°C. the resulting reaction mixture is cooled to room temperature, water is added, the insoluble matter is collected by filtration and obtain 58 mg of (2E)-3-[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]acrylamide.

Example 56

To a solution of 500 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde in 5.0 ml of ethanol is added 215 mg of the hydrochloride of these is aminoacetate and then the mixture is stirred at room temperature for 2 hours. Then to the mixture is added 50 mg of palladium-on-coal and the mixture is stirred at room temperature for 4 hours in hydrogen atmosphere. The reaction mixture was filtered through celite and then evaporated under reduced pressure. The resulting residue is purified column chromatography on silica gel. To a solution of the compounds obtained in 3.6 ml of dioxane is added to 4.0 ml of 4 M solution of hydrogen chloride in dioxane and the mixture is then stirred overnight at room temperature. The insoluble matter is collected by filtration and obtain 320 mg of the hydrochloride of the ethyl({[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]methyl}amino)acetate.

Example 57

Add 2.0 ml THF and 0,071 ml of chlorotrimethylsilane to 73 mg of zinc, and then the mixture is stirred at room temperature for 15 minutes. Then added to the mixture of 200 mg of ethyl (2E)-4-brombach-2-enoate and then the mixture is stirred at room temperature for 30 minutes. To the reaction mixture is added 7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde and then the mixture is stirred over night at room temperature. To the reaction mixture, water is added and the mixture is then extracted with chloroform. The organic layer was washed with aqueous saturated solution of sodium chloride, dried over anhydrous sodium sulfate and then evaporated under ponie nom pressure. The resulting residue is purified column chromatography on silica gel and receive 30 mg of ethyl-(2E)-5-[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]-5-hydroxyben-2-enoate.

Example 58

To a solution of 119 mg of 60% sodium hydride in 5 ml of THF at 0°C add 598 μl of ethyl(diethoxyphosphoryl)acetate and the mixture is then stirred for 30 minutes. To the mixture at the same temperature, add a solution of 400 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-(2-oxopropoxy)quinoline-4(1H)-it is in 5 ml of THF and the mixture is then stirred at room temperature for 2 hours. To the reaction mixture is added aqueous saturated solution of ammonium chloride and the mixture is then extracted with ethyl acetate. The organic layer was washed with aqueous saturated solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is purified column chromatography on silica gel and receive 200 mg of ethyl-(2E)-4-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]oxy}-3-methylbut-2-enoate.

Example 59

To a suspension 1081 mg bromide (3-benzyloxyphenyl)triphenylphosphine in 20 ml of THF added 258 mg of tert-butoxide potassium and the mixture is then stirred for 1.5 hours. To the mixture add a solution of 358 mg of 7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde in 10 methf and then the mixture is stirred for 1 hour. To the reaction mixture is added aqueous saturated solution of ammonium chloride, the mixture is then extracted with ethyl acetate and washed with aqueous saturated solution of sodium chloride. After drying over anhydrous sodium sulfate and subsequent concentration under reduced pressure the residue is purified column chromatography on silica gel and receive 488 mg of 3-[4-(benzyloxy)but-1-EN-1-yl]-7-(cyclohexylamino)-1-(1-ethylpropyl)-6-ftorhinolon-4(1H)-it.

Example 60

To a solution of 100 mg of 5-chlorothiophene-2-carboxylic acid in 2 ml of dichloromethane type of 0.55 ml chlorosulfonylisocyanate and then the mixture is stirred overnight at 40°C. the Solvent is evaporated under reduced pressure and the resulting residue is dissolved in 1.5 ml dichloromethane. Then add 150 mg of 3-amino-7-(cyclohexylamino)-1-cyclopentyl-6-ftorhinolon-4(1H)-she of 0.91 ml of triethylamine and the mixture is then stirred overnight at room temperature. To the reaction mixture, water is added and the mixture is then extracted with chloroform. The organic layer was washed with aqueous saturated solution of sodium chloride. After drying over anhydrous sodium sulfate and then filtered, the solvent is evaporated under reduced pressure. The resulting residue is purified column chromatography on silica gel and obtain 64 mg of 5-chloro-N-({[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroxy the Lin-3-yl]amino}sulfonyl)thiophene-2-carboxamide.

Example 61

To a suspension of 200 mg of 60% sodium hydride in 6 ml of DMSO added 1.1 g of iodide trimethylsulfoxonium and then the mixture is stirred for 30 minutes. To the reaction mixture 242 mg of ethyl-(2E)-3-[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]acrylate and the mixture is then stirred at room temperature for 1 hour and at 60°C for 1 hour. To the reaction mixture, water is added and the mixture is then extracted with diethyl ether. The organic layer was washed with aqueous saturated solution of sodium chloride. After drying over anhydrous sodium sulfate the solvent is evaporated under reduced pressure. The resulting residue is purified column chromatography on silica gel and obtain 55 mg of ethyl-2-[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]cyclopropanecarboxylate.

Example 62

To a solution of 1.5 g of {[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]oxy}acetonitrile in 30 ml of methanol, add 1.1 ml of triethylamine and 540 mg of hydroxylamine hydrochloride and the mixture is then refluxed for 27 hours. The solvent is evaporated under reduced pressure, the obtained residue is purified column chromatography on silica gel and obtain 850 mg of 2-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]oxy}-N'-hydroxyethylamide the A.

