Indazole acrylic acid amide derivative

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and ,

where the ring X represents benzole or pyridine; R1 represents substituted alkyl; R2 represents optionally substituted aryl or optionally substituted 4-7-member monocyclic heterocyclic group or optionally substituted condensed group of heterocyclic group with the benzole ring where the substitutes of optionally substituted aryl, optionally substituted 4-7-member monocyclic heterocyclic group and optionally substituted condensed group of heterocyclic group with the benzole ring are selected from a group consisting of; (1) alkyl optionally substituted by a group selected from halogen and alkoxycarbonyl, (2) alkoxy optionally substituted by halogen, (3) halogen, (4) 4-7-member monocyclic heterocyclic group or (5) amino, optionally mono- or disubstituted alkyl, and (6) hydroxyl, R3 represents hydrogen or alkyl: R4 represents hydrogen, halogen or alkyl; R5 represents hydrogen or alkyl; R6 and R7 are identical or different, and each represents hydrogen or halogen; or pharmaceutically acceptable salt. Also, the invention refers to a IKur blocker containing the compounds described above as an active ingredient, and also to a preventive and therapeutic agent for cardiac arrhythmia and atrial fibrillation.

EFFECT: there are produced and described new compounds applicable as a IKur blocker effective for preventing or treating cardiac arrhythmia, such as atrial fibrillation.

12 cl, 13 ex

 

The technical field to which the invention relates.

The present invention relates to a connection with IKur-blocking activity, applicable to the prevention or treatment of a disease such as atrial fibrillation.

The level of technology

Atrial fibrillation is one of the most common arrhythmia in clinical periods of illness, in which uneven and frequent excitation of the Atria stop the cycle of contraction and expansion as an auxiliary pump atrium, and in particular the frequency of it increases with age. Atrial fibrillation is not congenital arrhythmia, but impairs the function of the heart and is known to cause complications, such as congestive heart failure, thrombosis, ventricular fibrillation, etc.

Antiarrhythmic agents available on the market to date, have been developed as therapeutic agents for ventricular arrhythmia and atrial and supraventricular arrhythmias. Malignant ventricular extrasystole directly threaten life and requires immediate treatment, and for drug treatment of ventricular arrythmia used medicinal agent class Ia (eg, procainamide, quinidine), class Ic (e.g., flecainide, propafenone) or class III (e.g., to milid, amiodarone). Described that these agents of class I and class III prevent the recurrence of atrial fibrillation (non-patent document 1). However, they have the potential to increase mortality due to their potentially lethal ventricular arrhythmogenic activity (non-patent documents 2 and 4).

Because atrial fibrillation shortening the potential duration (APD) of the heart, APD-prolonging agent can be theoretically therapeutic agent for atrial fibrillation. The prolongation of the cardiac APD is caused by increase of the internal currents (for example, currents of Na+or Sa2+, which further indicate the INaor ICarespectively) or by reduction of external currents repolarizing potassium (K)+. Slow rectified (IK) K+currents are the main external currents involved in the repolarization of the action potential, and transient external current (Itothe internal straightened (IK1) K+the currents are related to the initial phase and final phase of repolarization, respectively. When the cellular electrophysiological study shows that the IKincludes two subtypes pharmacologically and kinetically different K+-currents, i.e. IKr(immediate activation) and IKs(delayed activation) (non-patent document 5).

Dofetilide, antiaris the economic agent class III, detects antiarrhythmic activity by blocking IKrthat is a fast activating ingredient IKlocated in the atrium and ventricle of a person (non-patent document 1). Because the blocker IKrprolong APD and refractory period in the Atria, and pagelock, without affecting the electrical conductivity, it theoretically has the potential to be an agent useful for the treatment of arrhythmias, such as atrial fibrillation (non-patent document 4). However, it was described that the blocker has arrhythmogenic activity and develops polymorphic Torsade de pointes ventricular (non-patent document 6).

In contrast, it has been described that amiodarone has properties antiarrhythmic agent of class III (non-patent documents 7 and 8). However, because it has many different activities for many ion channels and is not selective agent class III, its application is strictly limited because of its negative action (non-patent documents 9-11). According to this, the currently available agents, such as amiodarone and dofetilide, are potentially fatal, serious negative effects, such as ventricular arrhythmogenic activity, and therefore is desirable in high degree secure agent with a favorable eff what aktivnosti.

Recently in the atrium myocyte were identified sverhbystro activated slow straightened K+-the current (IKur), which are extended outward currents. IKurin particular are in the atrium, but not in the ventricle of a human. Molecular correlation of IKurin the atrium of the person is a potassium channel, denoted mRNA Kv 1.5 Kv 1.5 or less (non-patent document 12), and its protein (non-patent document 13) was detected in the tissues of the human Atria. It was thought that IKursignificantly contributes to the depolarization in the atrium of the person due to its rapid activation and slow inactivation. Consequently, it is possible to imagine that because the connection with blocking activity in respect of IKur, prolongs refractoriness in the Atria without delay ventricular repolarization and prolongation of the refractory period of the ventricle, it can solve the problem of the adverse action, such as induced arrhythmia syndrome distribution QT after depolarization, found in modern agents of class III (non-patent documents 14 and 15).

In contrast, it was shown that re-entry wave excitation (reciprocate) is an important mechanism that causes supraventricular arrhythmia in humans (non-patent document). Specifically, reciprocal occurs randomly in different locations in the atrium and atrial fibrillation is caused by multiple repetitions of electric excitations of a single stimulation. According to this, the increase of myocardial refractoriness prolongation of cardiac APD prevents and/or stops the arrhythmia, caused by the circulation of excitation pulses to the Atria in a circle. In addition, since the cardiac APD depends on contributions (deposits) potassium currents IKr, IKs, IKurthat relate to the repolarization phase, and transient external current (Ito), it is desirable that the blocker, which acts on any one of these currents, prolongs the potential duration and caused antiarrhythmic action.

In patent document 1 describes the applicable derivative of indazole as an inhibitor of SGK-1, but the document is not described any of their blocking activity against IKur.

[Patent document 1]WO 2005/011681
[Non-patent document 1]Circulation, 102:2665-2670
[Non-patent Document 2]Am. J. Cardiol., 65:20B-29B, 1990
[Nepal ntny Document 3] Lancet, 348:7-12, 1996
[Non-patent Document 4]Expert Opin. Invest. Drugs, 9:2695-2704, 2000
[Non-patent Document 5]J. Gen. Physiol. 1990, 96:195-215
[Non-patent Document 6]Am. J. Cardiol., 72:44B-49B, 1993
[Non-patent Document 7]Br. J. Pharmacol., 39:675-689, 1970
[Non-patent Document 8]Br. J. Pharmacol., 39:657-667, 1970
[Non-patent Document 9]J. Am. Coll. Cardiol., 20:1063-1065, 1992
[Non-patent Document 10]Circulation, 104:2118-2150, 2001
[Non-patent Document 11]A. Curr. Opin. Pharmacol. 2:154-159, 2002
[Non-patent Document 12]Basic Res. Cardiol., 97:424-433, 2002
[Non-patent Document 13]J. Clin. Invest., 96:282-292, 1995
[Non-patent Document 14]J. Med. Chem., 46:486-498, 2003
[Non-patent Document 15]Naunyn-Schmedieberg''s Arch. Pharmacol., 366:482-287, 2002/td>
[Non-patent Document 16]Nature, 415:219-226, 2002.

Disclosure of inventions

Problems that are resolved by this invention

The present invention relates to compounds applicable for the prevention or treatment of atrial fibrillation and has less negative actions and excellent blocking activities in respect of IKur.

The way to solve problems

As a result of extensive studies to resolve the above problems, the authors of the present invention found that the combination of the following formula has excellent blocking IKuractivity, and the present invention was completed.

The present invention includes the following options for implementation.

1. The compound of formula (1)

where the ring X represents a benzene or pyridine;

R1represents a substituted alkyl;

R2represents optionally substituted aryl or optionally substituted heterocyclic group;

R3represents hydrogen or alkyl;

R4represents hydrogen, halogen or alkyl;

R5represents hydrogen or alkyl;

R6and R7are the same or different and each is th represents hydrogen or halogen; or its pharmaceutically acceptable salt.

2. The compound of the formula (1-a)

where the ring X represents a benzene or pyridine;

R1represents a substituted alkyl;

R2represents optionally substituted aryl or optionally substituted heterocyclic group;

R3represents hydrogen or alkyl;

R4represents hydrogen, halogen or alkyl;

R5represents hydrogen or alkyl;

R6and R7are the same or different and each represents hydrogen or halogen; or its pharmaceutically acceptable salt.

3. The compound or its pharmaceutically acceptable salt according to any one of items 1 or 2, where R1represents alkyl, substituted 1 or 2 groups selected from hydroxyl, optionally substituted amino, alkylsulfonyl, alkoxy, optionally substituted heterocyclic group, optionally substituted, ureido, optionally substituted, carbamoylated, carbonyloxy, substituted by optionally substituted heterocyclic group.

4. The compound or its pharmaceutically acceptable salt according to any of the above paragraphs 1 to 3, where R2represents an optionally substituted benzene.

5. The compound or its pharmaceutically priemel who may salt according to any of the above paragraphs 1 to 4, where R3and R4represent hydrogen.

6. The compound or its pharmaceutically acceptable salt according to any of the above paragraphs 1 to 4, where R3represents hydrogen and R4represent alkyl.

7. The compound or its pharmaceutically acceptable salt according to any of the above paragraphs 1 to 4, where R3represents alkyl and R4represents hydrogen.

8. The compound or its pharmaceutically acceptable salt according to any of the above paragraphs 1 to 4, where R3represents hydrogen and R4represent halogen.

9. The compound or its pharmaceutically acceptable salt according to any of the above items 1 to 8, where R6and R7represent hydrogen.

10. Drug containing the compound or its pharmaceutically acceptable salt according to any of the above paragraphs 1-9.

11. Blocker IKurcontaining as active ingredient the compound or its pharmaceutically acceptable salt according to any of the above paragraphs 1-9.

12. Prophylactic or therapeutic agent from a cardiac arrhythmia, comprising as active ingredient the compound or its pharmaceutically acceptable salt according to any of the above paragraphs 1-9, or a method of treatment of this illness is Denmark, contains the introduction of this agent to the patient.

13. Prophylactic or therapeutic agent from atrial fibrillation, comprising as active ingredient the compound or its pharmaceutically acceptable salt according to any of the above paragraphs 1-9, or a method of treatment of this disease, containing the introduction of this agent to the patient.

Each group is represented by a specific symbol in the present description, is illustrated below. Each abbreviation used in the present description, has the following value.

THF: tetrahydrofuran

DMF: N,N-dimethylformamide

DMSO: dimethyl sulfoxide

DMA: dimethylacrylamide

DME: 1,2-dimethoxyethane

LDA: diisopropylamide lithium

DBU: 1,8-diazabicyclo[5.4.0]-7-undecene

DBN: 1,5-diazabicyclo[4.3.0]non-5-ene

DCC: dicyclohexylcarbodiimide

WSC: hydrochloride of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide

HOBt: 1-hydroxybenzotriazole

AC: acetyl

Me: methyl

Et: ethyl

Pr: n-propyl

iPr: isopropyl

t-Bu: tert-butyl

Boc: tert-butoxycarbonyl

Cbz: carbobenzoxy

Bn: benzyl

Ph: phenyl

RNG: p-methoxybenzyl

The term "alkyl" includes, for example, C1-C6-Akil with unbranched or branched chain, especially methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.

The term "aryl" include the AET in itself, for example, 3-15 membered monocyclic, bicyclic or tricyclic aromatic carbocycle, especially phenyl, naphthyl, tenantry, antrel etc.

"Heterocyclic group" include, for example, 3 to 15-membered monocyclic or bicyclic unsaturated and saturated or partially saturated heterocyclic group containing 1-4 heteroatoms selected from a nitrogen atom, oxygen atom and sulfur atom.

Unsaturated and saturated or partially saturated heterocyclic group includes, for example, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, azepine, diazepine, furyl, pyranyl, oxepin, thienyl, tierany, tiepins, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, furutani, oxadiazolyl, oxazinyl, oxadiazine, oxazepines, oxadiazine, thiadiazolyl, tadini, thiadiazines, thiazepines, thiadiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophene, indazole, chinoline, ethenolysis, honokalani, hintline, benzoxazolyl, benzothiazolyl, benzoimidazolyl, pyrrolidyl, pyrrolidinyl, imidazolyl, imidazolidinyl, pyrazolyl, pyrazolidine, dihydropyridine, tetrahydropyridine, dihydropyridine, tetrahydropyridine, dihydropyrimidines, tetrahydropyrimidines, dihydroxydiphenyl, tetrahydroazepine, hexahydroazepin is l, dehydrodidemnin, tetrahydroazepine, dihydroxydiphenyl, tetrahydroazepine, hexahydroazepin, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dehydration, tetrahydrothieno, dihydrothiophene, tetrahydrothiophene, piperidyl, piperazinil, morpholinyl, thiomorpholine, homopiperazine etc.

"Alicyclic heterocyclic group" includes, for example, a 5-7-membered monocyclic saturated heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, especially piperidyl, piperazinil, morpholinyl, thiomorpholine, homopiperazine, tetrahydrouridine etc.

"Alkoxycarbonyl" includes, for example, C2-C7-Alcoceber with unbranched or branched chain, especially methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide, tert-butoxycarbonyl etc. Preferred alkoxycarbonyl among them is C2-C5-alkoxycarbonyl.

"Halogen" includes fluorine, chlorine, bromine, iodine. The preferred halogen is chlorine or fluorine.

"Alkoxy" includes, for example, C1-C6-alkoxy with unbranched or branched chain, especially methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy etc. P is impactfully alkoxy is C1-C4 alkoxy.

"Cycloalkyl" includes, for example, C3-C8-cycloalkyl, especially cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc. Preferred cycloalkyl among them is C3-C6-cycloalkyl.

"Alkylsulfonyl" and alkylsulfonyl "alkylsulfonyl" includes, for example, C1-C6-alkylsulfonyl with unbranched or branched chain, especially, methylsulphonyl, ethylsulfonyl, propylsulfonyl, isopropylphenyl, butylsulfonyl etc. Preferred alkylsulfonyl among them is a C1-C4 alkylsulfonyl.

"Arylsulfonyl" includes, for example, sulfonyl, substituted 6 to 15-membered monocyclic or bicyclic aromatic carbocyclic, especially phenylsulfonyl, aftercooler etc.

"Alkanoyl" includes, for example, C1-C6-alkanoyl with unbranched or branched chain, especially formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl etc. Preferred alkanoyl among them is C1-C4 alkanoyl.

"Aralkyl" includes, for example, aryl (preferably, benzene, naphthalene), substituted C1-C6-alkyl with an unbranched or branched chain, preferably C1-C4-alkyl, especially benzyl, naphthylmethyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl etc.

"Halogenated" includes, for example, C1-C6-alkyl with an unbranched or branched chain, for ewenny 1-6 halogen atoms, preferably C1-C4-alkyl, especially vermeil, chloromethyl, trifluoromethyl, 2,2,2-triptorelin etc.

"Hydroxyalkyl" includes, for example, substituted by 1-3 hydroxyl, C1-C6-alkyl with an unbranched or branched chain, preferably C1-C4-alkyl, especially hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, etc.

The substituents of "substituted alkyl" in R1include, for example,

(1) hydroxyl,

(2) optionally substituted amino,

(3) alkylsulfonyl,

(4) arylsulfonyl,

(5) cyano,

(6) alkoxy,

(7) optionally substituted heterocyclic group,

(8) optionally substituted cycloalkyl,

(9) optionally substituted by ureido,

(10) optionally substituted carbarnoyl,

(11) optionally substituted by carbamoylated,

(12) carbonyl, substituted heterocyclic group,

(13) carbonyloxy, substituted by optionally substituted heterocyclic group,

(14) optionally substituted aminosulfonyl,

(15) alkoxycarbonyl,

(16) carboxy, etc.,

and "substituted alkyl" may not necessarily having 1-3 identical or different substituent.

The substituents of "optionally substituted amino" in the substituents of the above "substituted alkyl" include, for example, 1 or 2 groups selected from the following groups (a) through (K).

(A) alkyl, optionally substituted ALCO is si,

(B) alkanoyl, optionally substituted 1 or 2 groups selected from the group a,

(C) alkanolamine,

(D) alkoxycarbonyl, optionally substituted 1 or 2 groups selected from the group b,

(E) alkylsulfonyl, optionally substituted 1 or 2 groups selected from the group C,

(F) substituted heterocyclic group sulfonyl, optionally substituted 1 or 2 groups selected from the group d,

(G) arylcarbamoyl,

(H) aralkylamines,

(I) aminosulfonyl, optionally mono - or disubstituted by alkyl,

(J) cycloalkylcarbonyl, optionally substituted by hydroxyl or cyano, or

(K) carbamoylethyl, optionally mono - or disubstituted by alkyl, etc.

[Group a]

(a) alkoxy,

(b) cyano,

(c) heterocyclic group optionally substituted by 1-3 groups selected from halogen, cyano, hydroxyl, alkoxycarbonyl and alkyl, optionally substituted by 1-3 groups selected from halogen and alkoxy,

(d) amino, optionally substituted 1 or 2 groups selected from the following groups (i) to (iii)

(i) alkyl, optionally substituted by a group selected from alkoxy, cyano and alkylsulfonyl, and amino, optionally substituted 1 or 2 groups selected from alkylsulfonyl and alkyl,

(ii) alkoxycarbonyl and

(iii) alkanoyl, optionally substituted by a group selected from Alcock and, cyano, amino, optionally mono - or disubstituted by alkyl,

(e) alkylsulfonyl,

(f) hydroxyl, and

(g) halogen.

[Group b]

(a) alkoxy and

(b) hydroxyl.

[Group]

(a) alkoxy and

(b) hydroxyl.

[Group d]

(a) hydroxyl,

(b) alkyl,

(c) halogenated and

(d) alkoxycarbonyl.

The substituents of "optionally substituted heterocyclic group" in the above substituents of "substituted alkyl" include, for example, (A) oxo, (C) alkoxycarbonyl, (C) alkanoyl, optionally substituted by cyano, (D) alkyl, optionally substituted by hydroxyl, (E) alkylsulfonyl, (F) alkylsulfonyl, (G) a carbonyl, a substituted heterocyclic group, (H) aminosulfonyl, optionally mono - or disubstituted by alkyl, (I) carbarnoyl, optionally mono - or disubstituted by alkyl, or (J) halogen, and optionally substituted heterocyclic group" may optionally having 1-3 identical or different substituent.

The substituents of "optionally substituted cycloalkyl" in the above substituents of "substituted alkyl" include, for example, (A) alkoxy or (B) hydroxyl, and optionally substituted cycloalkyl" may not necessarily be 1-2 are the same or different substituent.

The substituents of "optionally substituted, ureido" in the above substituents of "substituted alkyl" include, includes, for example, alkyl, optionally substituted by a group selected from alkoxy and hydroxyl, and optionally substituted, ureido" may not necessarily be 1-3 identical or different substituent.

The substituents of "optionally substituted of carbamoyl" in the above substituents of "substituted alkyl" include, for example, 1 to 2 identical or different alkyl, etc.