Example 63

Under ice cooling 40 ál diketene added dropwise to a solution of 800 mg of 2-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]oxy}-N'-hydroxyethylamide in 8 ml of chloroform and the mixture is then stirred under ice cooling for 6 hours. Evaporation of the solvent under reduced pressure to obtain 180 mg of N'-(acetoacetate)-2-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]oxy}ethanamide.

Example 64 example 65

Add 5 ml of toluene and 41 mg of 60% sodium hydride to 180 mg of N'-(acetoacetate)-2-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]oxy}ethanamide and then the mixture is refluxed for 24 hours. The solvent is evaporated under reduced pressure, to the obtained residue, add diluted hydrochloric acid, the mixture is then extracted with ethyl acetate and washed with water and aqueous saturated solution of sodium chloride. After drying over anhydrous sodium sulfate the solvent is evaporated under reduced pressure, the obtained residue is purified column chromatography on silica gel and receive 10 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-[(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methoxy]quinoline-4(1H)-it (example 64) and 30 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-{[5-(2-oxopropyl)-1,2,4-oxadiazol-3-yl]methoxy}hee the Olin-4(1H)-it (example 65).

Example 66

At -50°C 0,14 ml N-(chlorocarbonyl)isocyanate is added dropwise to a solution of 110 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-[(hydroxyamino)methyl]quinoline-4(1H)-she's in 4 ml of THF and then the mixture is stirred at room temperature for 1 hour. To the reaction mixture was added 1 M hydrochloric acid, then the mixture is extracted with chloroform and washed with aqueous saturated solution of sodium chloride. After drying over anhydrous sodium sulfate the solvent is evaporated under reduced pressure, the obtained residue is purified column chromatography on silica gel and receive 45 mg of 2-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]methyl}-1,2,4-oxadiazolidine-3,5-dione.

Example 67

To a solution of 310 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-(4-hydroxybutyl)quinoline-4(1H)-she's in 4 ml of DMSO added 0.7 ml of triethylamine and 620 mg of a complex of sulfur trioxide and pyridine, and the mixture is then stirred at room temperature for 24 hours. After adding 1 M hydrochloric acid and water, the insoluble matter is collected by filtration and obtain 290 mg of 4-[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]butanal.

Example 68

To 285 mg of 4-[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]butanal add 9 ml of toluene and 250 mg of methyl(triphenylphosphonium)acetate and the ATEM the mixture is stirred at 80°C for 14 hours. The solvent is evaporated under reduced pressure, the obtained residue is purified column chromatography on silica gel and obtain 260 mg of methyl-(2E)-6-[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]Gex-2-enoate.

Example 69

To 500 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde add 5 ml of ethanol, 460 mg of sodium acetate and 290 mg of hydroxylamine hydrochloride and the mixture is then stirred at room temperature for 15 hours and at 70°C for 12 hours. The solvent is evaporated under reduced pressure, to the residue water is added, then the mixture is extracted with chloroform and washed with aqueous saturated solution of sodium chloride. After drying over anhydrous sodium sulfate the solvent is evaporated under reduced pressure and receive 300 mg of the oxime 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde.

Example 70

Add 15 ml of methanol, 15 ml of THF and 250 mg cyanoborohydride sodium to 300 mg of the oxime 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde. To the mixture while cooling with ice add 2 ml of 4 M solution of hydrogen chloride in dioxane and the mixture is then stirred at room temperature for 3 hours. To the mixture while cooling with ice, add water 1 M sodium hydroxide solution, C is the mixture extracted with chloroform and then washed with aqueous saturated solution of sodium chloride. After drying over anhydrous sodium sulfate the solvent is evaporated under reduced pressure, the obtained residue is purified column chromatography on silica gel and obtain 130 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-[(hydroxyamino)methyl]quinoline-4(1H)-it.

Example 71

To a suspension of 1.02 g of 9-(cyclohexylamino)-8-fluoro-6-oxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]quinoline-5-carboxylic acid in 50 ml of THF while cooling with ice, add 0.5 ml of triethylamine and 0.4 ml of isobutylacetate and then the mixture is stirred under ice cooling for 1 hour. To the mixture at -78°C is added dropwise an aqueous solution (4 ml) 431 mg of sodium borohydride and the mixture is then stirred at -15°C for 15 minutes and under ice cooling for 30 minutes. To the mixture is added aqueous saturated solution of ammonium chloride, the mixture is then extracted with ethyl acetate and then the organic layer is dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, the obtained residue is purified column chromatography on silica gel and obtain 495 mg of 9-(cyclohexylamino)-8-fluoro-5-(hydroxymethyl)-1,2,3,4-tetrahydro-6N-pyrido[1,2-a]quinoline-6-it.

In the same way as in the above examples 1-71, using appropriate starting compounds, are compounds of the examples listed in the following tables 10-73. Data on MS connection with the development are given in the following tables 10-73, and NMR data of some compounds of the examples in tables 74 and 75.

Structures of other compounds of the present invention are shown in tables 76-83. They can easily be obtained using the above-described methods of preparation and methods described in the examples or ways obvious to a person skilled in the art, or modifications.

Industrial applicability

As quinolone derivatives of the present invention or their salts have excellent activity of inhibiting platelet aggregation or activity inhibition of P2Y12, they are applicable as pharmaceuticals, in particular platelet aggregation inhibitors or inhibitors of P2Y12. Accordingly, the compounds according to the present invention is applicable as a means for the prevention and/or treatment of diseases of the circulatory system, closely associated with thrombus formation by platelet aggregation, such as unstable angina, acute myocardial infarction, and to prevent its recurrence, re-obstruction and restricture after bypass surgery coronary artery surgery RTSA or surgery stent placement, acceleration of thrombolysis in coronary artery and prevent re-obstruction and similar ischemic diseases such as cerebral infarction with transient ischemic impaired and cerebral circulation (TIA), subarachnoid hemorrhage (vasospasm) and a similar stroke; chronic occlusion of arteries and such peripheral artery disease; and similar diseases; and as an aid in heart surgery or surgery on the blood vessels.

1. Derived quinolone represented by the formula (I)or its pharmaceutically acceptable salt

where the symbols in the formula have the following meanings:
R1- C3-6cycloalkyl or lower alkylene3-6cycloalkyl,
R2Is h or halogen,
R3- H, halogen, -OR0or-O-(lower alkylene)-phenyl,
R0the same or different from one another and each represents-H or lower alkyl,
R4lower alkyl, halogen(lower alkyl), lower alkylene3-6cycloalkyl, the 3-7cycloalkyl or heterocyclic group,
where specified in R4cycloalkyl and heterocyclic group may be respectively substituted,
R5- -NO2, -CN, -L-Ra, -C(O)R0, -O-Rb, -N(R6)2lowest alkylene-N(R6)(Rc), -N(R6)C(O)-Rdlowest alkylene-N(R6)C(O)-Rdlowest alkylene-N(R0)C(O)O-(lower alkyl), -N(R0)C(O)N(R0)-Relowest alkylene-N(R0)C(O)N(R0)-Re, -N(R0)S(O)2N(R0)C(O)-Rd, -CH=NOH, C3-6cycloalkyl, (2,4-dioxo-1,3-thiazolidin-5-ilidene)methyl or (4-oxo-2-thioxo-1,3-thiazolidin-5-ilidene)methyl,
where specified in R5cycloalkyl may be respectively substituted,
R6- H, lower alkyl, lower alkylene-CO2R0or lower alkylene-P(O)(ORp)2,
where specified in R6lowest alkylene may be substituted,
L - low alkylene or lower albaniles, which may be respectively substituted,
Ra- -OR0, -O-(lower alkylene)-phenyl, -O-(lower alkylene)-CO2R0, -CO2R0, -C(O)NHOH, -C(O)N(R6)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-phenyl, -C(O)N(R0)-S(Oh)2-(heterocyclic group), -NH2OH, -OC(O)R0, -OC(O)-(halogen(lower alkyl)), -P(O)(ORp)2, phenyl or heterocyclic group,
where indicated the data in R aphenyl and heterocyclic group may be substituted,
Rp- R0lowest alkylene-OC(O)-(lower alkyl), lower alkylene-OC(O)-C3-6cycloalkyl, lower alkylene-OC(O)O-(lower alkyl),
Rb- H, lower alkylene-Rbaor lower albaniles-Rba,
where specified in Rblowest alkylene and lower albaniles may be substituted,
Rba- -OR0, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-phenyl, -C(NH2)=NOH, -C(NH2)=NO-C(O)-lower alkylene)-C(O)R0, -CO2-(lower alkylene)-phenyl, -P(O)(ORp)2, -C(O)R0-C(O)-phenyl, C3-6cycloalkyl, phenyl or heterocyclic group,
where specified in Rbaphenyl and heterocyclic group may be substituted,
Rc- H, lower alkylene-OR0lowest alkylene-CO2R0lowest alkylene-P(O)(ORp)2, phenyl,
where specified in Rclowest alkylene and phenyl may be substituted,
Rd- C1-7-alkyl, lower alkenyl, halogen(lower alkyl), lower alkylene-Rdalowest albaniles-RdaWith3-6cycloalkyl, phenyl, naphthyl or heterocyclic group,
where specified in Rdlowest alkylen, cycloalkyl, phenyl, naphthyl and heterocyclic group may be substituted,
Rda- -CN, -OR0, -O-(lower alkylene)-CO R0, -O-naphthyl, -CO2R0, -CO2-(lower alkylene)-N(R0)2, -P(O)(ORp)2, -N(R6)2, -C(O)N(R0)-phenyl, -C(O)N(R0)-(lower alkylene, which may be substituted by-CO2R0)-phenyl, -N(R0)C(O)-phenyl, -N(R0)C(O)-OR0, -N(R0)C(O)-O-(lower alkylene)-phenyl, -N(R0)S(O)2-phenyl, C3-6cycloalkyl, phenyl, naphthyl or heterocyclic group,
where specified in Rdaphenyl, naphthyl and heterocyclic group may be substituted,
Relowest alkylene-CO2R0, phenyl, -S(O)2-phenyl, or-S(O)2-(heterocyclic group),
where specified in Rephenyl and heterocyclic group may be substituted,
X is CH,
A - C(R7),
R7- H,
or R4and R7together may form a lower alkylene,
where the term "heterocyclic group" includes "aromatic geterotsiklicheskikh group" and "non-aromatic heterocyclic group",
where the term "aromatic heterocyclic group" means a monocyclic 5-6-membered aromatic group containing from 1 to 4 identical or different heteroatoms selected from the group consisting of nitrogen atoms, oxygen, and sulfur, a bicyclic aromatic heterocycle, in which the condensed monocyclic aromatic heterocycles or monocyclics the third aromatic heterocycle condensed with the benzene ring cycle, or tricyclic aromatic heterocycle, in which the bicyclic aromatic heterocycle condensed with a monocyclic aromatic heterocycle or a benzene cycle, and where the nitrogen atom and/or sulfur atom contained in such cycles can be oxidized, and these cycles can be partially saturated; and
where the term "nonaromatic heterocyclic group" means a saturated or partially saturated monocyclic 3-6-membered nonaromatic a heterocycle, which contains 1 to 4 heteroatoms selected from O, S or N, bicyclic nonaromatic a heterocycle, in which the monocyclic nonaromatic a heterocycle condensed with the benzene ring cycle or the above aromatic heterocycle, and where such non-aromatic heterocycles can form the oxide or dioxide through oxidation of S or N as cyclic atom or may form a bridging loop or spirits;
the term "may be substituted" means unsubstituted or substituted by same or different 1 to 5 substituents", where
an acceptable substitute for "lower alkylene"except "lower alkylene" in the definition of R6and for "lower Alcanena" means a group G1;
an acceptable substitute for "lower alkylene" in the definition of R6means halogen;
acceptable zamestitelja of cycloalkyl means a group G 2;
an acceptable substitute for phenyl and naphthyl, with the exception of phenyl and naphthyl in the definition of Rdmeans a group G3;
an acceptable substitute for phenyl and naphthyl in the definition of Rdmeans a group G4;
an acceptable substitute for heterocyclic group, with the exception of the heterocyclic group in the definition of Rdaand Rdmeans a group G5;
an acceptable substitute for the heterocyclic group in the definition of Rdameans a group G6;
an acceptable substitute for the heterocyclic group in the definition of Rdmeans a group G7; where
G1selected from halogen, -OR0, -CO2R0and-CO2lowest alkylen-phenyl;
G2selected from halogen, lower alkyl, -OR0, -CO2R0and-C(O)-phenyl;
G3selected from halogen, -CN, lower alkyl, halogen-lower alkyl, -OR0, -O -, halogen-lower alkyl, -CO2R0and-O-lower alkylene-CO2R0;
G4selected from halogen, -CN, lower alkyl, -OR0, -C(O)R0, -CO2R0, -N(R0)2, -S(O)2is lower alkyl and phenyl;
G5selected from halogen, lower alkyl, halogen-lower alkyl, -OR0, -O -, halogen-lower alkyl, oxo, -CO2R0the bottom alkylene-C(O)R0the bottom alkylene-CO2R0and-S(O 2is lower alkyl;
G6selected from halogen, lower alkyl, halogen-lower alkyl, -OR0, -O -, halogen-lower alkyl, oxo, -CO2R0the bottom alkylene-C(Oh)2R0, -S(O)2is lower alkyl, phenyl and-S-lower alkylene-phenyl; and
G7selected from halogen, nitro, lower alkyl, halogen-lower alkyl, -OR0, -O -, halogen-lower alkyl, oxo, -CO2R0the bottom alkylene-CO2R0, -N(R0)2, -S(O)2-lower alkyl, -S(O)2-phenyl, phenyl, lower alkylen-phenyl and-S-lower alkylene-CO2R0;
and provided that
excluded 7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbonitrile.