The substituents of "optionally substituted, carbamoylated" in the above substituents of "substituted alkyl" include, for example:

(A) heterocyclic group,

(B) alkyl, optionally substituted by 1 or 2 identical or different groups selected from (a) alkoxy, (b) hydroxyl, (C) cyano, (d) carbamoyl, optionally substituted by 1 or 2 identical or different alkilani, etc.

Deputies "carbonyloxy, substituted by optionally substituted heterocyclic group" in the above substituents of "substituted alkyl"include, for example, (A) hydroxyl, (B) alkyl, (C) hydroxyalkyl, (D) alkanoyl etc.

The substituents of "optionally substituted aminosulfonyl" in the above substituents of "substituted alkyl" include, for example, alkyl, optionally substituted by hydroxyl, and optionally substituted aminosulfonyl" may not necessarily be 1-2 are the same or different substituent.

The substituents of "optionally Zam the seal aryl" and "optionally substituted heterocyclic group" in R 2include, for example:

(1) optionally substituted alkyl,

(2) optionally substituted alkoxy,

(3) halogen,

(4) heterocyclic group, or

(5) amino, optionally mono - or disubstituted by alkyl,

(6) hydroxyl, etc.,

and they may not necessarily be 1-3 identical or different substituent.

The substituents of "optionally substituted alkyl" in the above substituents R2include, for example, (A) halogen, (C) alkoxycarbonyl etc. and "optionally substituted alkyl" may not necessarily be the same or different 1 or 2 groups. The substituents of "optionally substituted alkoxy" in the above substituents R2include, for example, 1-3 halogen atom, etc.

R2preferably represents optionally substituted aryl, especially optionally substituted phenyl. When R2is a substituted phenyl, at least one Deputy is preferably in meta-position. Deputy preferably represents optionally substituted alkoxy, more preferably C1-C4-alkoxy, particularly preferably methoxy.

"Heterocyclic group and heterocyclic group "of carbonyl, substituted heterocyclic group" and "carbonyloxy substituted heterocyclic group" in the substituents R1 preferably includes a 4-7-membered monocyclic heterocyclic group, especially morpholinyl, thiomorpholine, pyrrolidine, piperazinil, piperidyl, homopiperazine, hexahydroazepin, hexahydroazepin, azetidine, pyridyl, pyrimidyl, thiazole, pyrazole, tetrahydropyran etc.

"Heterocyclic group" of the substituents in the optionally substituted amino" and "optionally substituted, carbamoylated", and heterocyclic group "sulfonyl substituted heterocyclic group" and "carbonyl, substituted heterocyclic group" in the substituents R1preferably includes the above-mentioned heterocyclic group.

"Heterocyclic group" R2preferably includes a 4-7-membered monocyclic heterocyclic group or condensed heterocyclic group group with a benzene ring, especially pyridyl, pyrimidinyl, indolyl, hinely, 2,3-dihydroindole, 1,2,3,4-tetrahydroquinolin etc.

"Heterocyclic group" of the substituents in R2preferably includes a 4-7-membered monocyclic heterocyclic group, especially pyrrolidine, piperidine, piperazine, homopiperazine, morpholine, thiomorpholine etc.

When R4is a halogen, the halogen is preferably fluorine, and especially preferably, when R4predstavljaet a fluorine and R 3represents hydrogen.

R5preferably represents hydrogen.

Pharmaceutically acceptable salt of the compound of the present invention includes, for example, salt of an inorganic acid such as hydrochloride, sulfate, phosphate, hydrobromide, or salt of an organic acid, such acetate, fumarate, oxalate, citrate, methanesulfonate, bansilalpet, tosylate, maleate, etc. When the compound of the present invention has an acidic group such as carboxy, salt with a base (for example, salt of an alkali metal such as sodium salt, potassium salt, a salt of alkaline earth metal such as calcium salt, salt with organic base, such as salt of triethylamine, salt, amino acids, such as lysine salt) is also included in the context.

The compound of the present invention or its pharmaceutically acceptable salt includes both intramolecular salt, and its MES, such as its hydrate.

Connection (1) of the present invention can exist in the form of optically active isomers based on asymmetric carbon atom, and includes any of the forms of its isomers and their mixtures. In addition, when the compound (1) of the present invention has a double bond or cycloalkenyl, the connection may be in the form of CIS - or TRANS-configuration and the compound can exist in the ideal of tautomers based on unsaturated bonds, such as carbonyl. Connection (1) of the present invention may include any isomers and mixtures thereof.

Connection (1) of the present invention can be obtained according to the following methods. The following methods are illustrated by compounds (1-a), unless otherwise indicated, the compound (1) can be obtained by using the corresponding starting compound.

Method 1: compound (1-a) can be obtained according to the following method:

1) Halogenoalkane

where Hal' represents a halogen, such as bromine, iodine, and other characters have such

same values as above.

The compound (3) are obtained according to the method described in Tetrahedron 55 (1999) 6917-6922. Namely, the compound (2) is subjected to reaction with a halogen (e.g. bromine, iodine) in a solvent (such as DMF, DMSO) in the presence of alkali (e.g. potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate) or an organic base (e.g. triethylamine, diisopropylethylamine) at a temperature from the temperature achieved by cooling with ice to room temperature for from 30 minutes to 5 hours to obtain compound (3).

The compound (1-a) are obtained according to the method described in Tetrahedron Lett. 41 (2000) 4363-4366 and Journal of the American ChemicalSociety, 1968, 90, 5518-5526. Exactly, the compound (3) is subjected to reaction with compound (4) in a solvent (such as DMF, DMSO, dioxane, THF, diethyl ether, acetonitrile, methanol, ethanol, acetone, isopropanol) in the presence of a catalyst (e.g. palladium acetate-triphenylphosphine, dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)) and a base (e.g. triethylamine, tetrabutylammonium iodide), thus obtaining the compound (1-a).

Method 2: compound (1-a) can also be obtained according to the following method:

where RAis an alkyl and the other symbols have the same meanings as above.

The reaction of the compound (3) and compound (5) can be performed in a manner analogous to method 1.

The compound (6) is treated with an aqueous solution of an acid (e.g. hydrochloric acid, sulfuric acid) or base (e.g. sodium hydroxide, potassium hydroxide) in a solvent (e.g. methanol, ethanol, isopropanol, dioxane, THF, diethyl ether) or without solvent, thus obtaining the compound (7).

Compound (7) process of halogenation agent (for example, N-bromosuccinimide, N-chlorosuccinimide) and triphenylphosphine and a base (e.g. triethylamine, diisopropylethylamine, N,N-dimethylaniline) in a solvent (for example, dioxane, THF, diethyl ether) and then will versaut reaction with compound (8) at the same temperature for 1-12 hours thus obtaining the compound (1-a).

Method 3: compound (1-a) can also be obtained according to the following method:

where RBrepresents alkyl or aryl and the other symbols have the same meanings as above.

Compound (9) is subjected to reaction with compound (10-A) in a solvent (for example, dioxane, THF, diethyl ether) at a temperature of from room temperature to the temperature of phlegmy within 1-12 hours, thus obtaining the compound (1-a).

Compound (9) is subjected to the reaction with compound (10-B) in a solvent (for example, dioxane, THF, diethyl ether) in the presence of a base (e.g. sodium hydride, diisopropylamide lithium, n-utility) at a temperature of from room temperature to the temperature of phlegmy within 1-12 hours, thus obtaining the compound (1-a).

Method 4: compound (6) can also be obtained according to the following method:

1) the Reducing agent or the Grignard reagent

where RBrepresents alkyl or aryl, each of RCand RDrepresents alkyl, Q represents hydrogen, -B(OH)2, -B(ORE)(ORFor-Sn(RG)3each of REand RFrepresents an alkyl or REand RFto connect with one another with formation of alkylene with unbranched or branched chain, RG is an alkyl and the other symbols have the same meanings as above.

Compound (9) are obtained according to the following methods(1)-(3).

(1) Compound (3) is subjected to reaction with compound (14) in a solvent (for example, DME, THF, 1,4-dioxane, DMF, DMA, toluene, benzene, water or mixtures thereof) in the presence of a palladium catalyst (e.g. tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II)chloride, palladium(II)acetate) at a temperature of from room temperature to the temperature of phlegmy for from 1 hour to 3 days and then treated with acid (e.g. hydrochloric acid, sulfuric acid)thus the compound (9)in which R4represents methyl.

When using the compound (14)in which Q represents-B(OH)2or-B(ORE)(ORF), preferably you can add a base. The base may include, for example, inorganic base such as a carbonate of an alkali metal, a hydroxide of an alkali metal, a phosphate of an alkali metal, fluoride of an alkali metal, and an organic base such as triethylamine.

When using the compound (14)in which Q represents hydrogen, preferably can be added ligand and salt or base. The ligand can include, for example, 1,3-bis(diphenylphosphino)propane, 1,1'-bis(diphenylphosphino)ferrocene, m is telefonieren and salt or base may include, for example, metal salt such as silver nitrate, thallium acetate, and the organic base such as triethylamine.

(2) Compound (11) or the compound (13), which is obtained by condensation of compound (11) with compound (12) using a condensing agent (for example, DCC, WSC, etc. accepted way, restore a reducing agent (for example, sociallyengaged, natrojarosite) in solution (for example, dioxane, THF, diethyl ether) at 0-100°C for 1-24 hours, thus obtaining the compound (9)in which R4represents hydrogen.

(3) Compound (13) is subjected to reaction with R4MgHal, where every character have the same meanings as described above, in a solvent (for example, dioxane, THF, diethyl ether) at a temperature from the temperature achieved by cooling with ice to room temperature for 1-12 hours, thus obtaining the compound (9), where R4represents alkyl.

The reaction of the compound (9) and the compound (10-a) or compound (10-D) can be performed in a manner analogous to method 3.

Method 5: compound (7), in which R4represents alkyl and R3represents hydrogen, can also be obtained according to the following method:

1) Base, 2) Hydrolysis

where R4arepresents alkyl, Hal2represents chlorine and the bromine and the other symbols have the same meanings, as specified above.

Connection (3) and the compound (15) is treated with palladium catalyst (for example, dichlorobistriphenylphosphine, tetrahetarenoporphyrazines, palladium acetate, tridimensionality) in a solvent (such as DMSO, DMF, THF, 1,4-dioxane, diethyl ether, acetonitrile, toluene) in the presence of copper iodide (I) and base (e.g. sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine) at 0°C-100°C for 1-24 hours, thus obtaining the compound (16).

Compound (16) is subjected to reaction with compound (17-a) or compound (17-b) in the presence of a salt of copper (I) (e.g., iodide copper (I)bromide copper (I)cyanide, copper (I)) in a solvent (such as THF, 1,4-dioxane, diethyl ether, benzene, toluene, xylene, cyclohexane) at a temperature of from -78°C. to room temperature for 1-24 hours, thus obtaining the compound (18).

The compound (18) is treated with a base (e.g. sodium methoxide, ethoxide sodium, DBU) in a solvent (e.g. methanol, ethanol, THF, 1,4-dioxane, diethyl ether, acetonitrile) at a temperature of from room temperature to the temperature of phlegmy within 1-12 hours, thus obtaining the compound (19).

Hydrolysis of the compound (19) can be performed in a manner analogous to method 2.

Method 6: compound (7), where R is a halogen and R3represents hydrogen, can be obtained according to the following method:

1) Hydrolysis

where R4brepresents halogen and the other symbols have the same meanings as above.

Compound (16) is treated with cesium halide or a hydrogen halide in a solvent (such as DMSO, DMF) at a temperature of from room temperature to the temperature of phlegmy within 1-48 hours, thus obtaining the compound (20).

This reaction can be carried out in the presence of a base (for example, kalogeropoulou, natriciteres) and water, if necessary.

Hydrolysis of compound (20) can be performed in a manner analogous to method 2.

Method 7: method 1 instead of the compound (4) can be applied following compound (4')

to obtain the compounds (1-b):

The compound (1-b) can also be obtained by reaction and treatment in a manner analogous to method 2 or 3, using the corresponding starting compound, as described above.

Method 8: compound (2), in which R5represents hydrogen and the group of the formula

is a group of the formula

can be obtained according to the following method

where each symbol has the same meaning as above.

Compound (22) are obtained according to the method described in Chem. Pharm. Bull., 50(8), 1066 (2002). Namely, the compound (21) retrieve a reducing agent (for example, diisobutylaluminium, triacetoxyborohydride sodium, cyanoborohydride sodium, sociallyengaged, sodium borohydride) in a solvent (e.g. benzene, toluene, xylene) at a temperature of from -78°C. to room temperature for 1-24 hours, thus obtaining the compound (22).

The compound (2-a) are obtained according to the method described in Chemical Communications 293-294 (1966). Namely, the compound (22) is subjected to reaction with hydrazine or its hydrate in a solvent (e.g. methanol, ethanol, isopropanol), if necessary, in the presence of a catalyst (e.g. p-toluensulfonate acid) at a temperature of from room temperature to heating temperature within 1-48 hours, thus obtaining the compound (2-a).

Method 9: when the above methods, the compound of the present invention, an intermediate product or the original compound has a functional group (e.g. hydroxyl, amino, carboxy), it is possible to protect common in organic synthetic chemistry protecting group according to the method described in Theodora W. Greene, Peter G.M. Wuts, "Protective Groups in Organic Synthesis", 3rd. ed., John Wiley & Sons, Inc., 1999, and then provocatrice with the subsequent removal of the protective group to obtain the compounds being considered. The protective group includes conventional protective group used in synthetic organic chemistry and described in the literature. In particular, the protective hydroxyl group includes, for example, tetrahydropyranyl, trimethylsilyl, tert-butyldimethylsilyl, benzyl, 4-methoxybenzyl, methoxymethyl, acetyl, and so forth, the protective group of amino includes, for example, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trichlorocyanuric, tert-aryloxyalkyl, 4-methoxybenzyl, 2-nitrobenzenesulfonyl, 2,4-dinitrobenzenesulfonyl and so forth, and the protective group for carboxy include, for example, alkyl, such as methyl, ethyl, tert-butyl and benzyl.

The compound of the present invention or an intermediate product is obtained according to the above methods, and then the functional group can be turned or modify an accepted way. In particular, included the following methods.

(1) the transformation of the amino amide in

Amino can be converted into the corresponding amide by reaction with amino allelochemical or reaction of the carboxy with an amine in the presence of a condensing agent.

(2) the transformation of the carboxy or ester in carbarnoyl

Carboxy can be converted into the corresponding carbarnoyl transformation carboxy or its salts in allalone and then reaction with an amine or PE is the Ktsia carboxy or its salts with an amine in the presence of a condensing agent or by reaction of the ester with the amine.

(3) Hydrolysis of ester

Ester can be converted to the corresponding carboxy or its salt by hydrolysis of the ester alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide) or acid (e.g. hydrochloric acid, sulfuric acid) or an ester hydrogenation using a metal catalyst.

(4) N-Alkylation and N-familyromagna

Amino can be converted into the corresponding mono - or dialkylamines amino or phenylselenenyl amino by reaction with amino alkylhalogenide or fenilalanina. Amino can be converted into the corresponding mono - or dialkylamines amino or phenylselenenyl amino by reductive amination.

(5) N-Sulfonylurea

Amino can be converted into the corresponding alkylsulfonyl or phenylcarbonylamino reaction with amino alkylsulfonates or vinylsulfonylacetamido.

(6) the Conversion of amino in ureido

Amino can be converted into alkaluria reaction with amino alkylsulfonates or carbamoylation. Amino can also be made ureido transformation in amino isocyanate, carbamoylated or carbamate and then reaction with the amine.

(7) the Transformation of amino carbamate in

Amino can be converted to carbamate by reaction with amino alkylhalogenide (for example, methylcarbonate, atilhan what arboretum) or the conversion of amino to isocyanate and then reaction with the alcohol.

(8) the Transformation of amino 3-aminopropionic or 2-aminomethanesulfonic

Amino can be converted into the corresponding 3-aminopropionic or 2-aminomethanesulfonic by the interaction of the amino on Michael's reaction with 2,3-unsaturated carbonyl compound or vinylsulfonylacetamido.

(9) the Conversion of aromatic nitro aromatic amine

Aromatic nitro can be converted into aromatic amine by treatment of aromatic nitro reducing agent [for example, metal-containing reducing agent, such as borohydride sodium, borohydride lithium, sociallyengaged), recovery of metal (e.g. iron, zinc, tin, tin chloride (II), titanium, trichloride titanium), catalytic recovery with the use of transition metal (e.g. palladium on charcoal, platinum, Raney Nickel) accepted way. When the catalytic reduction as the source of hydrogen can also be applied ammonium formate, hydrazine, and so on.

The compound of the present invention and each intermediate product, which will receive the above methods, can be cleaned by using common methods, such as chromatography, recrystallization and so on. Solvent for recrystallization include, for example, an alcoholic solvent such as methanol, ethanol or 2-propanol, solvent type, the issue is on air, such as diethyl ether, diisopropyl ether and THF, the solvent of the type of ester, such as ethyl acetate, an aromatic solvent such as toluene, a ketone solvent such as acetone, hydrocarbon solvent such as hexane, water or a mixed solvent. The compound of the present invention can be converted into its pharmaceutically acceptable salt in the conventional manner and then subjected to recrystallization.

The effect of the invention

The compound of the present invention or its pharmaceutically acceptable salt has a blocking activity in respect of IKurand is applicable for the prevention or treatment of cardiac arrhythmia, such as atrial fibrillation, atrial fibrillation, atrial fibrillation, supraventricular tachycardia at a mammal. The compound of the present invention or its pharmaceutically acceptable salt is also applicable for the prevention of thromboembolism, including apoplexy, heart failure including congestive heart failure.

The compound of the present invention or its pharmaceutically acceptable salt can be made in the form of pharmaceutical compositions containing a therapeutically effective amount of the compounds and pharmaceutically acceptable carries the eh. Pharmaceutically acceptable carrier may include a diluent, a binder (for example, syrup, Arabian gum, gelatin, sorbitol, tragakant, polyvinylpyrrolidone), excipient (for example, lactose, sucrose, corn starch, potassium phosphate, sorbitol, glycine), grease (for example, magnesium stearate, talc, polyethylene glycol and silicon dioxide), disintegrity agent (e.g., corn starch) and wetting agents (e.g. sodium lauryl sulphate) etc

The compound of the present invention or its pharmaceutically acceptable salt can be administered orally or parenterally, and can be applied in the form of a suitable pharmaceutical preparation. Suitable pharmaceutical preparation for oral administration includes, for example, a solid preparation such as tablet, granule, capsule, powder, or liquid preparation, suspension or emulsion. Suitable pharmaceutical preparation for parenteral administration include suppositories, injectable solution or liquid preparation for intravenous administration, for the preparation of which use distilled water for injection, physiological saline or an aqueous solution of glucose, or drug inhalation.

The dose of a compound of the present invention or its pharmaceutically acceptable salts varies depending on the t route of administration, age, body mass or condition of the patient, but is usually about 0.003 to 100 mg/kg, preferably about 0.01 to 30 mg/kg, particularly about 0.05-10 mg/kg, per day.

The best way of carrying out the invention

The present invention additionally particularly illustrated by the following examples and reference examples, but is not limited to them.

Examples

Example 1-1

Compound 1 (200 mg) suspended in anhydrous THF (7 ml) and to the suspension was added triphenylphosphine (279 mg) under stirring and the mixture was slowly added N-chlorosuccinimide (156 mg) under ice cooling. To the mixture was added a solution of compound 2 (345 mg) in THF (0.5 ml) and the mixture was allowed to warm to room temperature and was stirred for 3 hours. To the mixture was added 10% aqueous citric acid solution and the mixture was extracted with chloroform, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluent: a mixture of 3% methanol-chloroform), to thereby obtain compound 3 (121 mg) as pale-yellow crystals.

MS (APCI): 349 [M+H]+.

Example 1-2

Connection 1 (270 mg) and triphenylphosphine (385 mg) suspended in THF (6 ml) and to the suspension was added N-chlorosuccinimide (214 mg) while cooling Lido and the mixture was stirred at room temperature for 1 minute. To the mixture was added a solution of compound 2 (357 mg) and diisopropylethylamine (465 μl) in THF (5 ml) under ice cooling and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added water and saturated aqueous sodium bicarbonate solution and the mixture was extracted with ethyl acetate. Layers of the extract were combined, washed with saturated salt solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (eluent: gradient of 3%-10% methanol in chloroform), was concentrated under reduced pressure and then the resulting mixture was led from a mixture of ethyl acetate-hexane (1:1), while receiving the connection 3.

MS (APCI): 363 [M+H]+.

Example 1-3

(1) Compound 1 (1,502 g) was dissolved in THF (70 ml) and the solution was sequentially added triphenylphosphine (2,510 g), then N-chlorosuccinimide (1,279 g) under stirring and cooling with ice. The mixture was stirred for 60 minutes while cooling with ice, and thereto was added dropwise a solution of compound 2 (2,391 g) and diisopropylethylamine (2,777 ml) in THF (30 ml) for 30 minutes. After the addition the mixture was allowed to warm to room temperature and was stirred for 25 hours. To the reaction mixture was added water under stirring and when ohla the Denia with ice and the mixture was extracted with ethyl acetate. Layers of the extract were combined, washed with saturated aqueous sodium bicarbonate and saturated salt solution and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the resulting residue was purified column chromatography on silica gel (eluent: a mixture of 1-2% methanol/chloroform), to thereby obtain compound 3 (1,877 g) as pale brown oil.

MS (APCI): 421 [M+H]+.

NMR (DMSO-d6) ppm of 1.27 and 1.35 (N, m), 2,74-2,78 (3H, m), 3,44 (2H, m)to 3.89 (2H, m), to 6.58 (1H, m), 7,10 (1H, m), and 7.3 and 7.6 (8H, m), 7,76 (1H, m), 13,41 (1H, user. C).

(2) Connection 3 (1,877 g) suspended in ethyl acetate (10 ml) and to the suspension was added a solution of 4 N. hydrochloric acid/ethyl acetate (9 ml) under stirring and cooling with ice. The reaction mixture was allowed to warm to room temperature and was stirred for 2 hours. To the reaction mixture was added isopropyl simple ether (10 ml) and precipitated crystals were separated by filtration, washed with a mixture of ethyl acetate-isopropyl simple ether (1:1) and dried under reduced pressure, thus obtaining the compound 4 (1,654 g) as pale yellow powder.

MS (APCI): 321 [M+H]+.

NMR (DMSO-d6) ppm 2,62 (3H, t, J=5 Hz)to 3.09 (2H, square, J=6 Hz), 4,08 (2H, t, J=6 Hz), 6,56 (1H, d, J=15.6 Hz), 7,11 (1H, t, J=7.5 Hz), 7,37 (2H, m), 7,45 to 7.62 (6N, m), 7,80 (1H, d, J=15.6 Hz), to 8.62 (2H, m), and 13.5 (1H user. C).

(3) Compound 4 (130 mg) suspend is ovale and stirred in chloroform (5 ml) and to the suspension was added triethylamine (152 μl). To the mixture was added dropwise a solution of methylchloroform (32 μl) in chloroform (2 ml) under cooling with ice. The mixture was stirred at room temperature for 7.5 hours, and thereto was added water and the mixture was extracted with chloroform. Layers of chloroform were combined, washed with saturated salt solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was dissolved in methanol (5 ml) and to the solution was added a solution of 28% sodium methoxide/methanol (7 ml). The mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure and was purified column chromatography on silica gel (eluent: chloroform-methanol = 9:1), thus obtaining the compound 5 (output reached 125.5 mg) as colorless foam.

MS (APCI): 379 [M+H]+.

NMR (DMSO-d6) and 2.79 ppm (3H, s), of 3.46 (2H, t, J=5,9 Hz), 3,51-of 3.54 (3H, m), 3,93 (2H, t, J=5,9 Hz), to 6.58 (1H, m), 7,11 (1H, t, J=7.5 Hz), and 7.3 and 7.6 (8H, m), 7,76 (1H, m), and 13.4 (1H, user. C).

Example 1-4

Compound 1 (150 mg) and triphenylphosphine (214 mg) was dissolved in THF (3.5 ml) and to the solution was added N-chlorosuccinimide (119 mg) under stirring and cooling with ice. The mixture was stirred at room temperature for 2 minutes. To the reaction mixture was added a solution of compound 2 (198 mg) and diisopropylethylamine (258 μl) in THF (2.5 ml) and the mixture was stirred at room themes is the temperature value within 2 hours. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. Layers extracts were combined, washed with saturated aqueous sodium bicarbonate and saturated salt solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified column chromatography on silica gel (eluent: a mixture of chloroform-2-9% methanol) and the resulting solid triturated with a mixture of ethyl acetate-hexane, thus obtaining the compound 3 (176 mg).

MS (APCI): 363 [M+H]+.

Examples from 1-5 to 2-59

The corresponding starting compound were subjected to reaction and was treated in a manner analogous to the methods of the above examples to give the compounds of examples 1-5 to 2-59.

Example 3-1

(1)

Connection 1 (2.25 g) was dissolved in THF (80 ml) and the solution was sequentially added triphenylphosphine (of 3.78 g), then N-chlorosuccinimide (1,923 g) under stirring and cooling with ice. The mixture was stirred for 60 minutes while cooling with ice, and thereto was added dropwise a solution of compound 2 (3,605 g) and diisopropylethylamine (4,18 ml) in THF (40 ml) for 10 minutes. After the addition the mixture was allowed to warm to room temperature and was stirred for 18 hours. To the reaction mixture was added water under stirring and cooling l is ω and the mixture was extracted with ethyl acetate. Layers of the extract were combined, washed with saturated aqueous sodium bicarbonate and saturated salt solution and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the resulting residue was purified column chromatography on NH-silica gel (eluent: a mixture of 50% ethyl acetate-hexane to 1% methanol-chloroform), to thereby obtain compound 3 (2,88 g) as a colourless solid.

MS (APCI): 421 [M+H]+.

IR (Nujor) 1709, 1651 cm-1.

(2) Connection 3 (2,88 g) suspended in ethyl acetate (10,27 ml) and to the suspension was added dropwise a solution of 4 N. hydrochloric acid-ethyl acetate (17,13 ml) under stirring and cooling with ice. The reaction mixture was allowed to warm to room temperature and stirred over night. The reaction mixture was cooled with ice, was podslushivaet by adding 10% aqueous sodium hydroxide solution and then was extracted with chloroform. Layers of the extract were combined, washed with saturated salt solution, dried over anhydrous sodium sulfate and the solvent is then drove away under reduced pressure, thus obtaining the compound 4 (1,83 g).

MS (APCI): 321 [M+H]+.

IR (Nujor) 3349, 1651 cm-1.

(3) Compound 4 (160 mg) suspended in pyridine (1.6 ml) and to the suspension was added a mixture of THF-chloroform, DMF (2 ml - 2 ml - 2 ml). To the mixture slowly we use and anhydrous acetic acid (0.05 ml) and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. Layer extract was washed with 0.5 N. the solution of hydrochloric acid, saturated sodium bicarbonate, water and saturated salt solution and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the resulting residue was purified column chromatography on silica gel (eluent: a mixture of chloroform - 5% methanol) and the resulting solid is triturated with ethyl acetate, thus obtaining the compound 5 (127 mg) as colorless powder.

MS (APCI): 363 [M+H]+.

IR (Nujor) 3272, 1650, 1618 cm-1.

Example 3-2

Connection 1 (of 120.5 mg) suspended in a mixture of chloroform (5 ml)-THF (3 ml) and to the suspension was added triethylamine (63 μl) with stirring and cooling with ice. Then to the mixture was added dropwise a solution of compound 2 (45 μl) in chloroform (1 ml) for 15 minutes. The mixture was stirred at room temperature for 1 hour and thereto was added water. The mixture is vigorously stirred and then was extracted with chloroform. Layers of the extract were combined, washed with saturated salt solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified column chromatography on silica gel (eluent: chloroform to the mixture of 20:1 is cloroform-methanol), while receiving the connection 3 (145,0 mg) as colorless powder.

MS (APCI): 423 [M+H]+.

Example 3-3

Connection 1 (120,2 mg) suspended in DMF (5 ml) and to the suspension was added zanoxolo acid (33,5 mg) and HOBt (66,1 mg)was then added WSC (93,5 mg) and the mixture was stirred under ice cooling. The mixture was allowed to warm to room temperature and was stirred for 1 hour. To the reaction mixture were added an aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. Layers of the extract were combined, washed with saturated salt solution and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the residue was purified column chromatography on NH-silica gel (eluent: a mixture of 20:1 chloroform-methanol), to thereby obtain compound 3 (113 mg) as colorless powder.

MS (APCI): 388 [M+H]+.

Example 3-4

Connection 1 (120,0 mg) suspended in DMF (2 ml) and to the suspension was added ethyl formate (3 ml). The mixture was stirred at room temperature for 3 days. To the reaction mixture were added ethyl acetate and the mixture was washed with water several times, washed with saturated salt solution and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the residue was purified column chromatography the raffia on silica gel (eluent: gradient from chloroform to the mixture 9:1 chloroform-methanol), while receiving the connection 2 (93,6 mg) as colorless powder.

MS (APCI): 349 [M+H]+.

Example 3-5

Connection 1 (110 mg) suspended in chloroform (10 ml) and to the suspension was added triethylamine (53 μl)was then added dropwise p-nitrophenylphosphate (73,0 mg) for 15 minutes under stirring and cooling with ice. The mixture was stirred for 1.5 hours while cooling with ice, and thereto were added 4-hydroxypiperidine (70 mg) and triethylamine (100 μl). The mixture was allowed to warm to room temperature and was stirred for 1 day. To the reaction mixture were added an aqueous solution of sodium bicarbonate and the mixture was extracted with chloroform. Layers of the extract were combined, washed with saturated salt solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on NH-silica gel (eluent: gradient from chloroform to the mixture 80:20 chloroform-methanol), to thereby obtain compound 2 (87,1 mg) as a colorless amorphous powder.

MS (APCI): 448 [M+H]+.

NMR (DMSO-d6) to 1.21 ppm (2H, m)to 1.61 (2H, square, J=7 Hz), of 1.64 (2H, m), 2,85 (2H, m), 3,05 (2H, square, J=6,7 Hz)to 3.58 (1H, m), the 3.65 (2H, dt, 13,5, 14 Hz), 3,80 (2H, t, J=7,4 Hz)and 4.65 (1H, d, J=4 Hz), 6.48 in (1H, t, J 5.5 Hz), 6,55 (1H, d, J=15 Hz), 7,10 (1H, t, J=7 Hz), and 7.3 and 7.6 (8H, m), 7,74 (1H, d, J=16 Hz), and 13.4 (1H, user. C).

Examples 3-6 and 3-7

The relevant source is e compounds were subjected to reaction and was treated the way similar to the methods of the above examples to give the compounds of examples 3-6 and 3-7.

Example 4-1

Compound 1 (5.0 g) was dissolved in THF (720 ml) under heating and the solution was added triphenylphosphine (11,09 g) and N-chlorosuccinimide (5,27 g) under stirring and at room temperature. The mixture was stirred for 5 minutes. Then thereto was added a solution of compound 2 (6,64 g) and N,N-dimethylaniline (7,37 ml) in THF (50 ml) under stirring at room temperature and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. Layers extracts were combined, washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluent: gradient of chloroform-0%-5% methanol), to thereby obtain compound 3 (15,588 g) as colorless crystalline powder.

MS (APCI) 400 [M+H]+.

(Alternate method)

Connection 1 (630 mg) was dissolved in a mixture of chloroform (50 ml)-THF (15 ml) and to the solution was added triethylamine (641 μl) and was added dropwise methanesulfonanilide (160 ml) under stirring and cooling with ice. The mixture was stirred for 1 hour while cooling l the house and the reaction mixture was poured into water and was extracted with chloroform. Layers extracts were combined, washed with aqueous sodium bicarbonate solution and saturated salt solution and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the residue was purified column chromatography (eluent: a mixture of 100:1-30:1 chloroform-methanol). The solvent is kept off and the resulting residue was led from ethyl acetate and triturated with isopropyl simple ether, thus obtaining the compound 2 (561 mg) as colorless powder.

MS (APCI) 400 [M+H]+.

IR (Nujol) 1656 cm-1

Examples 4-2 to 4-61

The corresponding starting compound were subjected to reaction and was treated in a manner analogous to the methods of the above examples to give the compounds of examples 4-2 to 4-61.

Example 5-1

To a solution of compound 1 (110 mg) and triphenylphosphine (184 mg) in THF (3 ml) was added N-chlorosuccinimide (101 mg) under stirring and at room temperature and the mixture was stirred for 1 minute under cooling with ice. Then to the mixture was added compound 2 (167 mg) and N,N-dimethylaniline (148 μl) and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added an aqueous solution of citric acid and the mixture was extracted with ethyl acetate. The layer of the extract were combined, washed with saturated salt solution and dried over anhydrous Sul is blockhead sodium. The solvent is kept under reduced pressure and the resulting residue was purified column chromatography on silica gel (eluent: gradient of a mixture of chloroform-methanol 97:3 to 11:89), thus obtaining the compound 3 (196 mg) as a colorless amorphous powder.

MS (APCI) 409 [M+H]+.

Examples from 5-2 to 5-35

The corresponding starting compound were subjected to reaction and was treated in a manner analogous to the methods of the above examples to give the compounds of examples 5-2 to 5-35.

Example 6-1

To a solution of compound 1 (25 mg) in methylene chloride (3 ml) was added oxalicacid (36 μl) and a drop of DMF and the mixture is then boiled under reflux for 1 hour under heating. The reaction solution was cooled and then concentrated under reduced pressure. The residue is suspended in chloroform (3 ml) and to the suspension was added a solution of 2-anilinomethyl (51 μl) in chloroform (3 ml). The mixture was stirred at room temperature for 16 hours. To the reaction mixture were added an aqueous solution of sodium bicarbonate and the mixture was extracted with chloroform. Layers of the extract were combined, washed with saturated salt solution and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel (eluent: gradient of chloroform-1-8% m is tanol), while receiving the connection 2 (11.5 mg) as colorless powder.

MS (APCI): 309 [M+H]+.

Example 6-2

Connection 1 (12.4 g) was dissolved in THF (1860 ml) under heating and the solution was added triphenylphosphine (27.5 g) and N-chlorosuccinimide (13,1 g) under stirring at room temperature. The mixture was stirred for 1 minute. Then thereto was added a solution of compound 2 (14.1 g) and N,N-dimethylaniline (16.6 ml) in THF (140 ml) under stirring at room temperature and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into a mixture of 2 N. aqueous sodium hydroxide solution (900 ml) and saturated salt solution (900 ml) and was extracted with ethyl acetate. Layers of the extract were combined, washed with saturated salt solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To the residue was added ethyl acetate, and precipitated crystals were separated by filtration and recrystallized from ethanol, thus obtaining the compound 3 (15,588 g) as a pale yellow crystalline powder.

MS (APCI): 367 [M+H]+.

IR (Nujol) 1651 cm-1.

Example 6-3

To compound 1 (154 mg) was added to a mixture of acetonitrile (5 ml)-THF (5 ml), then N,N'-disuccinimidyl (323 mg) and N,N'-dimethylaminopyridine (6 mg) and the mixture was stirred at to the room temperature for 20 hours. Then to the mixture was added compound 2 (178 mg) and the mixture was stirred at room temperature for 24 hours. To the reaction mixture was added 5% aqueous potassium carbonate solution and the mixture was extracted with ethyl acetate. Layers of the extract were combined, washed with saturated salt solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was dissolved in methanol (5 ml) and to the solution was added water (2.5 ml) and potassium carbonate (346 mg) under stirring and cooling with ice. The mixture was stirred at room temperature for 2.5 hours. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. Layers of the extract were combined, washed with saturated salt solution, dried over anhydrous sodium sulfate and the solvent is then drove away under reduced pressure. The residue was purified column chromatography on silica gel (eluent: a mixture of methanol-ethyl acetate gradient 3:97-12:88), thus obtaining the compound 3 (91 mg) as a colourless oil.

MS (APCI) 424 [M+H]+.

Examples from 6-4 to 7-5

The corresponding starting compound were subjected to reaction and was treated in a manner analogous to the methods of the above examples to give the compounds of examples from 6-4 to 7-5.

Example 8-1

(1) Compound 1 (200 mg) was dissolved in THF (20 ml) and p is the target) was added triphenylphosphine (254 mg) under stirring at room temperature, then was added N-chlorosuccinimide (147 mg). The mixture was stirred for 1 minute and then thereto was added a solution of 3-anilinophenol (108 mg) and diisopropylethylamine (225 μl) in THF (1 ml). The mixture was stirred at room temperature for 1.5 hours. To the reaction mixture were added an aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. Layers of the extract were combined, washed with saturated salt solution, dried over anhydrous sodium sulfate and the solvent is then drove away under reduced pressure. The residue was purified column chromatography on silica gel (ethyl acetate-chloroform, 1:1), thus obtaining the compound 2 (143,6 mg) as pale yellow powder.

MS (APCI) 443 [M+H]+.

(2) Compound 2 (136,3 mg) suspended in triperoxonane acid (4.5 ml) and the mixture is boiled under reflux for 4.5 hours under heating. The reaction solution was concentrated under reduced pressure and to the residue was added aqueous sodium bicarbonate solution and the mixture was extracted with ethyl acetate. Layers of the extract were combined, washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel (mixture of chloroform-methanol to 8% gradient), thus obtaining the compound 3 (35,8 mg) as colorless powder.

MS(APCI) 323 [M+H] +.

Examples from 8-2 to 8-39

The corresponding starting compound were subjected to reaction and was treated in a manner analogous to the methods of the above examples to give the compounds of examples from 8-2 to 8-39.

Example 9-1

Compound 1 (200 mg) suspended in anhydrous THF (7 ml) and to the suspension was added triphenylphosphine (307 mg) and then slowly added N-chlorosuccinimide (170 mg) under stirring and cooling with ice. Then to the mixture was added a solution of compound 2 (408 mg) in a mixture of THF (0.5 ml) - methylene chloride (1.5 ml) and the mixture was allowed to warm to room temperature and was stirred for 2 hours. Then to the mixture was added 10% aqueous citric acid solution and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, concentrated under reduced pressure and then the residue was purified column chromatography on silica gel (chloroform to 2% methanol), to thereby obtain compound 3 (338 mg) as a pale yellow oil.