2. The compound according to claim 1, where R3represents-H, -HE or-F.

3. The compound according to claim 2, where a represents CH.

4. The compound according to claim 3, where R1represents a cyclohexyl or cyclopropylmethyl.

5. The compound according to claim 4, where R2is a-F.

6. The compound according to claim 5, where R4represents a lower alkyl or cycloalkyl.

7. The connection according to claim 6, where R5represents-N(R6)C(O)-(lower alkylene)-CO2R0where R6means H or lower alkyl, lower alkylene-CO2R0lowest albaniles-CO2R0, -O-(lower alkylene)-CO2R0, -O-(lower alkylene, which can b shall be substituted-CO 2R0)-phenyl or-O-(lower albaniles)-CO2R0.

8. The compound according to claim 1, which is selected from the group consisting of
4-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]amino}-4-oxobutanoic acid,
5-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]amino}-5-oxopentanoic acid,
(2E)-3-[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]acrylic acid,
(2S)-2-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]oxy}-3-phenylpropane acid,
(2E)-3-[7-(cyclohexylamino)-6-fluoro-1-isopropyl-4-oxo-1,4-dihydroquinoline-3-yl]acrylic acid,
(2S)-2-{[7-(cyclohexylamino)-6-fluoro-1-isopropyl-4-oxo-1,4-dihydroquinoline-3-yl]oxy}-3-phenylpropane acid,
(2S)-2-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl]oxy}propanoic acid and
(2S)-2-{[7-(cyclohexylamino)-6-fluoro-1-isopropyl-4-oxo-1,4-dihydroquinoline-3-yl]oxy}propanoic acid,
or its pharmaceutically acceptable salt.