MS (APCI): 384 [M+H]+.

Example 9-2

To a solution of compound 1 (400 mg) and triphenylphosphine (613 mg) in THF (17 ml) was added N-chlorosuccinimide (341 mg) was stirred at room temperature and the mixture was stirred for 1 minute under cooling with ice. Then to the mixture was added methyl ether 3-phenylamino pianoboy acid (686 mg) under ice cooling and the mixture was stirred at room temperature for 4 hours. Then thereto was added triphenylphosphine (112 mg) and N-chlorosuccinimide (57 mg) under ice cooling and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture were added an aqueous solution of citric acid and the mixture was extracted with ethyl acetate. Layers of the extract were combined, washed with saturated salt solution and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the resulting residue was purified column chromatography on silica gel (eluent: chloroform-methanol 40:1), thus obtaining the compound 3 (565 mg) as colorless solids.

MS (APCI): 352 [M+H]+.

(2) Connection 3 (648 mg) suspended in methanol (4.6 ml) and to the suspension was added THF (2.3 ml), then 2 N. aqueous sodium hydroxide solution (4.6 ml). The mixture was stirred at room temperature for 2 hours, and thereto was added 2 n hydrochloric acid (4.6 ml) under ice cooling and the mixture was extracted with ethyl acetate. Layers extracts were combined, washed with saturated salt solution and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and the residue triturated with isopropyl simple ether, filtered and then dried, thus obtaining the compound 4 (535 mg) as colorless powder.

MS (ESI) 334 [M-N]-.

(3) Compound 4 (140 mg) and HOBt (73 mg) was dissolved which in DMF (2 ml) and to the solution was added a solution of 2 N. methylamine/THF (522 ml) and WSC (104 mg). The mixture was stirred at room temperature for 5 hours. Then thereto was added an aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. Layers of the extract were combined, washed with saturated salt solution and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel (eluent: chloroform-ethanol, 98:2 gradient), thus obtaining the compound 5(111 mg) as colorless powder.

MS (APCI) 349 [M+H]+.

Example 9-3

To a solution of compound 1 (120 mg) and triphenylphosphine (184 mg) in THF (5 ml) was added N-chlorosuccinimide (102 mg) under stirring at room temperature and the mixture was stirred at room temperature for 1 minute. Then to the mixture was added compound 2 (169 mg) and diisopropylethylamine (222 μl) with stirring at room temperature and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added a saturated salt solution and the mixture was extracted with ethyl acetate. Layers of the extract were combined, washed with saturated salt solution and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the resulting residue was purified column chromatography on silica gel (eluent: chlorof the RM-methanol, 98:2), thus obtaining the compound 3 (195 mg) as colorless foam.

MS (APCI) 391 [M+H]+.

Examples from 9-4 to 10-32

The corresponding starting compound were subjected to reaction and was treated in a manner analogous to the methods of the above examples to give the compounds of examples from 9-4 to 10-32.

Example 11-1

A suspension of compound 1 (100 mg) in thionyl chloride (2.9 ml) was stirred at 60°C for 1.5 hours under heating. After cooling, the suspension was concentrated under reduced pressure, and the resulting pale yellow solid is suspended in THF (4 ml) and chloroform (6 ml). Then, to the suspension was added dimethylaminopyridine (71 mg), then a solution of compound 2 (363 mg) in THF (2 ml) under ice cooling and the mixture was stirred at room temperature for 22 hours. To the reaction mixture were added water and saturated aqueous sodium bicarbonate solution, then the mixture of methanol-chloroform (1:5) and the mixture vigorously stirred. The insoluble substance was separated by filtration through celite and washed with a sufficient amount of the mixture of methanol-chloroform (1:5). The filtrate and washing liquid were combined and the layers were separated and the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (E. went: gradient mixture of 1%-6% methanol-chloroform), while receiving the connection 3 (61 mg) as colorless powder.

MS (APCI) 380 [M+H]+.

Example 12-1

To a solution of compound 1 (30 mg) and triphenylphosphine (51 mg) in THF (6 ml) was added N-chlorosuccinimide (24 mg) under stirring and ice cooling and the mixture was stirred for 10 minutes under ice cooling. Then to the mixture was added compound 2 (43 mg) and N,N-dimethylaniline (42 mg) under stirring and under cooling with ice and the mixture was stirred at room temperature for 20 hours. To the reaction mixture were added an aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. Layer extract was washed with saturated salt solution and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the resulting residue was purified column chromatography on silica gel (eluent: chloroform-methanol, 98:1-92:8), thus obtaining the compound 3 (56 mg) as colorless powder.

MS (APCI) 408 [M+H]+.

Example 12-2

To a solution of compound 1 (62 mg) and triphenylphosphine (126 mg) in THF (12 ml) was added N-chlorosuccinimide (60 mg) under stirring at room temperature and the mixture was stirred at room temperature for 2 minutes. Then to the mixture was added compound 2 (75 mg) and N,N-dimethylaniline (76 ml) under stirring at on the th temperature and the mixture was stirred at room temperature for 4 hours. To the reaction mixture were added a saturated salt solution and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the resulting residue was purified column chromatography on silica gel (eluent: chloroform-methanol, 98:2-92:8), thus obtaining the compound 3 (79 mg) as colorless powder.

MS (APCI) 398 [M+H]+.

Examples from 12-3 to 12-13

The corresponding starting compound were subjected to reaction and was treated in a manner analogous to the methods of the above examples to give the compounds of examples from 12-3 to 12-13.

Example 13-1

(1) Compound 1 (400 mg) and triphenylphosphine (723 mg) was dissolved in THF (58 ml) and to the solution was added N-chlorosuccinimide (342 mg) under stirring and ice cooling. The mixture was stirred for 5 minutes under ice cooling, and thereto was added dropwise a solution of compound 2 (720 mg) and N,N-dimethylaniline (596 mg) in THF (2 ml). After the addition the mixture was stirred at 60°C for 18 hours under heating. The reaction solution was cooled to room temperature and the solvent drove away. To the residue was added saturated aqueous sodium bicarbonate solution and the mixture was extracted with ethyl acetate. Layer extract was washed with saturated dissolve the Ohm salt and dried over anhydrous magnesium sulfate. The solvent is kept under reduced pressure and the resulting residue was purified column chromatography on silica gel (eluent: methanol-chloroform, 0:1-1:9), thus obtaining the compound 3 (116 mg) as a pale yellow oil.

MS (APCI) 491 [M+H]+.

(2) Connection 3 (1016 mg) was dissolved in methylene chloride (10 ml) and to the solution was added dropwise a solution of 4 N. hydrochloric acid/ethyl acetate (20 ml) under stirring at room temperature. To the reaction mixture were added ethanol (20 ml) and the mixture was stirred at 50°C for 20 minutes when heated. The reaction solution was cooled to room temperature and the solvent drove away. The residue is triturated with diethyl simple ether, filtered and dried, thus obtaining the compound 4 (898 mg) as pale yellow powder.

MS (APCI) 391 [M+H]+.

(3) Compound 4 (150 mg) suspended in THF (4 ml) and the suspension was sequentially added triethylamine (184 μl) and dimethylcarbamoyl (34 mg) under stirring and cooling with ice. The mixture was stirred at room temperature for 18 hours and the solvent drove away. To the residue was added a saturated salt solution and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent is kept under reduced pressure and the resulting residue was purified column chromatography on silica gel (who eluent: methanol-chloroform, 0:1-1:9), thus obtaining the compound 5 (105 mg) as colorless powder.

MS (APCI) 462 [M+H]+.

Examples from 13-2 to 13-11

The corresponding starting compound were subjected to reaction and was treated in a manner analogous to the methods of the above examples to give the compounds of examples from 13-2 to 13-11.

Reference example 1

(1) According to the method described in J. Prak. Chem. 1924, 297-320, compound 1 (60,0 g) was dissolved in DMF (800 ml) and the solution was slowly added granulated potassium hydroxide (114,08 g) and iodine (255,2 g) under cooling with ice. The reaction mixture was stirred at room temperature for 1 hour and poured into ice 10% aqueous solution of sodium bisulfite (3 l). The precipitated white solid was separated by filtration, washed with water and dried, thus obtaining compound 2 (107,4 g) as pale yellow crystals. The melting point 140,3-141,3°C.

The filtrate was extracted with diethyl simple ether, dried over sodium sulfate and then diethyl simple ether drove away under reduced pressure. The resulting residue was recrystallized from a mixture of ethyl acetate-hexane, thus obtaining the compound 2 (4,939 g) as pale yellow crystals.

(2) Compound 2 (100 g) and dimethylaminopyridine (2.5 g) suspended in acetonitrile (1200 ml) and to the suspension was added triethylamine (115 ml, then di-tert-BUTYLCARBAMATE (98,6 g) at room temperature. The mixture was stirred at the same temperature for 1 day. The solvent is kept under reduced pressure, and to the mixture was added ethyl acetate (800 ml). The mixture was washed with water (1 l) and saturated salt solution (approximately 1 liter). The washed aqueous layer was extracted with ethyl acetate (200 ml) and the product extraction was combined with the previous layer of ethyl acetate and then dried over anhydrous sodium sulfate. The ethyl acetate layer was concentrated under reduced pressure and to the residue was added hexane. The precipitated crystalline powder was separated by filtration. The filtrate was concentrated and to the residue was added hexane. Again precipitated crystalline powder was separated by filtration, thus obtaining the compound 3 (115,22 g) as pale brown powder.

The filtrate was concentrated and the residue was purified by chromatography on silica gel (ethyl acetate-hexane, 1:20-1:10), thus obtaining the compound 3 (11,92 g) as a white solid.

MS (APCI) 345 [M+H]+.

(3) Compound 3 (1.0 g), palladium acetate (16,3 mg), triphenylphosphine (38,2 mg) and triethylamine (3.2 ml) suspended in dioxane (15 ml) and to the suspension was added to the acrylate (2.5 ml) in an argon atmosphere. Then the mixture was stirred at 80°C when heated. After 19 hours the reaction solution was cooled to room temperature and drove actuarial. To the residue was added water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified column chromatography on silica gel (hexane-ethyl acetate: gradient elution), to thereby obtain compound 4 (634,1 mg) as pale brown powder.

MS (APCI) 317 [M+H]+.

(4) Compound 4 (2,31 g) was dissolved in ethanol (36,5 ml) and to the solution was added 2 N. aqueous sodium hydroxide solution (18,25 ml) at room temperature. The reaction mixture was stirred at room temperature for 21 hours and the pH was adjusted to 4 by adding hydrochloric acid under ice cooling and then to the mixture was added water. The mixture was extracted with chloroform. The crystals were besieged in the layer of chloroform and then the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the residue triturated with isopropyl simple ether, thus obtaining the compound 5 (1.25 g) as a pale yellow powder.

MS 187 [M-N]-.

(Alternate method)

Compound 1 (200 mg), 10% palladium on coal (15,4 mg) and triethylamine (0,650 ml) suspended in anhydrous dioxane (3 ml) and WM is ansii added acrylate (0,500 ml) in an argon atmosphere. Then the mixture was stirred at 100°C when heated. After 19 hours the mixture was cooled to room temperature and the insoluble substance was separated by filtration and then the filtrate was concentrated under reduced pressure. To the residue was added water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified column chromatography on silica gel (gradient elution with a mixture of hexane-ethyl acetate), to thereby obtain compound 2 (53,4 mg) as colorless powder.

MS (APCI): 217 [M+H]+.

NMR (DMSO-d6, ppm): of 1.29 (3H, t, J=7.2 Hz), to 4.23 (2H, square, J=7,2 Hz), 6,76 (1H, d, J=16.4 Hz), 7,26 (1H, d, J=7.5 Hz), the 7.43 (1H, t, J=7.9 Hz), a 7.62 (1H, d, J=8.34 per Hz), of 7.90 (1H, d, J=16.2 Hz), 8,11 (1H, d, J=8,2 Hz), 13,65 (1H, user. C).

(2) Compound 2 was subjected to the reaction, or processed in a manner analogous to the method of reference example 1(4), while receiving the connection 3.

Reference example 2

(1)

Compound 1 (3.0 g), the hydrochloride of N,O-dimethylhydroxylamine (2.35 g) and HOBt (3.25 g) was dissolved in DMF (37 ml) and to the solution was added triethylamine (a 3.87 ml) under cooling with ice, then added WSC (4.61 in). The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure, and then to the mixture to relax is whether the water. The mixture was extracted with ethyl acetate. Layer extract was washed with an aqueous solution of sodium bicarbonate and a saturated salt solution and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the residue triturated with isopropyl simple ether, thus obtaining the compound 2 (3,61 g) as colorless powder.

MS (APCI): 206 [M+H]+.

(2) Sociallyengaged (277 mg) suspended in THF (5 ml) and was cooled to approximately 0°C in a bath of ice-acetone, and to the suspension was added dropwise a solution of compound 2 (of 1.00 g) in THF (25 ml) for 5 minutes. The mixture was stirred for 30 minutes under ice cooling and then sequentially added water (277 μl), 15% aqueous sodium hydroxide solution (277 μl) and water (830 ml). Then to the mixture was added ethyl acetate and stirred at room temperature for 5 hours. The insoluble matter is separated by filtration and washed with a mixture of ethyl acetate-chloroform-methanol. The filtrate was concentrated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: methanol-chloroform, 1/30), thus obtaining the compound 2 (622 mg) as pale brown powder.

MS (APCI) 147: [M+H]+, 161: [M+H+Meon-H2O]+.

(3) Compound 3 (620 mg) was dissolved in THF (21 ml) and to the solution was added compound 4 (of 3.84 g). The mixture was stirred at 40-45°n and heated. The solvent is kept under reduced pressure and the residue was purified column chromatography (eluent: ethyl acetate-toluene, 1:8), thus obtaining the compound 5 (516 mg) as colorless powder and unreacted compound 3 (272 mg).

MS (APCI) 231 [M+H]+.

(4) Connection 5 (515 mg) suspended in ethanol (11.2 ml) and to the suspension was added THF (5.6 ml). Then to the mixture was added 2 N. aqueous sodium hydroxide solution (11.2 ml) under stirring and cooling with ice. The mixture was stirred at room temperature for 18 hours, acidified by adding 2 N. hydrochloric acid (11.2 ml) under cooling with ice and extracted with ethyl acetate. Layer extract was washed with saturated salt solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue triturated with a mixture of ethyl acetate-hexane (1:1) and dried, thus obtaining the compound 6 (338 mg) as colorless powder.

MS (ESI-MS) 201 [M-N]-.

Reference example 3

(1) To a solution of compound 1 (17,67 g) in THF (690 ml) was added dropwise 3.0 M solution methylacrylamide in THF (86,1 ml) at -8°C for 50 minutes with stirring and cooling. The mixture was stirred at the same temperature for 1 h, then poured into 10% aqueous solution of ammonium chloride (860 ml) and was extracted with atilas what tatom. Layer extract was washed with water and saturated salt solution, dried over anhydrous sodium sulfate, and then the residue was purified column chromatography on silica gel (eluent: a mixture of ethyl acetate-chloroform, 1/7-1/2), thus obtaining the compound 2 (9,03 g) as colorless powder.

MS (APCI) 161 [M+H]+.

(2) 60% sodium hydride (3.11 g) suspended in dioxane (160 ml) and to the suspension was added dropwise a solution of compound 3 (13,6 g) in dioxane (80 ml) under cooling with ice for 10 minutes. The mixture was stirred at room temperature for 10 minutes and to it was added in portions compound 2 (5,67 g) for 10 minutes under ice cooling. The mixture was stirred at room temperature for 10 minutes and then stirred at 80°C for 24 hours under heating. The reaction solution was cooled and thereto was added water and a saturated salt solution. The mixture was extracted with ethyl acetate. Layers of the extract were combined, washed with saturated salt solution and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and the residue was purified column chromatography on silica gel (eluent: ethyl acetate/hexane, 1/4). The resulting solid is triturated with isopropyl simple ether, thus obtaining the compound 4 (of 93.96 g) as pale yellow crystals.

MS (APCI) 231 [M+H]+.

(3) Compound 4 (287 g) was dissolved in ethanol (62 ml) and to the solution was added 2 N. aqueous sodium hydroxide solution (31 ml) under cooling with ice. The mixture was stirred at room temperature for 14 hours. Then thereto was added 2 N. aqueous sodium hydroxide solution (31 ml) under ice cooling and the mixture was stirred at room temperature for 3 days. Then thereto was added dropwise 2 n hydrochloric acid solution (62 ml) under cooling with ice. The precipitated solid was separated by filtration, washed with water and then dried, thus obtaining the compound 5 (2,13 g) as colorless powder.

MS (APCI) 203 [M+H]+.

Reference example 4

(1)

According to the method described in Chemical Communications 293-294 (1966), to a mixture of compound 1 (20,0 g) and monohydrate p-toluensulfonate acid (15.6 g) was slowly added hydrazine monohydrate (26,6 ml) under stirring and cooling with ice. The mixture was stirred at 130°C for 21 hours under heating. The reaction mixture was left to cool when standing and then was poured into 25% aqueous potassium carbonate solution and extracted with ethyl acetate. Layers of extract was combined, dried over anhydrous magnesium sulfate. The solvent is kept under reduced pressure, and the resulting residue was purified column chromatography on silica gel (eluent: hexane-ethyl acetate, 2:1-1:1). The resulting solid is triturated with a mixture of hexa is-ethyl acetate (1:1), while receiving the connection 2 (12,27 g) in the form of colorless crystals in the form of powder.

The melting point of 97.3-98°C.

(2) Compound 2 (12.2 g) was dissolved in DMF (200 ml) and to the solution was added potassium hydroxide (26,86 g) with stirring under ice cooling, and then the portions was added iodine (52,24 g). The mixture was allowed to warm to room temperature and was stirred at room temperature for 1 hour. The reaction mixture was poured into 10% aqueous solution of sodium bisulfite (1 l) and the precipitated crystals were separated by filtration, washed with water and then dried, thus obtaining the compound 3 (21,07 g) as pale yellow crystals.

The melting point 183,7-186,3°C.

MS (APCI) 246 [M+H]+.

(3) 60% sodium hydride (10.8 g) was washed with anhydrous hexane and suspended in DMF (350 ml). Then, to the suspension was added dropwise a solution of compound 3 (55,11 g) in DMF (200 ml) with stirring and cooling over the course of approximately 2 hours and the mixture was stirred for 1 hour under ice cooling. To the mixture was added p-methoxybenzylamine (36,6 ml) and then the mixture was allowed to warm to room temperature and was stirred for 1 hour. The reaction mixture was poured into ice water (3.5 l) and the precipitated crystals were separated by filtration, washed with water and then dried. The resulting solid is triturated with a mixture of chloroform and profilemy ether (2:1), while receiving the connection 4 (35,0 g) as pale red crystals.

The filtrate was concentrated under reduced pressure, and the residue was purified column chromatography on silica gel (eluent: chloroform-ethyl acetate, 100:1), thus obtaining the compound 4 (29.0 g) as pale red crystals.

The melting point 134,3-135,5°C.

MS (APCI) 366 [M+H]+.

(4) To a solution of compound 4 (24,7 g) in dioxane was added triphenylphosphine (3.55 g), palladium acetate (1.52 g) and triethylamine (123 ml). After replacement of air with argon to a mixture was added to the acrylate (74 ml) and the mixture was stirred at 100°C for 4 hours under heating. The reaction mixture was left to cool to room temperature when standing and concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water and saturated salt solution and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and the resulting residue was purified column chromatography on silica gel (eluent: hexane-ethyl acetate, 4:1 to 3:1). The resulting solid is triturated with isopropyl simple with ether, and dried, thus obtaining the compound 5 (20,838 g) as colorless crystals.

The melting point 105,9-106,8°C.

MS (APCI) 338 [M+H]+.

(5) To a solution of compound 5 (19.2 g) in a mixture of THF-ethanol (80 ml 160 ml) was added 2 N. water races is the thief of sodium hydroxide (140 ml) under ice cooling and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added 2 N. hydrochloric acid (140 ml) under cooling with ice and then add water. Precipitated crystals were separated by filtration, washed with water and then dried, thus obtaining the compound 6 (16,9 g) as colorless crystals. The filtrate was extracted with a mixture of ethyl acetate-THF layer and the extract was washed with saturated salt solution and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and the residue triturated with diethyl ether, thus obtaining the compound 6 (0.52 g) as colorless crystals. The crystals were combined with the previously obtained crystals, thus obtaining the compound 6 (17,42 g).

MS (ESI) 308 [M-N]-.

(6) Compound 6 (522,9 mg) suspended in triperoxonane acid (5 ml) and boiled under reflux by heating. After 16 hours the reaction mixture was concentrated under reduced pressure and triturated with a mixture of methanol-ethyl acetate, thus obtaining the compound 7 (0,303 g) as pale yellow crystals.

The melting point 269,0-271,2°C.

MS (APCI) 190 [M+H]+.

(7) Compound 5 (of 45.7 g) suspended in triperoxonane acid (300 ml) and the mixture is boiled under reflux for 3.5 hours under heating. The reaction mixture was cooled, concentrated under reduced pressure and then the residue was added ethyl acetate (100 ml) and 10% wagnerstr potassium carbonate. The mixture was stirred. Precipitated crystals were separated by filtration, washed with water, isopropyl simple ether and ethyl acetate and dried, thus obtaining the compound 8 (28,12 g) as colorless crystals.

The melting point 170,5-171,0°C.

MS (APCI) 218 [M+H]+.

IR (Nujor) 1672 cm-1.

(8) To a solution of compound 8 (33,22 g) in a mixture of THF-ethanol (200 ml 200 ml) was added 2 N. aqueous sodium hydroxide solution (338 ml) under ice cooling and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and the pH was adjusted to 3 by addition of 2 N. hydrochloric acid (340 ml) under stirring and cooling with ice. Precipitated crystals were separated by filtration, washed with water and then dried and triturated with chloroform, thus obtaining the compound 7 (26,63 g) as colorless crystals.

The melting point 272,4-274°C.

MS (APCI) 190 [M+H]+.

IR (Nujor) 1685 cm-1.

Reference example 5

(1) Compound 1 (500 mg) and 1-ethoxybenzothiazole (663 mg) suspended in dioxane (5 ml). To the mixture was added dichlorobistriphenylphosphine(II) (49 mg) in an argon atmosphere and the mixture is boiled under reflux for 21 hours under heating. The reaction mixture was left to cool when standing and then thereto was added etilize is t, then added a 10% aqueous solution of potassium fluoride. The mixture was stirred at room temperature for 1 hour. The insoluble substance was separated by filtration through celite and to the filtrate was added water and the mixture was separated. To the organic layer were added 1 N. hydrochloric acid. The mixture is vigorously stirred at room temperature and neutralized by adding saturated aqueous sodium bicarbonate solution and then the organic layer was separated, washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is kept under reduced pressure and the resulting residue was purified column chromatography on silica gel (eluent: hexane-ethyl acetate, 9:1-2:1), thus obtaining the compound 2 (321,6 mg) as a pale yellow solid.

MS (APCI) 282 [M+H]+.

NMR (DMSO-d6) ppm 2,63 (3H, s), 3,71 (3H, s), of 5.75 (2H, s), make 6.90 (2H, d, J=8.5 Hz), 7,31 (2H, d, J=8.5 Hz), 7,47 (1H, m), 8,58 (1H, d, J=8 Hz), 8,71 (1H, d, J=3 Hz).

(2) To a suspension of 60% sodium hydride (2,13 g) in dioxane (40 ml) was added dropwise a solution of ethyl ester diethylphosphonate acid (11,95 g) in dioxane (40 ml) under stirring at room temperature for 15 minutes. The mixture was stirred at room temperature for 1 hour and thereto was added compound 2 (5,00 g). The mixture was stirred at 55-58°C for 3 hours. The reaction mixture was cooled the to it was added water (100 ml). The mixture was extracted with ethyl acetate. Layers of the extract were combined, washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluent: chloroform). The resulting fraction (9,41 g) was dissolved in dioxane (30 ml) and to the solution was added 60% sodium hydride (1.07 g) at room temperature was added dropwise a solution of ethanol (1,56 ml) in dioxane (10 ml). The mixture was stirred at 45-55°C when heated, cooled, and then thereto was added water (40 ml). The mixture was extracted with ethyl acetate. Layers of the extract were combined, washed with saturated salt solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified column chromatography on silica gel (eluent: gradient mixture of hexane-ethyl acetate), to thereby obtain compound 3 (a 4.86 g) as a colourless solid.

MS (APCI) 352 [M+H]+.

NMR (DMSO-d6) of 1.27 ppm (3H, t, J=7 Hz), to 2.66 (3H, s), 3,70 (3H, s), 4,18 (2H, square, J=7 Hz), to 5.66 (2H, s), 6,59 (1H, s), 6.87 in (2H, d, J=8.7 Hz), 7,27 (2H, d, J=8.7 Hz), was 7.36 (1H, DD, J=4,5, 8,71 Hz), 8,51 (1H, d, J=7.9 Hz), 8,65 (1H, d, J=4,1 Hz).

(3) Compound 3 (a 4.86 g) suspended in triperoxonane acid (48.6 ml) and boiled under reflux by heating. After 4 hours, the suspension was cooled and then concentrated under pony is hinnon pressure and the residue was dissolved in ethyl acetate. The mixture was washed with an aqueous solution of sodium bicarbonate and a saturated salt solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluent: gradient of a mixture of chloroform-ethyl acetate), to thereby obtain compound 4 (3,36 g) as colorless powder.

MS (APCI) 232 [M+H]+.

NMR (DMSO-d6) of 1.27 ppm (3H, t, J=7 Hz), 2,68 (3H, s), 4,19 (2H, square, J=7 Hz), 6,59 (1H, s), 7,31 (1H, DD, J=4,8 Hz), of 8.47 (1H, d, J=8 Hz), 8,58 (1H, d, J=4 Hz), 14,18 (1H, user. C).

(4) Compound 4 (3,36 g) was dissolved in a mixture of THF-ethanol (34 ml 34 ml) and to the solution was added 2 N. aqueous sodium hydroxide solution (34,6 ml). The mixture was stirred at 50°C when heated. After 8 hours the reaction solution was cooled to room temperature. The solvent is kept under reduced pressure and to the residue was added 2 N. hydrochloric acid (34,5 ml). The mixture was slowly cooled. The precipitated colorless crystals were separated by filtration and dried, thus obtaining the compound 5 (2,05 g) as colorless powder.

MS (APCI) 204 [M+H]+.

NMR (DMSO-d6) to 2.65 ppm (3H, s), to 6.58 (1H, s), 7,31 (1H, DD, J=4,8 Hz), 8,46 (1H, d, J=8 Hz), to 8.57 (1H, d, J=4 Hz), and 12.4 (1H, user. C)14,0 (1H, s).

Reference example 6

(1) Compound 1 (4,20 g) was dissolved in DMF (70 ml) and to the solution was added potassium hydroxide (9,20 g) under ice cooling is m, then portions were added iodine (17.9 g). The mixture gave the opportunity to slowly warm to room temperature and was stirred for 30 minutes. The reaction mixture was poured into 10% aqueous solution of sodium metabisulfite (350 ml) and precipitated crystals were separated by filtration, washed with water and then dried, thus obtaining compound 2 (5,76 g) as pale brown powder.

MS (APCI) 246 [M+H]+.

(2) 60% sodium hydride (204 mg) suspended in DMF (4.3 ml) and to the suspension was added dropwise a solution of compound 2 (1,00 g) in DMF (12 ml) under cooling with ice for about 5 minutes. The mixture was stirred at room temperature for 1 hour. The mixture was cooled with ice, and thereto was added n-methoxybenzylamine (664 μl). Then the mixture was allowed to warm to room temperature and was stirred for 2 hours. The reaction mixture was poured into ice water (80 ml) and was extracted with ethyl acetate. Layers of the extract were combined, washed with saturated salt solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue is triturated with a mixture of ethyl acetate-isopropyl simple ether (1:1) and the product was filtered, thus obtaining the compound 3 (746 mg) as a pale pink powder. The filtrate was concentrated under reduced pressure and the residue was purified column chromatography on si is imagele and then triturated with isopropyl simple ether, while receiving the connection 3 (309 mg) as a pale pink powder.

MS (APCI) 366 [M+H]+.

(3) To a solution of compound 3 (744 mg) in dioxane (10,2 ml) was added triphenylphosphine (26,8 mg), palladium acetate (11.4 mg) and triethylamine (2,27 ml). To the mixture was added to the acrylate (1.77 ml) in an argon atmosphere and the mixture was stirred at 100°C for 22 hours under heating. The reaction mixture was left to cool to room temperature when standing and concentrated under reduced pressure. The resulting residue was purified column chromatography on silica gel (eluent: chloroform-ethyl acetate, 2:1) and the resulting solid is triturated with isopropyl simple ether, thus obtaining the compound 4 (328 mg) as pale yellow powder.

MS (APCI) 218 [M+H]+.

(4) Compound 4 (590 mg) suspended in triperoxonane acid (17.5 ml) and boiled under reflux by heating. After 23 hours the reaction solution was concentrated under reduced pressure and was purified column chromatography on NH-silica gel (eluent: methanol-chloroform, 1:50), thus obtaining the compound 5 (328 mg) as pale yellow powder.

MS (APCI) 218 [M+H]+.

(5) Compound 5 (327 mg) was dissolved in a mixture of THF-ethanol (3.8 ml to 3.8 ml) and to the mixture was added 2 N. aqueous sodium hydroxide solution (3,76 ml). The mixture was stirred at room temperature for 1 hour. To the mixture was added dropwise 2 N. hydrochloric acid (3,76 ml) under stirring and cooling with ice. The precipitated colorless crystals were separated by filtration, washed with a mixture of water-ethanol (10:1) and isopropyl simple with ether, and dried, thus obtaining the compound 6 (279 mg) as colorless powder.

MC (ESI) 188 [M-H]-.

Reference example 7

(1)

Compound 1 (2.00 g), copper iodide (I) (105 mg), sodium bicarbonate (953 mg) and methylpropionate (1.84 g) suspended in DMF (50 ml). To the mixture was added dichlorobistriphenylphosphine (II) (384 mg) in an argon atmosphere and the mixture was stirred at 60°C for 6 hours under heating. The reaction mixture was left to cool when standing and to it was added ethyl acetate. Then the mixture was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is kept under reduced pressure and the resulting residue was purified column chromatography on silica gel (eluent: hexane-ethyl acetate, 20:1-3:1), thus obtaining the compound 2 (1,09 g) as pale yellow powder.

MS (APCI) 322 [M+H]+.

(2) Iodide copper (I) (1,94 g) suspended in diethyl ether (20 ml). Then, to the suspension was added dropwise a 0.5 M solution utility in a mixture of benzene-cyclohexane (41 ml) under stirring at 0°C for 30 minutes. Then to the mixture was added dropwise R is the target compound 2 (1,09 g) in THF (10 ml) under stirring at -78°C for 20 minutes. The mixture was stirred at -78°C for 30 minutes, and then thereto was added water (2 ml). The mixture was allowed to warm to room temperature. The insoluble substance was separated by filtration through celite and washed with ethyl acetate. To the filtrate was added an aqueous solution of citric acid and the mixture was separated. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluent: hexane-ethyl acetate, 20:1-7:3), thus obtaining the compound 3 (1,15 g) as a red oil.

MS (APCI) 352 [M+H]+.

(3) To a solution of compound 3 (1,00 g) in dioxane (30 ml) was added a 28% solution of sodium methoxide in methanol (0.2 ml). The mixture was stirred at 50°C for 1 hour under heating. The reaction mixture was cooled and then thereto was added an aqueous solution of citric acid. The mixture was extracted with ethyl acetate. Layer extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluent: hexane-ethyl acetate, 20:1-7:3), thus obtaining the compound 4 (289 mg) as colorless powder.

MS (APCI) 352 [M+H]+.

(4) Compound 4 (280 mg) suspended in triperoxonane acid (6 ml) and the mixture is boiled with about the feats of the fridge when heated. After 18 hours, the suspension was cooled and then concentrated under reduced pressure. To the residue was added a mixed solvent of 3:1 of methanol and ethanol and insoluble substance was separated by filtration through celite. The filtrate was concentrated under reduced pressure. To the residue was added ethanol (3 ml), THF (3 ml) and 2 N. aqueous sodium hydroxide solution (1 ml) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and then thereto was added 2 N. hydrochloric acid (1 ml) under cooling with ice. The mixture was extracted with ethyl acetate. Layer extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is triturated with a mixed solvent of ethyl acetate and isopropyl simple ether, filtered and dried, thus obtaining the compound 5 (124 mg) as colorless powder.

MS (APCI) 218 [M+H]+.

Reference example 8

(1) To a solution of compound 1 (8,11 g) in DMF (325 ml) was added cesium fluoride (11.5g), before potassium (2.76 g) and water (3,63 ml) and the mixture was stirred at 80°C for 24 hours under heating. The reaction mixture was left to cool when standing and to it was added ethyl acetate. Then the mixture was washed with saturated salt solution and dried the hell anhydrous sodium sulfate. The solvent is kept under reduced pressure and the resulting residue was purified column chromatography on silica gel (eluent: hexane-ethyl acetate, 4:1-2:1), thus obtaining the compound 2 (4,34 g) as a pale yellow solid.

MS (APCI) 342 [M+H]+.

(2) Compound 2 (4,34 g) was dissolved in triperoxonane acid (87 ml) and the mixture is boiled under reflux by heating for 3 days. The mixture was cooled and then concentrated under reduced pressure. To the residue was added chloroform and aqueous sodium bicarbonate solution and the mixture was separated. Layer extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified column chromatography on silica gel (eluent: chloroform-THF-methanol, 10:1:0-20:1:1), thus obtaining the compound 3 (2.70 g) as pale brown powder.

MS (APCI) 222 [M+H]+.

(3) Compound 3 (2.70 g) suspended in THF (30,5 ml) and to the suspension was added 2 N. aqueous sodium hydroxide solution (30,5 ml) under cooling with ice. The mixture was stirred at room temperature for 5 hours. Then thereto was added dropwise 1 n hydrochloric acid (61 ml) under cooling with ice and the precipitated solid substance was separated by filtration, washed with water and then dried, thus obtaining the compound 4 (2,13 g) as a gray-white powder

MS (APCI) 208 [M+H]+.

Reference example 9

To a solution of compound 2 (4,82 g) in toluene (80 ml) was added compound 1 (11.1 g) and the mixture was boiled under reflux under heating for 6 hours. The reaction mixture was cooled with ice, and thereto was added a saturated aqueous solution of sodium bicarbonate. The mixture was extracted with ethyl acetate. Layers of extract was combined, dried over anhydrous sodium sulfate and the solvent is kept at reduced pressure. The resulting residue was purified column chromatography on silica gel, thus obtaining the compound 3 (2,77 g) as pale brown oil.

MS (APCI) 179 [M+H]+.

Reference example 10

To a solution of compound 2 (1,38 g) in toluene (17 ml) was added compound 1 (4,01 g) and the mixture was boiled under reflux under heating for 2 days. The reaction mixture was cooled with ice, and thereto was added a saturated aqueous solution of sodium bicarbonate. The mixture was extracted with ethyl acetate. Layers of extract was combined, dried over anhydrous sodium sulfate and the solvent is kept at reduced pressure. The resulting residue was purified column chromatography on silica gel, thus obtaining the compound 3 (1.10 g) as a pale brown oil.

MS (APCI) 214 [M+H]+.

Reference example 11-1

Connection 2 (1.50 g) was added compound 1 (2.25 ml), iodide, Tetra-n-butylamine (30 mg) and sodium iodide (30 mg) and the mixture was stirred at 100°C for 2 days when heated. The reaction mixture was cooled with ice, and thereto was added a saturated aqueous solution of sodium bicarbonate. The mixture was extracted with ethyl acetate. Layer extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent is kept at reduced pressure. The resulting residue was purified column chromatography on silica gel (eluent: hexane-ethyl acetate, 20:1-4:1), thus obtaining the compound 3 (508 mg) as orange oil.

MS (APCI) 269 [M+H]+.

Reference example 11-2

Compound 2 (12.3 g), compound 1 (12.0 g), cesium acetate (28,2 g) and copper iodide (11.2 g) was dissolved in DMSO (15 ml). The mixture was stirred in argon atmosphere at 90°C when heated during the night. After cooling, thereto was added water and the mixture was extracted with ethyl acetate. Layers of the extract were combined, washed with saturated aqueous sodium bicarbonate and saturated salt solution and dried over anhydrous sodium sulfate and the solvent is then drove away under reduced pressure. The residue was purified column chromatography on silica gel (eluent: gradient mixture of ethyl acetate-n-hexane), to thereby obtain compound 3 (8,71 g) as a colorless oil.

MS (APCI) 251 [M+H]+.

IR (Nujol) 3356, 1683 cm-1.

Reference examples from 11-3 to 11-6

The following compounds were obtained by reaction or processing in a manner analogous to the method of reference example 11-2.

Reference examplesRnMS (APCI) [M+H]+
11-32-OMe1281
11-43-OMe1281
11-53-OMe0267
11-64-OMe1281

Reference example 11-7

The cesium acetate (7,29 g) and copper iodide (2,89 g) was subjected to azeotropic distillation with toluene to dryness and to the residue was sequentially added a solution of compound 1 (2,41 g) in DMSO (10 ml), iadanza (1.90 ml) and DMSO (5 ml). The mixture was wearisomely and then filled with argon. The mixture was stirred at 90°C for 2 hours under heating. Then thereto was added ammonia water (15 ml), saturated salt solution (15 ml), water (15 ml) and ethyl acetate (100 ml) under ice cooling and the mixture was stirred and then separated. The aqueous layer was extracted with ethyl acetate and the layers of the extract were combined, washed with saturated salt solution and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the resulting brown oil (3,66 g) was purified column chromatography on silica gel (eluent: gradient of 5-20% mixture of ethyl acetate-chloroform), to thereby obtain compound 2 (1536 mg) as a pale yellow oil.