9. Pharmaceutical composition, which is an inhibitor of platelet aggregation, comprising the compound according to claim 1 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

10. Pharmaceutical composition, which is a P2Y12 inhibitor, comprising the compound according to claim 1 or its pharmaceutically als the salt and a pharmaceutically acceptable carrier.

11. The use of compounds according to claim 1 or its pharmaceutically acceptable salt to obtain an inhibitor of platelet aggregation or P2Y12 inhibitor.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel organic compounds of formula where R1 denotes H; halogen; -C0-C7-alkyl-O-R3; -NR4R5; R2 denotes phenyl, substituted with one or two substitutes selected from a group consisting of C1-7alkyl, halogen-C1-7alkyl, C1-7alkoxy, halogen-C1-7alkoxy, phenoxy, halogen, C1-7alkylpiperazinyl-C1-7alkyl, C3-C8-cyclalkyl, C1-7alkylpiperidinyl-C1-7alkyl and C1-7alkylimidazolyl; R3 denotes H or phenyl-lower alkyl; R4 and R5 are independently selected from a group consisting of H; lower alkyl; lower alkoxy-carbonyl and amino; A, B and X are independently selected from C(R7) or N, provided that not more than one or A, B and X denotes N; R7 denotes H; R8 denotes hydrogen; n equals 0; Y denotes O; Z denotes C; W is absent; K denotes N or C, and either a) if K denotes C, the bond shown by a wavy line () is a double bond, Q is selected from O-N, S-N, O-CH and S-CH, where in each case, the left-hand O or S atom is bonded through a bond shown in formula I to K, the right-hand N or carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by the dotted line, is a double bond with C; and the bond shown by a thick line () is a single bond; or b) if K denotes N, the bond shown by a wavy line () is a single bond; Q denotes N=CH, where the left-hand N atom is bonded through a bond shown in formula I to K, the right-hand carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by a dotted line, is a single bond with C; and the bond shown by thick line () is a double bond; or salt thereof (preferably pharmaceutically acceptable salt). The invention also relates to a pharmaceutical composition, having inhibiting action on protein kinase, containing a compound of formula I or salt thereof in an effective amount and at least one pharmaceutically acceptable carrier material.

EFFECT: heterocyclic carboxamides as kinase inhibitors.

12 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of azabicyclo{3,1,0}hexane of general formula (I) or pharmaceutically acceptable salts thereof (values of radicals are given in the claim), synthesis method thereof, intermediate compounds, a pharmaceutical composition and use of the novel compounds in therapy as dopamine receptor D3 modulators, for example, for treating drug dependence or as antipsychotic agents.

EFFECT: improved properties of the derivatives.

34 cl, 122 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and salts thereof (I), where T is a tetrazolyl group which is not substituted or substituted with [C1-C8]alkyl; L1 denotes (CR1R2)n-, where n equals 1, 2, 3 or 4; R1 and R2 denote hydrogen; L2 denotes a direct bond; A is selected from a group comprising A2, A8 and A20 , where Z1, Z2, Z3 and Z4 are independently selected from a group comprising hydrogen, -NR5R6, -N(R5)C(=O)R6, -N(R5)C(=O)OR6, -N(R5)C(=O)NR6R7, -N(R5)C(=S)NR6R7; Q is selected from a group comprising , where X1, X2 and X3 are independently selected from a group comprising hydrogen, halogen, [C1-C8]alkyl, phenyl or phenyl which is substituted by 1-5 halogen atoms; R5-R7 are independently selected from a group comprising hydrogen, [C1-C8]alkyl, [C1-C8]halogenalkyl, [C2-C8]alkenyl, [C3-C6]cycloalkyl, phenyl and phenyl [C1-C8]alkyl.

EFFECT: invention also relates to a fungicide composition containing an active ingredient in form of an effective amount of the disclosed compound, use of the disclosed compound or fungicide composition thereof for treatment or prophylactic control of phytopathogenic fungi of plants or agricultural crops and a method for treatment or prophylactic control of phytopathogenic fungi of plants or agricultural crops.

14 cl, 3 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel carbamoyl benzotriazole derivatives of general formula , (values of radicals are given in the description), tautomers thereof and pharmaceutically acceptable salts and use thereof as endothelial lipase inhibitors.

EFFECT: improved properties of the derivatives.

11 cl, 148 ex

FIELD: chemistry.

SUBSTANCE: compound of formula (I) has antiviral activity toward the human cytomegalovirus (HCMV) or some other representative of the Herpes virida group. In formula (I)

, R1 is a group of formula , where * denotes the point of bonding to a carbonyl group, R3 denotes a pyridyl which can be substituted with a substitute independently selected from a group comprising C1-C6alkyl or a cyano group, R5 and R6 independently denote hydrogen, R2 denotes a phenyl which can be substituted with a substitute selected from a group comprising a trifluoromethoxy group, a difluoromethoxy group and a monofluoromethoxy group, A is a group of formula

or , where * denotes the point of bonding to the carbonyl group, # denotes the point of bonding to the nitrogen atom of urea, R7 denotes C1-C6alkyl which can be substituted with a substitute selected from a group comprising C3-C6cycloalkyl, R8 and R9 independently denote hydrogen, halogen or C1-C6alkyl. The invention also relates to a method of producing a compound of formula (I) from a compound of formula , a method of producing a compound of formula (V), a medicinal agent containing the disclosed compound, use of the compound in preparing a medicinal agent and a method of fighting viral infections, among them human cytomegalovirus (HCMV) or some other representative of the Herpes viridae group.