MS (APCI) 209 [M+H]+.

Reference example 12

Connection 1 (2,971 g) was dissolved in methanol (30 ml) and the solution was slowly added dropwise a solution of di-tert-BUTYLCARBAMATE (4,46 g) in methanol (30 ml) at room temperature. The mixture was stirred for 2.5 hours and the solvent is kept at reduced pressure. Then the residue was purified column chromatography on silica gel (eluent: hexane-ethyl acetate, 5:1), thus obtaining the compound 2 (a 2.71 g) as colorless powder.

MS (APCI) 251 [M+H]+.

Reference example 13-1

To a solution of compound 1 (of 3.78 g) in toluene (50 ml) was added dropwise a solution of compound 2 (2,50 ml) in toluene (10 ml) under ice cooling and the mixture was stirred at whom atoi temperature for 2 hours. The precipitate was separated by filtration and thereto was added 5% aqueous citric acid solution. The mixture was extracted with ethyl acetate. Layers of the extract were combined, washed with saturated salt solution and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the resulting oil was dissolved in ethanol (25 ml). Then to the solution was added potassium hydroxide (of 5.55 g) and the mixture is boiled under reflux by heating for 1 hour. The reaction mixture was cooled to room temperature and to it was added ethanol. The insoluble substance was separated by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified column chromatography on silica gel (eluent: chloroform-ethyl acetate, 10:1), thus obtaining the compound 3 (of 2.92 g) as a pale brown oil.

MS (APCI) 152 [M+H]+.

Reference examples from 13-2 to 13-12

The following compound was obtained by reaction and treatment in a manner analogous to the method of reference example 13-1.

0
Reference examplesRnMS (APCI) [M+H]+
13-22-OMe168
13-33-OMe0168
13-44-OMe0168
13-52-IU0152
13-63-IU0152
13-74-IU0152
13-83-F0156
13-94-F0156
13-104-AC0180
13-114-Cl-3-OMe0202/204
13-123-OMe1182

Reference example 14

To a solution of compound 1 (MT 19 : 18 g) and a mixture of ethyl acetate-hexane, 1:20-1:10, in ethanol (600 ml) was added dropwise a solution of compound 2 (54,1 ml) in ethanol (30 ml) at 3°C for 30 minutes. The reaction mixture was stirred at 7°C for 18.5 hours and to the mixture was added water (600 ml), was added Oxon (504,6 g) at 3°C. the Mixture was stirred at the same temperature for 3 hours. The insoluble substance was separated by filtration through celite and the filtrate was concentrated under reduced pressure and then extracted with ethyl acetate. Layers of the extract were combined, washed with saturated salt solution and dried over anhydrous sodium sulfate and the solvent is then drove away under reduced pressure. The residue was distilled under reduced pressure, thus obtaining the compound 3 (38,047 g).

Boiling point: 112-123°C/1 mm Hg

MS (APCI) 176 [M+NH4+2]+/174 [M+NH4]+.

NMR (DMSO-d6) ppm 2,12-2,17 (2H, m), 3,01 (3H, s), 3,22-of 3.25 (2H, m), 3,76 (2H, t, J=6.5 Hz).

Reference example 15-1

Compound 2 (1,38 g) was dissolved in toluene (17 ml) and to the solution was added compound 1 (4,01 ml). The mixture was boiled under reflux under heating for 2 days. The reaction mixture was cooled and then thereto was added an aqueous solution of sodium bicarbonate. The mixture was extracted with ethyl acetate. Layers of the extract were combined, washed with a saturated solution of the m salt, was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified column chromatography on silica gel (eluent: chloroform-ethyl acetate, 10:1), thus obtaining the compound 3 (1.10 g) as colorless crystals.

MS (APCI) 214 [M+H]+.

Reference examples from 15-2 to 15-8

The following compound was obtained by reaction and treatment in a manner analogous to the method of reference example 15-1.

Reference examplesRMS (APCI) [M+H]+
15-22-IU228
15-33-IU228
15-44-IU228
15-53-OMe244
15-63-OEt258
15-73-OiPr272
15-82,-OMe di 274

Reference example 16

Connection 1 (1.28 g), which are synthesized from the hydrobromide 3-bromopropylamine and aniline (1,38 g), stirred under heating at 110°C for 1 hour in argon atmosphere. The reaction mixture was cooled, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and saturated salt solution and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel (eluent: hexane-ethyl acetate, 2:1-1:1), thus obtaining the compound 2 (1.10 g) as a pale brown oil.

MS (APCI) 229 [M+H]+.

Reference example 17-1

The lithium perchlorate (of 14.76 g) suspended in diethyl simple ether (27.7 ml) and to the suspension was added compound 1 (1,38 ml) and compound 2 (1.23 ml) under cooling with ice. The mixture was stirred at room temperature for 1.5 hours and then poured into water and was extracted with chloroform. Layers of the extract were combined, washed with saturated salt solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified column chromatography on silica gel (eluent: gradient mixture of hexane-ethyl acetate), while receiving is connected to the e 3 (895 mg) as a colourless oil.

MS (APCI) 166 [M+H]+.

Reference examples 17-2 to 17-10

The following compound was obtained by reaction and treatment in a manner analogous to the method of reference example 17-1.

Reference examplesRMS (APCI) [M+H]+
17-23-OMe196
17-34-OMe196
17-42-OMe196
17-52,3-di-OMe226
17-63-Me180
17-73-F184
17-84-F184
17-92-F184
17-103-CN191

Reference example 18-1

Connection 1 (835 μl) was mixed with compound 2 (500 mg) and the mixture was stirred at 120°C for 1 hour. The reaction solution was left to cool when standing and to the solution was added 10% aqueous potassium carbonate solution. The mixture was extracted with chloroform. Layers of extract was combined, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified column chromatography on silica gel (eluent: chloroform-methanol, 1:30), thus obtaining the compound 3 (631 mg) as pale brown oil.

MS (APCI) 221 [M+H]+.

Reference examples 18-2 to 18-6

The following compound was obtained by reaction and treatment in a manner analogous to the method of the above reference example.

Reference examplesWMS (APCI) [M+H]+
18-2207
18-3 191
18-4188
Sheet 18-5174
18-6218

Reference example 19

Compound 2 was obtained according to the method described in J. Chem. Soc., 4166 (1957).

The melting point 36,0-37,5°C.

MS (APCI) 180 [M+H]+.

Reference example 20-1

(1)

Connection 1 (1.50 g) was dissolved in chloroform (22 ml) and to the solution was added pyridine (1,33 ml) under ice cooling and was added dropwise a solution carbobenzoxy (1,87 ml) in chloroform (5 ml) for 3 minutes. The mixture was stirred for 30 minutes. Then thereto was added 1 N. hydrochloric acid (22 ml) under ice cooling and the mixture was extracted with chloroform. Layers of the extract were combined, washed with saturated salt solution, dried over anhydrous sodium sulfate and the solvent is then drove away under reduced pressure. The residue was purified column chromatography on silica gel (eluent: chloroform-ethyl acetate, 6:1), thus obtaining the compound 2 (3006 mg) as a colourless oil.

(2) Compound 2 (100 mg) was dissolved in acetonitrile (25 ml) and to the solution was added N,N'-succinimidylester (1856 mg) and N,N'-dimethylaminopyridine (68 mg). The mixture was stirred at room temperature for 15 hours. Then thereto was added N,N'-succinimidylester (286 mg) and the mixture was stirred for 3 hours. Then thereto was added a solution of 2-methylaminoethanol (831 mg) in acetonitrile (3 ml) and the mixture was stirred at room temperature for 1 hour. Then thereto was added an aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The layer of the extract were combined, washed with saturated salt solution and dried over anhydrous sodium sulfate and the solvent is then drove away under reduced pressure. The residue was purified column chromatography on silica gel (eluent: ethyl acetate-chloroform, 3:2), thus obtaining the compound 3 (1876 mg) as a colourless oil.

MS (APCI) 373 [M+H]+.

(3) Compound 3 (1874 mg) was dissolved in methanol (25 ml) and to the solution was added 10% wet palladium on coal (583 mg). The mixture was vigorously stirred for 4 hours in hydrogen atmosphere. Palladium on coal was separated by filtration through celite and washed with a mixture of methanol-ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: chloroform-methanol 30:1), thus obtaining the compound 4 (904 mg) as a pale yellow oil.

MS (APCI) 239 [M+H]+.

Reference examples from 20-2 to 20-11

The following compounds which were alocale reaction and processing method similar to the above reference example.

Reference examplesRnWMS (APCI) [M+H]+
20-2N0-NHMe195
20-3N0-NMe2209
20-4N0265
20-5N0-NH(CH2)2OH225
20-6N0-NH(CH2)3HE239
20-73-OMe0-NHMe 225
20-8N1-NHMe209
20-9N1-N(Me)(CH2)2OH253
20-10N1-NH(CH2)2OH239
20-11N1-NH(CH2)3OH253

Reference example 21

(1) To a solution of compound 1 (3.0 g) in THF (18 ml) was added dropwise a 2.0 n solution of dimethylamine in THF (17,8 ml) under cooling with ice. The mixture was stirred for 20 minutes under ice cooling and then to the reaction mixture were added ice-cold water. The mixture was extracted with ethyl acetate. Layers of the extract were combined, washed with saturated salt solution and dried over anhydrous sodium sulfate and the solvent is then drove away under reduced pressure. The residue was purified column chromatography on silica gel (eluent: hexane-ethyl acetate, 3:1), thus obtaining the compound 2 (1642 mg) as a colorless oil./p>

MS (APCI) 205/203 [M+H]+.

(2) To aniline (1,03 g) was added compound 2 (820 mg) and the mixture was stirred at 120°C for 5 hours. Then thereto was added a hot toluene (2.2 ml) and the mixture is then left to cool when standing. Then to the mixture was added ethyl acetate (4,4 ml) and the mixture was stirred for 1 hour. The precipitated insoluble substance was separated by filtration and washed with ethyl acetate. To the filtrate was added an aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. Layers of the extract were combined, washed with saturated salt solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluent: hexane-ethyl acetate, 3:1-1:1), thus obtaining the compound 3 (141 mg) as colorless powder.

MS (APCI) 291 [M+H]+.

(3) Compound 3 (820 mg) was subjected to reaction or processed m-anisidine (1,36 g) in the same way as described above in (2), thus obtaining the compound 4 (325 mg) as pale brown oil.

MS (APCI) 351 [M+H]+.

Reference example 22

To a solution of compound 1 (600 mg) in THF (9 ml) was added dropwise complex 1,17 M borane-THF (4,81 ml) under cooling with ice for 3 minutes. The mixture was stirred at room temperature for 15 hours, and thereto were added to complement the local complex 1,17 M borane-THF (2.4 ml). The mixture was stirred at 30°C for 6 hours under heating. Then it was added to 0.5 N. aqueous solution of sodium hydroxide under ice cooling and the mixture was stirred for 30 minutes and then was extracted with ethyl acetate. Layers of the extract were combined, washed with saturated salt solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel, thus obtaining the compound 2 (495 mg) as a colourless oil.

MS (APCI) 200 [M+H]+.

Reference example 23

(1) Thiomorpholine (11,55 g) was dissolved in THF (120 ml) and to the solution was added triethylamine (13,6 g) and was added dropwise a solution of di-tert-BUTYLCARBAMATE (25,7 g) in THF (80 ml) under cooling with ice for 20 minutes. The mixture was stirred at room temperature for 4 hours, and thereto was added ethyl acetate. The organic layer was washed with an aqueous solution of citric acid and saturated salt solution and dried over anhydrous sodium sulfate and the solvent is then drove away under reduced pressure. The residue was purified by chromatography on a short column of silica gel (eluent: chloroform), to thereby obtain compound 1 (22,2 g) as colorless crystals.

(2) Compound 1 (11.1 g) was dissolved in chloroform (220 ml) and to the solution was added m-chloroperbenzoic Ki the lot (23,6 g) under cooling with ice for 30 minutes. The mixture was stirred for 1 hour under ice cooling, gave her the opportunity to warm to room temperature and then was stirred for 20 hours. To aqueous sodium bicarbonate solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. Layer extract was washed with saturated aqueous sodium bicarbonate solution and saturated sodium bicarbonate and dried over anhydrous sodium sulfate and the solvent is then drove away under reduced pressure. The residue was purified column chromatography on silica gel (eluent: chloroform-methanol, 100:1-30:1), thus obtaining the compound 2 (of 8.92 g) as colorless powder.

MS (APCI) 253 [M+NH4+]+.

(3) Compound 2 (2.00 g) was dissolved in chloroform (8.5 ml) and to the solution was added triperoxonane acid (8.5 ml) under cooling with ice. The mixture was allowed to warm to room temperature and then was stirred for 30 minutes. The mixture was concentrated under reduced pressure and to the residue was added diisopropyl simple ether and the mixture was again concentrated under reduced pressure. The residue is triturated with diisopropyl ether, thus obtaining the compound 3 (2.10 g) as colorless powder.

(4) Compound 3 (2.10 g) suspended in ethanol (43 ml) and to the suspension was added sodium bicarbonate (2.14 g) at room temperature. After 5 minutes the mixture on balali 2 bromoethoxy-tert-butyldimethylsilyl (2,74 ml) and the mixture was stirred at 60°C for 3 hours. The mixture was allowed to warm to 80°C and was stirred for 4 days when heated. Then thereto was added 2-bromoethoxy-tert-butyldimethylsilyl (0,91 ml) and sodium bicarbonate (0.71 g) and the mixture was stirred at 80°C for an additional 1 day when heated. The reaction mixture was cooled and thereto was added water. The mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated salt solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluent: ethyl acetate-chloroform, 1:5), thus obtaining the compound 4 (1,94 g) as colorless crystals.

MS (APCI) 294 [M+H]+.

(5) Compound 4 (1,94 g) suspended in THF (10 ml) and to the suspension was added 1 n solution of tetrabutylammonium fluoride in THF (to 9.9 ml, 9.9 mmol) at room temperature. The mixture was stirred for additional 1 hour. The mixture was concentrated under reduced pressure and then the residue was purified column chromatography on NH-silica gel (eluent: chloroform-methanol, 100:1), thus obtaining the compound 5 (1,100 g) as colorless crystals.

MS (APCI) 180 [M+H]+.

(6) Compound 5 (2.50 g), compound 6 (of 4.66 g) and triphenylphosphine (5.49 g) was dissolved in chloroform (70 ml) and to the solution was added dropwise a 40% solution of DEAD in toluene (9,10 ml) for 5 m the chickpeas while cooling with ice. The mixture was allowed to warm to room temperature and then was stirred for 1 hour. To the reaction mixture were added toluene (5 ml) and the precipitate was separated by filtration and washed with a mixture of chloroform-toluene (5:1). The filtrate was concentrated under reduced pressure and was purified column chromatography on silica gel (eluent: ethyl acetate-chloroform, 1:20), thus obtaining the compound 7 (6,07 g) as a colourless foam.

MS (APCI) 440 [M+H]+.

[Compound 6]

Aniline (to 4.41 g) was dissolved in THF (90 ml) and to the solution was added triethylamine (at 7.55 ml) and portions were added 2-nitrobenzenesulfonamide (10.0 g) under cooling with ice. The mixture was allowed to warm to room temperature and then was stirred for 3 hours. The reaction mixture was poured into a 0.5 N. hydrochloric acid and was extracted with ethyl acetate. Layers of the extract were combined, washed with saturated salt solution and dried over anhydrous sodium sulfate and the solvent is then drove away under reduced pressure. The residue was led by addition of diisopropyl simple ether, thus obtaining the compound 6 (9,54 g).

MS (ESI) 277 [M-N]-.

(7) 60% sodium hydride (829 mg) suspended in THF (69 ml) under ice cooling, and to the suspension was added 1-dodecanthiol (from 5.29 ml). The mixture was stirred at room temperature for 16 hours. Then to Speedball solution of compound 7 (6,07 g) in THF (104 ml) over 10 minutes under ice cooling and the mixture was stirred at room temperature for 2 hours. Then to the mixture was added to a suspension of 60% sodium hydride (276 mg) and 1-dodecanethiol (1,98 ml) in THF (23 ml) and the mixture was stirred at room temperature for 1 hour. Then to the reaction mixture was added a suspension of 60% sodium hydride (276 mg) and 1-dodecanethiol (1,98 ml) in THF (23 ml) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a solution of acetic acid (1,98 ml) in a saturated salt solution (360 ml) and was extracted with chloroform. Layers of the extract were combined, washed with saturated salt solution and dried over anhydrous sodium sulfate and the solvent is then drove away under reduced pressure. The resulting residue was purified column chromatography on silica gel (eluent: chloroform-methanol, 200:1-70:1) and the resulting oil was led by addition of hexane, thus obtaining the compound 8 (2,802 g) as colorless crystals.

MS (APCI) 255 [M+H]+.

Reference example 24-1

(1) a Mixture of 1-bromo-2-chlorethane (14.3 g) and aniline (28,0 g) was stirred at 60-70°C for 1.5 hours under heating. The reaction mixture was cooled and thereto was added ethyl acetate (80 ml). The precipitated solid was separated by filtration. The filtrate was concentrated under reduced pressure and the residue was purified column chromatography on silica gel (chloroform-hexane, 1:1-2:3), procapra this connection 1 (3,40 g) as pale brown oil.

MS (APCI) 156/158 [M+H]+.

(2) Compound 1 (202 mg) and 1-acetylpiperidine (416 mg) was dissolved in acetonitrile (3.9 ml) and to the solution was added potassium carbonate (359 mg) and sodium iodide (19 mg). The mixture was stirred at 95°C for 24 hours under heating. The reaction solution was cooled and thereto was added water. The mixture was extracted with ethyl acetate. Layers of the extract were combined, washed with saturated salt solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluent: chloroform-methanol, 99:1-91:9), thus obtaining the compound 2 (251 mg) as a colourless oil.

MS (APCI) 248 [M+H]+.

Reference example 24-2

Compound 1 (300 mg) and 2-piperazinone (483 mg) was dissolved in acetonitrile (6 ml) and to the solution was added potassium carbonate (533 mg) and sodium iodide (29 mg). The mixture was stirred at 90°C for 3 days when heated. The reaction solution was cooled and thereto was added water. The mixture was extracted with ethyl acetate. Layers of the extract were combined, washed with saturated salt solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluent: chloroform-methanol, 98:2-90:10), thus obtaining the compound 1 (239 mg) as a colourless mass is A.

MS (APCI) 220 [M+H]+.

Reference example 24-3

(1)

Compound 1 (1.0 g) was dissolved in chloroform (20 ml) and to the solution was added triethylamine (1.35 ml) and was added dropwise benzylchloride (1,38 g) under cooling with ice. Then to the mixture was added pyridine (783 ml) and was added dropwise benzylchloride (1.73 g) and gave her the opportunity to slowly warm to room temperature and stirred it at the same temperature. The reaction mixture was concentrated under reduced pressure and to the residue was added water. The mixture was extracted with ethyl acetate. Layers of the extract were combined, washed with hydrochloric acid and a saturated salt solution and dried over anhydrous magnesium sulfate and the solvent is then drove away under reduced pressure. The residue was purified column chromatography on silica gel (eluent: hexane-ethyl acetate, 9:1), thus obtaining the compound 2 (1,2846 g) as a pale yellow oil.

MS (APCI) 290/292 [M+H]+.

(2) sodium Hydride (144 mg) suspended in DMSO (6 ml) and stirred at 70°C. the Suspension was cooled to room temperature and to it was added a solution of 1-tert-butoxycarbonyl-3-oxopiperidine (600 mg) in DMSO (10 ml) and was added dropwise a solution of compound 2 (956 mg) in DMSO (4 ml). The mixture was stirred at room temperature for 3 hours and then stirred at 50°C for hours. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. Layers of the extract were combined, washed with saturated salt solution and dried over anhydrous magnesium sulfate and the solvent is then drove away under reduced pressure. The residue was purified column chromatography on silica gel (eluent: hexane-ethyl acetate, 1:1-1:2), thus obtaining the compound 3 (505,9 mg) as a colorless amorphous powder.

MS (APCI) 454 [M+H]+.

(3) Compound 3 (150 mg) was dissolved in methanol (3 ml) and to the solution was added 10% palladium on coal (75 mg). The mixture was subjected to catalytic hydrogenation in a hydrogen atmosphere at room temperature and at ambient pressure. The catalyst was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluent: hexane-ethyl acetate, 1:1-1:4), thus obtaining the compound 4 (39.9 mg) as a colourless oil.

MS (APCI) 320 [M+H]+.

Reference example 25-1

(1)

Compound 1 (10.0 g) was dissolved in 48% solution of hydrogen bromide in water (140 ml) and the solution was stirred at 140°C for 15 hours under heating. The reaction solution was cooled to room temperature and the solvent drove away. To the residue was added diethyl simple ether and slowly added an aqueous solution of sodium bicarbonate when is remesiana and while cooling with ice. The mixture was separated and the organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is kept under reduced pressure and the resulting residue was purified column chromatography on silica gel (eluent: n-hexane-ethyl acetate, 9:1), thus obtaining the compound 2 (11.6 g) as a pale yellow oil.

MS (APCI) 200/202 [M+H]+.

(2) Compound 2 (5,63 g) was dissolved in acetonitrile (150 ml) and to the solution was added potassium carbonate (9.75 g), sodium iodide (0,42 g) and compound 3 (7,86 g). The mixture was stirred at 90°C for 5 hours. The reaction solution was cooled to room temperature and the solvent drove away. Then to the residue was added a saturated salt solution and the mixture was extracted with ethyl acetate. Layer extract was dried over anhydrous magnesium sulfate and the solvent is kept at reduced pressure. The residue was purified column chromatography on silica gel (eluent: n-hexane-ethyl acetate, 20:1-3:2), thus obtaining the compound 4 (of 7.69 g) as a pale yellow oil.

MS (APCI) 306 [M+H]+.

Reference example 25-2

To a solution of compound 1 (475 mg) in acetonitrile (8 ml) was added triphenylphosphine (1.24 g). Then to the solution was added dropwise a solution of tetrabromide carbon (1.56 g) in acetonitrile (8 ml) under stirring and cooling with ice. The mixture was stirred at the room for the Noah temperature for 1 hour and the solvent drove away. To the residue was added saturated aqueous sodium bicarbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is kept under reduced pressure and the resulting residue was purified column chromatography on silica gel (eluent: n-hexane-ethyl acetate, 20:1-5:1), thus obtaining the compound 2 (456 mg) as a pale yellow oil.

MS (APCI) 214/216 [M+H]+.

(2) Compound 2 (349 mg) was dissolved in acetonitrile (8 ml) and to the solution was added potassium carbonate (452 mg), sodium iodide (24 mg) and compound 3 (461 mg). The mixture was stirred at 75°C for 5 hours. The reaction solution was cooled to room temperature and the solvent is distilled off. To the residue was added saturated aqueous sodium bicarbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is kept under reduced pressure and the resulting residue was purified column chromatography on silica gel (eluent: methanol-chloroform, 0:1-1:10), thus obtaining the compound 4 (168 mg) as a pale yellow oil.

MS (APCI) 262 [M+H]+.

The following compound was obtained by reaction and treatment in a manner analogous to the method of the above reference example.

Reference examplesRWMS (APCI) [M+H]+
25-33-IU262
25-43-Cl282/284
25-5N306
25-6N209
25-7N269
25-8N283
25-9N262
25-10-N(Me)(CH2)2NHMe208

Reference example 26-1

(1) Compound 1 (1,041 g), compound 2 (1.20 g) and triphenylphosphine (1.70 g) was dissolved in chloroform (21 ml) and to the solution was added dropwise a 40% solution of DEAD in toluene (2,81 ml) for 3 minutes under ice cooling. The mixture was allowed to warm to room temperature and the mixture was stirred for 17 hours. The reaction mixture was concentrated under reduced pressure and to the residue was added hexane. The precipitate was separated by filtration and washed with hexane-chloroform (1:1). The filtrate was concentrated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: hexane-ethyl acetate, 4:1-3:1), thus obtaining the compound 3 (1055 mg) as a colourless oil.

MS (APCI) 479 [M+H]+.

(2) 60% sodium hydride (52 mg) suspended in THF (5.5 ml) and to the suspension was added 1-dodecanthiol (324 μl) under ice cooling. The mixture was allowed to warm to room temperature and was stirred for 30 minutes. Then to the mixture was added a solution of compound 3 (500 mg) in THF (5.5 ml) under ice cooling and the mixture was allowed to warm to room temperature and then was stirred for 19 hours. Then to the reaction mixture was added to a suspension of 60% of the hydride into three is (13 mg) and 1-dodecanethiol (91 μl) in THF (3 ml) and the mixture was stirred at room temperature for 4 hours. To the reaction mixture were added a saturated salt solution and the mixture was extracted with ethyl acetate. Layers of the extract were combined and dried over anhydrous sodium sulfate and the solvent is then drove away under reduced pressure. The residue was purified column chromatography on silica gel (eluent: hexane-ethyl acetate, 5:1), thus obtaining the compound 4 (206 mg) as a colourless oil.

MS (APCI) 277 [M+H]+.

Reference example 26-2

(1) Compound 1 (150 mg), compound 2 (300 g) and triphenylphosphine (425 g) was dissolved in chloroform (5,4 ml) and to the solution was added dropwise a 40% solution of DEAD in toluene (0,704 ml) for 1 minute under cooling with ice. The mixture was allowed to warm to room temperature and was stirred for 4 hours. The reaction mixture was concentrated under reduced pressure and to the residue was added hexane. The precipitate was separated by filtration and washed with hexane-chloroform (1:1). The filtrate was concentrated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: a mixture of 1:1 chloroform-ethyl acetate to ethyl acetate), to thereby obtain compound 3 (395 mg) as colorless foam.

MS (APCI) 376 [M+H]+.

(2) 60% sodium hydride (63 mg) was dissolved in THF (10.5 ml) and to the solution was added 1-dodecanthiol (402 μl) under ice cooling. The mixture was allowed to heat the I to room temperature and was stirred for 30 minutes. Then to the mixture was added a solution of compound 3 (394 mg) in THF (2 ml) under ice cooling and the mixture was allowed to warm to room temperature and then was stirred for 2 hours. To the reaction mixture were added a saturated salt solution and the mixture was extracted with ethyl acetate. Layers of the extract were combined and dried over anhydrous sodium sulfate and the solvent is then drove away under reduced pressure. The residue was purified column chromatography on silica gel (eluent: gradient from ethyl acetate to a mixture of 1%-3% ethyl acetate-methanol), to thereby obtain compound 4 (334 mg) as a colorless amorphous powder.

MS (APCI) 461 [M+H]+.

The following table shows the chemical structure and property data of the compounds of the above examples.

1. The compound of formula (1)

where the ring X represents a benzene or pyridine;
R1represents a substituted alkyl;
R2represents optionally substituted aryl or optionally substituted 4-7-membered monocyclic heterocyclic group or optionally substituted condensed heterocyclic group group with a benzene ring, where the substituents optionally substituted aryl, optionally substituted 4-7-membered monocyclic heterocyclic group and optionally substituted condensed heterocyclic group group with the benzene ring selected from the group consisting of:
(1) alkyl, neoba is consequently substituted by group(s), selected(I) from halogen and alkoxycarbonyl,
(2) alkoxy, optionally substituted with halogen(s),
(3) halogen,
(4) 4-7-membered monocyclic heterocyclic group, or
(5) amino, optionally mono - or disubstituted by alkyl, and
(6) hydroxyl,
R3represents hydrogen or alkyl;
R4represents hydrogen, halogen or alkyl;
R5represents hydrogen or alkyl;
R6and R7are the same or different and each represents hydrogen or halogen; or its pharmaceutically acceptable salt.

2. The compound of the formula (1-a)

where the ring X represents a benzene or pyridine;
R1represents a substituted alkyl;
R2represents optionally substituted aryl or optionally substituted 4-7-membered monocyclic heterocyclic group or optionally substituted condensed heterocyclic group group with a benzene ring, where the substituents optionally substituted aryl, optionally substituted 4-7-membered monocyclic heterocyclic group and optionally substituted condensed heterocyclic group group with the benzene ring selected from the group consisting of:
(1) alkyl, optionally substituted by group(s)selected(s) halogen and alcox is carbonyl,
(2) alkoxy, optionally substituted with halogen(s),
(3) halogen,
(4) 4-7-membered monocyclic heterocyclic group, or
(5) amino, optionally mono - or disubstituted by alkyl, and
(6) hydroxyl,
R3represents hydrogen or alkyl;
R4represents hydrogen, halogen or alkyl;
R5represents hydrogen or alkyl;
R6and R7are the same or different and each represents hydrogen or halogen; or its pharmaceutically acceptable salt.

3. The compound or its pharmaceutically acceptable salt according to any one of claims 1 or 2, where R1represents alkyl, substituted 1 or 2 groups selected from
(1) hydroxyl,
(2) amino, optionally substituted by group(s)selected from the following groups (a) to (K):
(A) alkyl, optionally substituted alkoxy,
(B) alkanoyl, optionally substituted 1 or 2 groups selected from the group a,
(C) alkanolamine,
(D) alkoxycarbonyl, optionally substituted 1 or 2 groups selected from the group b,
(E) alkylsulfonyl, optionally substituted 1 or 2 groups selected from the group C,
(F) sulfonyl, substituted 4-7-membered monocyclic heterocyclic group, optionally substituted 1 or 2 groups selected from the group d,
(G) arylcarbamoyl,
(H) aralkylamines,
(I) aminosulfonyl is, optionally mono - or disubstituted by alkyl,
(J) cycloalkylcarbonyl, optionally substituted by hydroxyl or cyano, or
(K) carbamoylethyl, optionally mono - or disubstituted by alkyl,
[Group a]
(a) alkoxy,
(b) cyano,
(c) 4-7-membered monocyclic heterocyclic group, optionally substituted by 1-3 groups selected from halogen, cyano, hydroxyl, alkoxycarbonyl and alkyl, optionally substituted by 1-3 groups selected from halogen and alkoxy,
(d) amino, optionally substituted 1 or 2 groups selected from the following groups (i) to (iii),
(i) alkyl, optionally substituted by a group selected from alkoxy, cyano and alkylsulfonyl, and amino, optionally substituted 1 or 2 groups selected from alkylsulfonyl and alkyl,
(ii) alkoxycarbonyl and
(iii) alkanoyl, optionally substituted by a group selected from alkoxy, cyano, amino, optionally mono - or disubstituted by alkyl,
(e) alkylsulfonyl,
(f) hydroxyl, and
(g) halogen,
[Group b]
(a) alkoxy and
(b) hydroxyl,
[Group]
(a) alkoxy and
(b) hydroxyl,
[Group d]
(a) hydroxyl,
(b) alkyl,
(c) halogenated and
(d) alkoxycarbonyl;
(3) alkylsulfonyl;
(4) alkoxy;
(5) 4-7-membered monocyclic heterocyclic group, optionally substituted by group(s)selected(I) from (A) oxo, (C) alkoxycarbonyl, (alkanoyl, optionally substituted by cyano, (D) alkyl, optionally substituted by hydroxyl, (E) alkylsulfonyl, (F) alkylsulfonyl, (G) carbonyl, substituted 4-7-membered monocyclic heterocyclic group, (H) aminosulfonyl, optionally mono - or disubstituted by alkyl, (I) carbamoyl, optionally mono - or disubstituted by alkyl, or (J) halogen;
(6) ureido, optionally substituted alkyl, optionally substituted by a group selected from alkoxy and hydroxyl;
(7) carbanilate, optionally substituted by group(s)selected(s) (A) 4-7-membered monocyclic heterocyclic group, and (C) alkyl, optionally substituted by group(s)selected(and) (and) alkoxy, (b) hydroxyl, (C) cyano, (d) carbamoyl, optionally substituted by alkyl(s); and
(8) carbonyloxy, substituted 4-7-membered monocyclic heterocyclic group optionally substituted by group(s)selected(I) from (A) hydroxyl, (b) alkyl, (C) hydroxyalkyl, (D) alkanoyl.

4. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 2, where R2represents an optionally substituted benzene.

5. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 2, where R3and R4represent hydrogen.

6. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 2, where R3 represents hydrogen and R4represent alkyl.

7. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 2, where R3represents alkyl and R4represents hydrogen.

8. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 2, where R3represents hydrogen and R4represent halogen.

9. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 2, where R6and R7represent hydrogen.

10. Blocker IKurcontaining as active ingredient the compound or its pharmaceutically acceptable salt according to any one of claims 1 to 2.

11. Prophylactic or therapeutic agent from a cardiac arrhythmia, comprising as active ingredient the compound or its pharmaceutically acceptable salt according to any one of claims 1 to 2.

12. Prophylactic or therapeutic agent from atrial fibrillation, comprising as active ingredient the compound or its pharmaceutically acceptable salt according to any one of claims 1 to 2.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted methyl-amines of general formula 1, having serotonin 5-HT6 receptor antagonist properties. In formula 1 , W is naphthalene, indolysin or quinoline; R1 is hydrogen, fluorine, chlorine, methyl; R2 is hydrogen, fluorine, methyl, phenyl, thiophen-2-yl, furan-2-yl, pyridyl, piperazin-1-yl or 4-methylpiperazin-1-yl; R3 is methyl; or W is benzene, R3 assumes the value given above; R1 is 3-Cl, R2 is 3-piperazin-1-yl or 3-(4-methylpiperazin-1-yl); or R1 is hydrogen, R2 is phenyl or pyridyl; or R1 is hydrogen, fluorine, chlorine, methyl; R2 is 4-piperazin-1-yl or 4-(4-methylpiperazin-1-yl); or W is oxazole, R3 is optionally substituted methyl; R1 is chlorine or fluorine, R2 is methyl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is piperazin-1-yl, 4-methylpiperazin-1-yl, or R1 is chlorine, fluorine or methyl; R2 is furan-2-yl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is furan-2-yl, R3 is (tetrahydrofuran-2-yl)methyl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is thiophen-2-yl, R3 is 2-methoxyethyl, or R1 is chlorine or fluorine, R2 is thiophen-2-yl, R3 is methyl.

EFFECT: compounds can be used to treat central nervous system (CNS) diseases, such as psychiatric disorders, schizophrenia, anxiety disorders, as well as for improving mental capacity, for treating obesity or for studying the molecular mechanism of inhibiting serotonin 5-HT6 receptors.

15 cl, 27 dwg, 2 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the field of chemistry of heterocyclic compounds, and in particular to the compound of formula where X denotes a phenyl group; R1, R3 and R4 denote hydrogen atoms; R2 denotes a non-saturated monocyclic heterocyclic group containing 5 or 6 atoms including from 1 to 2 heteroatoms chosen from N and O; the mentioned heterocyclic group can be replaced by the group -NRcRd; Rc and Rd denotes hydrogen; in the form of a hexone base or acid additive salt. The invention also refers to a drug and pharmaceutical composition based on the formula (I) compound, to application of the formula (I) compound for preparation of the drug. Besides, the invention describes the compound of phenyl[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]piridin-2-yl]methanone and its application in synthesis of the formula (I) compounds.

EFFECT: new compounds of imidazo[1,2-a]piridines that are applicable in treatment or prevention of diseases in which NOT receptors are active.

15 cl, 2 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the field of organic chemistry, notably to derivatives of dihydroimidazole with the general formula (I) and to its pharmaceutically acceptable salts where X1 and X2 denote halogen; R1 and R2 are chosen from the group including -H, -CH3, -CH2CH3 on the condition that both R1 and R2 do not denote hydrogen; R3 denotes -H or -C(=O)-R7; and if R6 denotes hydrogen, then R4 denotes -OCH3, -OCH2CH3 or -OCH(CH3)2; R5 denotes -H, - halogen, -CF3, -OCH3, -C(CH3)2, - cyclopropyl, - cyano group, -C(CH3)3, -C(CH3)2OR (where R denotes -H), -C(CH3)2CH-OR (where R denotes -CH3), -C(CH3)2CN, -C(CH3)2COR (where R denotes -CH3), -SR (where R denotes -CH2CH3) or -SO2R (where R denotes -CH3, -CH2CH3, 1-pyrrolidine, -NH-tert-butyl); and if R6 does not denote hydrogen, then R4 denotes -OCH2CH3; R5 denotes hydrogen, -Cl, -OCH3, tert butyl; R6 denotes -Cl, cyclopropyl, -SO2R (where R denotes -CH3, 1-pyrrolidine, -NH-tert-butyl or -N(CH3)2); and R7 is chosen from the group including i) -CH3, -CH(CH3)2, -CH2CH(CH3)2, cyclopropyl, cyclobutyl, -CH2CH2Ph, 2-furanyl, phenyl or phenyl substituted with chlorine, -OCH3 or cyano group, ii) 1-piperidinyl, iii) -NRc2 (where Rc denotes -CH2CH2OH, -CH2CH2OCH3 or -CH2CH(OH)CH2OH, iv) substituted piperazidine with the formula where R is chosen from the group including a) hydrogen, c) -CH(CH3)2, k) -CH2CH2Rd (where Rd denotes -OH, -OCH3, -CF3, -SO2CH3, -NH2, -NHCOCH3, -NHSO2CH3, 4-morfolinil, 2-izotiazolidinil-1, 1-dioxide), l) -CH2CH2CH2Re (where Re denotes -OCH3, -SO2CH3, -SO2CH2CH3, -CN), m) -CH2-CO-Rh (where Rh denotes -NH2, 1-pyrrolidinyl, 4-morfolinil), n) -SO2Ri (where Ri denotes -CH3, -CH2CH3), o) -CORj (where Rj denotes -CH3, 2-tetrahydrofuranyl, -NH2, -N(CH3)2), p) 4-tetrahydro-2H-thiopiranyl-1,1-dioxide, q) 4-piperidinyl-1-acetyl, r) 4-piperidinyl-1-dimethylcarboxamide, and s) 3-tetrahydrothiophenyl-1,1-dioxide; v) substituted oxopiperazine with the formula where R denotes -H; and vi) substituted piperidine with the formula where R denotes -CONH2, -OH, -CH2OH, -CH2CH2OH, 1-pyrrolidinyl, 1-piperidinyl, 1-(4-methylpiperazinyl) or 4-morfolinil. Moreover, the invention refers to the pharmaceutical composition based on the compound with the formula (I), to application of the formula (I) compound for production of a drug, to the production process of the formula (I) compound.