EFFECT: high antiviral activity.

9 cl, 1 tbl, 39 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

where R1 is a phenyl group (said phenyl group is substituted with one or more C1-6alkyl groups, one C1-3alkyl group (said C1-3alkyl group is substituted with one or more halogen atoms), one C1-3alkoxy group (said C1-3alkoxy group is substituted with one or more halogen atoms) or one or more halogen atoms), R2 is a C1-3alkyl group, R3 is a phenyl group (said phenyl group is substituted with one or more substitutes selected from a group comprising halogen atoms or a (C=O)R5' group (where R5' is NR6'R7', (where R6' is a hydrogen atom, and R7' is a C1-6alkyl group substituted with a hydroxyl group))), a thienyl group (said thienyl group is substituted with one or more substitutes selected from a group comprising hydrogen atoms and a (C=O)R5 group (where R5 is NR6R7 (where R6 is a hydrogen atom or a C1-3alkyl group, and R7 is a C1-6alkyl group (said C1-6alkyl group can be substituted with one or more hydroxyl groups, one C1-3alkoxy group or a 5-6-member aromatic heterocyclic group containing 1-2 heteroatoms selected from oxygen or nitrogen (where the 5-6-member aromatic heterocyclic group can be substituted with one or more C1-3alkyl groups, one or more C1-3alkoxy groups, and in case of a 5-6-member aromatic heterocyclic group containing one nitrogen atom, can be in be in form of N-oxides)), a pyridyl group, or overall NR6R7 is a nitrogen-containing heterocyclic group which is a 5-6-member hetero-monocyclic group which contains one or two nitrogen atoms and can additionally contain on oxygen atom (said nitrogen-containing heterocyclic group can be substituted with one or more hydrogen atoms, one or more C1-6alkyl group, one or more hydroxyl groups)) or C1-6alkyl group (said C1-6alkyl group can be substituted with one or more halogen atoms and is substituted with one cyano group))), and R4 is a hydrogen atom or to a pharmaceutically acceptable salt of said compound. The invention also relates to a medicinal agent for preventing or treating diseases, in which activation of the thrombopoietin receptor is effective, based on said compounds.

EFFECT: obtaining novel compounds and agents based thereon, which can be used in medicine to increase the number of thrombocytes.

33 cl, 7 tbl, 43 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention describes compounds of formula I: formula I or its pharmaceutically acceptable salt, where the radical values R3, R4, R2, X1, X2, R1 are such as presented in claim 1. Also, the invention describes a pharmaceutical composition exhibiting a Tec-family kinase inhibitor activity and based on the compounds of formula I, a method of Tec-family kinase activity inhibition, and a method of producing the compound of formula I.

EFFECT: produced and described new compounds which are effective as Tec-family (eg, Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) protein kinase inhibitors, and acceptable compositions are applicable for treatment or prevention of some diseases, disorders or conditions including but not limited, autoimmune, inflammatory, proliferative or hyperproliferative, or immunologically mediated diseases.

50 cl, 18 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound having structure

, radicals are as described in the formula of invention, as well as pharmaceutically-acceptable salt, prodrug, tautomer and stereoisomer thereof. The invention also relates to a composition, a set for modulating PPAR based on said compound, a method of treating a patient suffering from a disease or condition or at risk of a disease or condition, for which PPAR modulation is therapeutically useful.

EFFECT: novel compounds which are active towards PPAR are obtained and described.

41 cl, 622 ex, 8 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula

where there are R3/R3', R4/R4' and R5/R5' where at least one of either R4/R4' or R5/R5' always represents a fluorine atom, and the other radical values are disclosed in the description.

EFFECT: making the compounds which are γ-secretase inhibitors, and can be effective in treating Alzheimer's disease or advanced cancers, including but not limited to carcinoma of uterine cervix and breast carcinoma and malignant tumours of hematopoietic system.

15 cl, 3 tbl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compound of formula I in which cycle A represents unsaturated carbocycle with double bonds, which is selected from phenyl or naphtyl; 1 can take value from 1 to 3; m can take value 0, 2 or 3; n can take value 0 or 2; R1 represents a hydrogen atom, (C1-3)alkyl group; R2 represents(C1-6)alkyl group, which is possibly substituted with substituent, selected from C6-cycloalkyl, monocyclic heteroaryl, selected from thiophene, aryl group, selected from phenyl, in form of base or salt of bonding with an acid. Invention also relates to pharmaceutical composition, based on formula I compound, to application of formula I compound for obtaining medication, to method of obtaining formula I compound and to application of formula compound for obtaining formula 1 compound.

EFFECT: obtained are novel isoquinoline and benzo[h]isoquinoline derivatives, possessing properties of antagonists of histamine type H3 receptor.

9 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula

, where X denotes a 5-member heterocylic group bonded through a carbon atom, selected from thiophenyl, furanyl, pyrazolyl and pyrrolyl, which can be substituted with 1-3 Ra groups; T denotes O, S; B is as indicated in the claim; Z1 denotes an unsubstituted cyclopropyl; Z2 denotes a hydrogen atom, C1-C8alkyl; or C1-C8alkoxycarbonyl; Z3 independently denotes a hydrogen atom. The invention also relates to a fungicidal composition containing a compound of formula (I) as an active ingredient, and a plant pathogenic fungus control method in agricultural plants.

EFFECT: obtaining compounds of formula (I), having fungicidal activity.

9 cl, 3 dwg, 255 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel organic compounds of formula where R1 denotes H; halogen; -C0-C7-alkyl-O-R3; -NR4R5; R2 denotes phenyl, substituted with one or two substitutes selected from a group consisting of C1-7alkyl, halogen-C1-7alkyl, C1-7alkoxy, halogen-C1-7alkoxy, phenoxy, halogen, C1-7alkylpiperazinyl-C1-7alkyl, C3-C8-cyclalkyl, C1-7alkylpiperidinyl-C1-7alkyl and C1-7alkylimidazolyl; R3 denotes H or phenyl-lower alkyl; R4 and R5 are independently selected from a group consisting of H; lower alkyl; lower alkoxy-carbonyl and amino; A, B and X are independently selected from C(R7) or N, provided that not more than one or A, B and X denotes N; R7 denotes H; R8 denotes hydrogen; n equals 0; Y denotes O; Z denotes C; W is absent; K denotes N or C, and either a) if K denotes C, the bond shown by a wavy line () is a double bond, Q is selected from O-N, S-N, O-CH and S-CH, where in each case, the left-hand O or S atom is bonded through a bond shown in formula I to K, the right-hand N or carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by the dotted line, is a double bond with C; and the bond shown by a thick line () is a single bond; or b) if K denotes N, the bond shown by a wavy line () is a single bond; Q denotes N=CH, where the left-hand N atom is bonded through a bond shown in formula I to K, the right-hand carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by a dotted line, is a single bond with C; and the bond shown by thick line () is a double bond; or salt thereof (preferably pharmaceutically acceptable salt). The invention also relates to a pharmaceutical composition, having inhibiting action on protein kinase, containing a compound of formula I or salt thereof in an effective amount and at least one pharmaceutically acceptable carrier material.

EFFECT: heterocyclic carboxamides as kinase inhibitors.

12 cl, 25 ex

7FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a combination of a co-drug (an auxiliary) and a compound o formula (IV) in which radicals and symbols have the values defined in cl. 1 of the patent claim, or salts, or tautomers, or N-oxides, or solvates of this compound; where the specified auxiliary is specified from a monoclonal antibody, an alkylating agent, a malignant growth agent, other cycline-dependent kinase (CDK) inhibitor and a hormone, a hormone agonist, a hormone antagonist or a hormone-modulating agent specified in cl. 1 of the patent claim. The offered combination is used for tumour cell growth inhibition.

EFFECT: invention also refers to a pharmaceutical composition based on the offered combination, application of the combination and its separate ingredients and methods of treating, preventing and relieving the cancer symptoms in a patient.

77 cl, 2 dwg, 8 tbl, 257 ex

FIELD: chemistry.

SUBSTANCE: pharmaceutical compositions containing at least one compound of formula (IIIa) or (IIIb) or (IVa) or (IVb), where -X- and Y are described in the claims, or pharmaceutically acceptable salts, esters or amides thereof and a pharmaceutically acceptable carrier, which can be used in processes with modulation or E- and P-selectin expression.

EFFECT: obtaining low-molecular non-glycoside and non-peptide compounds, capable of creating antagonism to selectin-mediated processes.

11 cl, 38 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention describes novel carbamoyl benzotriazole derivatives of general formula , (values of radicals are given in the description), tautomers thereof and pharmaceutically acceptable salts and use thereof as endothelial lipase inhibitors.

EFFECT: improved properties of the derivatives.

11 cl, 148 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I), which have protein kinase inhibiting properties and can be used in treating diseases which are dependent on any one or more protein kinases from FGFR1, FGFR2, FRF3 and/or FGFR4, KDR, HER1, HER2, Bcr-Abl, Tie2 and/or Ret Such diseases can be proliferative diseases, for example bladder cancer, breast cancer and multiple myeloma. In formula

the left-side ring , right-side ring , there are the following fragments, denoted "left-side ring" and "right-side ring", respectively: where X denotes C-R5, and Y and Z both denote N. The left-side ring corresponds to fragment (A):

n equals 0, 1, 2, 3, 4 or 5, X1 denotes hydrogen, where R1 denotes a group of formula Rz-NRa-, where Ra denotes hydrogen and Rz is selected from (1) a straight or branched C1-C4alkyl or (2) a group of formula , where ring A denotes phenyl, cyclohexenyl, cyclohexyl or pyridyl, m equals 0, 1 or 2, one or each of Rb is independently selected from a group -L2-NRcRd; -L2-RING, where RING denotes a 5- or 6-member saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen and oxygen, optionally substituted, as indicated below, halogen; hydroxy; amino; cyano, and a straight or branched C1-C4alkyl optionally substituted with one or more halogens and/or one or two hydroxy groups, wherein the hydroxy and amino groups are in turn optionally substituted on at least one heteroatom with one or, if necessary, more C1-C7aliphatic groups, where L2 denotes a direct bond, a link selected from a group comprising -O-, -S-, -C(O)-, -OC(O)-, -NRaC(O)-, -C(O)-NRa -OC(O)-NRa, -NRa-; or denotes a straight C1-C4alkyl which is optionally interrupted and/or ends in one terminal fragment or in two terminal fragments with the said link, and where Rc and Rd are each independently selected from a group comprising hydrogen and straight or branched C1-C4alkyl, or Rc and Rd together with a neighbouring nitrogen atom form a 5- or 6-member heterocyclic ring which optionally contains an additional heteroatom selected from nitrogen and oxygen, and optionally substituted as indicated below, said optionally substituted rings are independently substituted with 0, 1, 2, 3, 4 or 5 C1-C7aliphatic substitutes which are optionally substituted with one or more halogen atoms; R2 denotes hydrogen or C1-C4alkyl; R3 denotes hydrogen or straight or branched C1-C4alkyl or straight C1-C4alkyl substituted with a 5- or 6-member saturated or unsaturated heterocyclic ring containing 1 or 2 heteroatoms in the ring, selected from nitrogen, oxygen and sulphur; R4 is selected from hydroxy, protected hydroxy group, alkoxy, alkyl, trifluoromethyl and halogen, where the alkyl or alkyl part of the alkoxy is straight or branched and contains 1, 2, 3 or 4 carbon atoms; or R5 denotes hydrogen or C1-C4alkyl; or pharmaceutically acceptable salts, hydrates, solvates, ethers, N-oxides thereof, optionally in form of trans-isomers thereof.

EFFECT: improved properties of the compound.

38 cl, 1 tbl, 231 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where: X is a nitrogen or carbon atom; Ar is phenyl or a heteroaromatic ring selected from pyrazolyl, furanyl, thiophenyl and isoxazolyl; R1 is hydrogen, halogen, CN or (C1-C4)alkyl; R2 is halogen or (C1-C3)alkoxy optionally fluorinated with 1-3 fluorine atoms; R3 and R5 independently denote hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkenyl or hydroxymethyl; R4 is hydrogen, halogen, optionally fluorinated (C1-C4)alkoxy or aryl(C1-C4)alkoxy; R6 is hydrogen, optionally fluorinated (C1-C4)alkyl; each R7 independenlty denotes hydrogen, halogen, optionally fluorinated (C1-C4)alkyl or (C1-C4)alkoxy optionally fluorinated with 1-3 fluorine atoms; or pharmaceutically acceptable acid addition salts thereof. The invention also relates to use of compounds of formula (I) in a pharmaceutical composition and when preparing a medicinal agent meant for treatment, the aim of which is to change the secondary signal activity level after activation of glucocorticoid receptors.

EFFECT: compounds of formula I for changing the secondary signal activity level after activation of glucocorticoid receptors.

7 cl, 5 dwg, 49 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound selected from N-((1S)-1-{4-[2-fluoro-1-(fluoromethyl)ethoxy]phenyl}ethyl)-2-(7-nitro-1H-benzimidazol-1-yl)acetamide, 2-(7-nitro-1H-benzimidazol-1-yl)-N-{1-[6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl]ethyl}acetamide, N-[1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamde and N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide. The invention also relates to use of said compounds in preparing a medicinal agent.

EFFECT: novel compounds which are useful in treating VR1 mediated disorders or acute and chronic algesic disorders are obtained.

6 cl, 5 tbl, 5 ex

Iap inhibitors // 2425838

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

, which can inhibit binding of protein Smac with apoptosis protein inhibitor (IAP).

EFFECT: improved properties of the inhibitor.

4 cl, 198 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to drugs and concerns a combination for tumour cell growth inhibition containing a cytotoxic compound selected from camptothecin compounds; metabolic antagonists; periwinkle alkaloids; taxanes; platinum compounds; topoisomerase 2 inhibitors; and a combination of two or more said types, or a signal transfer inhibitor selected from antibodies a target of which is EGFR receptor; tyrosine kinase EGFR inhibitors; from antibodies a target of which is a VEGF/VEGF receptor system; PDGFR inhibitors; Raf inhibitors and PKB transfer inhibitors in an effective amount and a compound of formula (IV).

, where R1, R2, R11, T, U and g have the values specified in formula.

EFFECT: what is offered is a pharmaceutical composition, a method for tumour cell growth inhibition, a method of treating a malignant growth in a patient and application of the combination for preparing a drug; the new effective combinations for tumour cell growth inhibition are presented.

77 cl, 20 dwg, 7 tbl, 257 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 5-nitrofuran derivatives of formula I: where R=piperidino, pyrrolidineo, diethylamino, morpholino.

EFFECT: presented preparation of new biologically active compounds which exhibit antimicrobial activity.

1 cl, 4 ex, 2 tbl

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