EFFECT: new derivatives of dihydroimidazole that may be used as anticancer drugs.

40 cl, 204 ex

Antiviral compouds // 2441869

FIELD: pharmacology.

SUBSTANCE: invention refers to the new compounds or its pharmaceutically acceptable salts where the compound has formula I possessing the activity towards hepatitis C virus (HCV). In the compound of formula I, Each W1 and W2 means nitrogen, W3 is chosen out of group consisting of nitrogen and -CH-, and W4 is -CH-; A is phenyl and is not mandatory substituted, X is chosen out of group consisting out of bond, -O- and -S-, Z is chosen out of group consisting of -CH2- and -NH-; R22 is chosen out of group consisting of hydrogen, benzimidazole, indole and thiophene, where R22 is not mandatory substituted, Y is chosen out of group consisting of C(O)N(R15)- and -N(R15)C(O)-, where R15 in each case is chosen out of group consisting of hydrogen and C1-C6alkyl; R50 is -L1-A1 where L1 is chosen out of group consisting of bond and C1-C6alkylene, and A1 is chosen out of group consisting of phenyl, pyridyl, benzothiazolyl, thiadiazole, isothiazole and thiophene, where A1 is not mandatory replaced, each R10 and R35 means hydrogen; R17 is C1-C6alkyl; and each C3-C18carbocyclil and M3-M18heterocyclil in -LE-Q-LE-(C3-C18carbocyclil) and -LE-Q-LE-( M3-M18heterocyclil) is not mandatory independently substituted in each case.

EFFECT: enhanced cure of hepatitis C.

13 cl, 12 dwg, 459 ex

Antiviral compound // 2441010

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds or their pharmaceutically acceptable salts where the compound has formula (I). The compounds have the properties of hepatitis C virus (HCV) replication inhibition and can be used for treating HCV-infection. In formula (I) B represents heterocyclyl selected from thieno, thiazolo, pyrazolo, pyrido and pyrimidogroup with B being optionally substituted by one or more R18, A represents phenyl which is optionally substituted by one or more R18; each W1 and W2 are independently selected from N or C(R33); Z represents -NH-; each R10 and R33 containing of hydrogen; X is selected from a group consisting of -Ls-O-, -Ls-S-; R22 means hydrogen or phenyl optionally substituted by one or more R26 ; Y is selected from a group consisting of -Ls-O-, -Ls-S-; -Ls-C(O)- and -Ls-NH(SO)2-; R50 represents -L1-A1, where L1 represents a bond, and A1 is selected from a group consisting of carbocyclyl where carbocyclyl represents phenyl or C3-C6carbocyclyl, banzimidazolyl and C1-C6alkyl optionally substituted by phenyl where A1 is optionally substituted by one or more R30 ; the substitute values are specified in the patent claim.

EFFECT: preparing the compounds exhibiting the properties of hepatitis C virus replication inhibition.

17 cl, 8 dwg, 255 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to imidazopyridines of formula I

and to their pharmaceutically acceptable salts where Z1 represents CR1; R1 represents H; R1' represents H; Z2 represents CR2; Z3 represents CR3 or N; R2 and R3 are independently selected from H, halogen; R4 represents H; Y represents W-C(O)-; W represents or , R5 represents H; X1 is selected from R11' and -OR11'; each R11 independently represents H, C1-C12alkyl, C2-C8alkenyl; X4 represents , R6 represents H, halogen, cyclopropyl or -(CR19R20)n-SR16; R6 represents H, halogen; p represents 0, 1, 2 or 3; n represents 0, 1 or 2; where each specified alkyl in R11 is independently substituted by one or two groups independently selected from halogen, -(CR19R20)nOR16 and R21; each R16 independently represents H, C1-C12alkyl; R19 and R20 are independently selected from H, C1-C12alkyl; R21 represents cyclopropyl.

EFFECT: invention refers to a pharmaceutical composition for treating hyperproliferative disorder.

10 cl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula:

in which: X represents one of the following groups: - a phenyl group optionally substituted by one or more groups, optionally selected from one of the following atoms and groups: halogen, (C1-C6)alkoxy, (C1-C6)alkyl, (C3-C7)cycloalkyl(C1-C6)alkyl, (C3-C7)cycloalkyl(C1-C6)alkoxy, NRaRb, R1 represents hydrogen atom, halogen, (C1-C6)alkoxy, (C1-C6)alkyl, (C3-C7)cycloalkyl(C1-C6)alkyl, (C3-C7)cycloalkyl(C1-C6)alkoxy, amino, the group NRcRd; with the alkyl and alkoxy groups being optionally substituted by one or more halogens, hydroxy, amino or (C1-C6)alkoxy, R2 represents one of the following groups: -hydrogen atom, - (C1-C6)alkyl group optionally substituted by one or more groups optionally substituted by hydroxy, halogen, amino, the group NRaRb, the phenyl group, the - (C1-C3)alkoxygroup optionally substituted by one or more groups independently selected from hydroxy, halogen, amino, the group NRaRb, - (C3-C7)cycloalkyl((C1-C6)alkyl, - (C3-C7)cycloalkyl(C1-C6)alkoxy, -(C2-C6)alkenyl, - (C2-C6)alkinyl, - the group -CO-R5,- the group -CO-NR6R7,- the group -CO-O-R8,- the group -NR9-CO-R10,- the group -NR11R12,- halogen atom,- the cyanogroup,- the phenyl group optionally substituted by one or more groups optionally selected from the following atoms and groups: halogen, (C1-C6)alkoxy, NRaRb, -CO-R5, -CO-NR6R7, -CO-O-R8, (C3-C7)cycloalkyl(C1-C6)alkyl, (C3-C7)cycloalkyl(C1-C6)alkoxy, (C1-C6)alkyl group optionally substituted by one or more hydroxy groups or NRaRb R3 represents hydrogen atom, (C1-C6)alkyl, (C1-C6)alkoxy or halogen atom, R4 represents hydrogen atom, (C1-C4)alkyl, (C1-C4)alkoxy or fluorine atom, R5 represents hydrogen atom, the phenyl group or (C1-C6)alkyl, R6 and R7, the same or different represents hydrogen atom or (C1-C6)alkyl, or together with nitrogen atom forms a 4-7-member cycle optionally containing the other heteroatom selected from N, O or S,R8 represents (C1-C6)alkyl, R9 and R10, the same or different, represent hydrogen atom or (C1-C6)alkyl, R11 and R12, the same or different, represent (C1-C6)alkyl, or together with nitrogen atom form a 4-7-member cycle optionally containing the other heteroatom selected from N, O or S, Ra and Rb independently represent hydrogen atom, (C1-C6)alkyl or together with nitrogen atom form a 4-7-member cycle, Rc represent hydrogen atom, and Rd represents (C1-C6)alkyl and at least one of the substitutes R1, R2, R3 and R4 are different from hydrogen; and when R3 means methyl, X is unsubstituted; when R1 means methyl, X is unsubstituted; when R2 means chlorine, X is other than parafluorophenyl; in the form of a base or an acid addition salt. The invention also refers to the compounds selected from the group, to a drug, to a pharmaceutical composition, as well as to application of the compounds of formula (I) by any of cl. 1-4.

EFFECT: preparing new biologically active compounds for treating or preventing the diseases associated with nuclear receptor NOT.

13 cl, 18 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to novel synthesis of 11H-indolo[2,3-c]quinoline derivatives of formula I, which can be used in synthesis of novel preparations for pharmaceutical purposes. In the method of producing 11H-indolo[2,3-c]quinoline derivatives of general formula I

indexRR1R2НННIbClННIcClОСН3ОСН3IdСН3ННIeНОСН3Н

, the corresponding 4-[2-(2-nitrophenyl)-1H-indol-3-yl]-but-3-en-2-ones II are boiled in acetic acid in the presence of twenty-fold molar excess of carbonyl iron for 5 minutes.

EFFECT: method widens the range of obtained products and simplifies the process owing to use of other initial compounds and conditions.

1 cl, 4 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are offered an agent showing properties of a cognitive function activator representing 1,3-dimethyl-5-(pyridyl-4-amino)methylene-barbituric acid

and an agent of the same purpose, 4-amino-1-(3-nitro-2-oxo-1-phenyl-1,2-dihydronaphthiridinyl)pyridinium chloride -versions.

EFFECT: high biological activity in scopolamine amnesia of the offered agents is presented.

2 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula (I) and pharmaceutically acceptable salt thereof, where m denotes a direct bond; n equals 0, 1, 2, 3 or 4 and n equals zero indicates a direct bond; p equals 1; s denotes a direct bond; t denotes a direct bond; R1 and R2 each independently denotes hydrogen; A denotes a radical selected from , where R4 and R5 are each independently selected from hydrogen or C1-6alkyloxy; Z denotes a radical (b-2), where R6 and R7 each independently denotes hydrogen. The invention also describes a pharmaceutical composition for treating cancer and preparation method thereof, based on compounds of formula I, use of these compounds to obtain a medicinal agent, as well as a method of producing said compounds.

EFFECT: novel compounds which can be used as p53-MDM2 interaction inhibitors are obtained and described.

10 cl, ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound of general formula I

,

and a pharmaceutically acceptable salt thereof, where X denotes CH2, CHF or S, Y denotes CN, R1, R2, R3 and R4 denotes hydrogen, n equals 1, m equals 0 or 1, R denotes R11, R12 or R13, where R11 includes at least one group selected from the following b) or c), where optionally substituted heterocyclic and heteroaryl groups are bonded with a noradamantyl part either directly or through a methylene adjacent group or a C-C bond or C-N bond; b) the substituted 5-member heteroaryl group, in which the heteroaryl ring is a monocyclic aromatic ring system, includes two or more heteroatoms selected from nitrogen and oxygen; c) the heterocyclic group is optionally substituted with a C1-C3 alkyl or oxo group, where the heterocyclic ring system is a 5-9-member mono- or bicyclic ring system with one or more heteroatoms selected from a group consisting of nitrogen and sulphur, where heteroatoms can also be present as functional groups, where the heterocyclic ring system can contain one or two double bonds, and where the monocyclic heterocyclic ring can be condensed with a phenyl ring, R12 is selected from hydrogen, halogen, hydroxy, amino and C1-C4 alkoxy; R13 is a substituted phenyl, where the substitutes, which can be identical or different, include at least one group selected from a) hydrogen; b) nitro, amino; c) the saturated or unsaturated monocyclic heterocyclic ring system is optionally substituted with one or more groups selected from C1-C3 alkyl and oxo, where the heterocyclic ring system is a 5-member ring with one or more heteroatoms selected from a group consisting of nitrogen and sulphur, where the heteroatoms can also be present as functional groups. The present invention also relates to a pharmaceutical composition having dipeptidyl peptidase IV inhibiting activity, methods of obtaining the novel compound of formula I and use in treating type II diabetes and diabetic complications as well as for treating dyslipidaemia, hypercholesteremia, obesity and hyperglycaemia.

EFFECT: novel dipeptidyl peptidase IV inhibitors.

10 cl, 1 tbl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new indazole derivants with the formula (1.0) or to their pharmaceutically acceptable salts and isomerides that act as inactivators in relation to ERK2. In formula (1.0): meanings of the chemical groups Q, R1, R2 are given in the invention formula. The invention also refers to the pharmaceutical composition containing the mentioned compounds and to application of the compounds with the formula (1.0) for production of crude drugs used in malignant growth treatment.

EFFECT: application of the compounds for production of crude drugs used in malignant growth treatment.

65 cl, 611 ex, 27 tbl

FIELD: chemistry.

SUBSTANCE: compounds can be used to treat such diseases as hypertension, congestive heart failure, cardiac hypertrophy and others. In formula I R1 denotes a) cyclohexyl or trifluoromethyl; or b) phenyl, 2-thienyl, 3-thienyl, 2-pyridyl, 2-imidazolyl, 2-thiazolyl, 2-benzothienyl, 4-benzofuryl, 4-benzothienyl, 7-benzofuryl, 2,3-dihydro-7-benzofuryl, 7-benzothienyl, 1,3-benzodioxol-4-yl, 7-indazolyl, or 8-quinolinyl, optionally substituted with 1-3 substitutes, and X and Y each denotes a single bond; R2 denotes methyl, ethyl, propyl, butyl, pentyl, hexyl, 5-pentenyloxy, 3,33-trifluoropropyl, 4,4-difluoropentyl, 3-(cyclopropyl)propyl, 4-(cyclopropyl)butyl, 3-hydroxypropyl, 4-hydroxybutyl, 4-hydroxypentyl, 4-hydroxyhexyl, 5-hydroxyhexyl, 2-hydroxyethoxy etc, given in the claim; R3 denotes H, F, OH, methoxy, ethoxy, 3-hydroxypropoxy, acetylamino, propionylamino, (2-methylpropionyl)amino, or butanoylamino; A denotes 2,4-disubstituted morpholine with R1XCR2R3Y, bonded on the second position and Q bonded on the fourth position, 1,3-disubstituted piperidine with R1XCR2R3Y bonded on the third position and Q bonded on the first position, 1,3-dibustituted-3-methylpiperidine with R1XCR2R3Y bonded on the third position and Q bonded on the first position, 1,3-disubstituted benzene or 1,3-disubstituted cyclohexane; Q denotes Q1, Q2, Q4, Q5, Q9, or Q10 given in the claim, to which A and N are bonded on cut-off bonds, R4 denotes H or methyl.

EFFECT: obtaining novel compounds having aspartic protease inhibitor properties, particularly renin inhibitor.

10 cl, 1 tbl, 166 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula or pharmaceutically acceptable salt thereof, synthesis methods thereof, pharmaceutical compositions containing said compounds, and use thereof to prepare a medicinal agent having mTOR kinase and/or PI3K kinase inhibiting action.

EFFECT: improved properties of the derivatives.

15 cl, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula where: R1 denotes COORa1, CONRa2Ra2', CONRa4ORa4', where: each of Ra1 and Ra4 denotes a hydrogen atom; each of Ra2 and Ra2' denotes a hydrogen atom; Ra4' denotes a lower alkyl; or R1 denotes a heterocyclic group selected from the following groups, where Y2 denotes a hydrogen atom or a lower alkyl: R2 denotes O, S, SO, SO2; R3 denotes a phenyl which is substituted with 2 substitutes selected from halogen, CF3; X2 denotes CH or N; W denotes the following residue: where: W1 denotes CH or S; W2 denotes CH; W3 denotes C or N; and at least one of W1, W2 and W3 denotes a carbon atom; or pharmaceutically acceptable salt or ester thereof. The invention also relates to a pharmaceutical composition having Avrora A selective inhibitory action, which, along with a pharmaceutically acceptable carrier or diluent, contains at least one compound of formula I a an active ingredient.

EFFECT: aminopyridine or aminopyrazine derivatives which inhibit growth of tumour cells based on Avrora A kinase selective inhibitory action.

11 cl, 3 tbl, 24 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

FIELD: chemistry.

SUBSTANCE: present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof, where R1 denotes C1-C8-alkylaminocarbonyl, which is optionally substituted with a 5- or 6-member heterocyclic ring containing 3-4 ring heteroatoms selected from a group consisting of oxygen, nitrogen and sulphur, where the ring can be optionally substituted with C1-C8-alkyl or C1-C8-alkoxy group ; R2 denotes C1-C3-alkyl or a halogen; one of R3 and R4 denotes R6, and the other denotes R7; R5 denotes hydrogen or halogen; R6 denotes hydrogen, hydroxy group amino group, -SO2R8, -SO2NH2, -SO2NR9R10, -COR8, -CONHR8, -NHSO2R8, nitrile, carboxy, -OR8 or C1-C8-halogenalkyl; R7 denotes hydrogen, OR11, halogen, carboxy, -SO2R8, cyanogroup or C1-C8-halogenalkyl, or when R4 denotes R7, then R7 can also denote -NR12 R13 ; R8 R11 independently denote C1-C8-alkyl or C3-C8-cycloalkyl, which can be optionally substituted with hydroxy group, C1-C8-alkoxy group, nitrile, amino group, C1-C8-alkylamino group or di-C1-C8-alkyl)amino group; any R9 denotes C1-C8-alkyl or C3-C8-cycloalkyl, which can optionally be substituted with hydroxy group, C1-C8-alkoxy group, nitrile, amino group, C1-C8-alkylamino group, di(C1-C8-alkyl)amino group or a 5- or 6-member heterocyclic ring containing one or two ring heteroatoms selected from a group consisting of oxygen and nitrogen, where the ring can optionally be substituted with C1-C8-alkyl, and R10 denotes hydrogen or C1-C8-alkyl; or R9 and R10 together with a nitrogen atom with which they are bonded form a 5- or 6-member heterocyclic ring which can contain one or two additional nitrogen heteroatoms, where the ring can be optionally substituted with C1-C8-alkyl; any R12 denotes C1-C8-alkyl or C3-C8-cycloalkyl which can be optionally substituted with di(C1-C8-alkyl)aminogroup, and R13 denotes hydrogen or C1-C8-alkyl; or R12 and R13 together with a nitrogen atom with which they are bonded form a 5- or 6-member heterocyclic ring which contains one or two additional nitrogen heteroatoms, where the ring can optionally be substituted with C1-C8-alkyl.

EFFECT: possibility of using the compounds to produce a pharmaceutical agent for treating diseases mediated by phosphatidylinositol-3 kinase.

6 cl, 3 tbl, 181 ex

FIELD: chemistry.

SUBSTANCE: invention relates to hydroximoyl-tetrazole derivatives of formula (I), , where T is a tetrazole substitute, A is a phenyl or heterocycle, L1 and L2 are different linker groups, and Q is a carbocycle, use thereof as fungicide active agents, particularly in form of fungicide compositions, and methods of controlling phytopathogenic fungi, especially plants, using said compounds or compositions.

EFFECT: more effective use of the compounds.

13 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel diarylamine-containing compounds of formula (I) or formula (4b), pharmaceutically acceptable salts thereof, which have c-kit inhibiting properties. In formulae (I) and (4b), each R1 independently denotes H, -C(O)OH and -L1-C1-6alkyl, where L1 denotes -O- or -C(O)O-, or any two neighbouring R1 groups can together form a 5-6-member heterocyclic ring containing a nitrogen atom or an oxygen atom as a heteroatom, a 6-member heterocyclic ring with one or two nitrogen atom s as heteroatoms, optionally substituted with a C1-4alkyl, and R5 denotes hydrogen or C1-C6alkyl; values of radicals Ar and Q are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds, and a method of treating diseases whose development is promoted by c-kit receptor activity.

EFFECT: more effective use of the compounds.

17 cl, 3 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R denotes a thiazolyl group of formula R2 and R3 are selected from: hydrogen, C1-C3linear alkyl; R4 is selected from: C1-C3linear or C3cyclic alkyl, phenyl and thiophenyl; Z denotes a group of formula: -(L)n-R1; R1 is selected from: i) C1-C3linear or branched alkyl, optionally substituted with C1-C4alkoxycarbonyl, halogen; ii) substituted phenyl or substituted with one or two substitutes selected from halogen, methoxy- or hydroxy group, C1-C4alkoxycarbonyl; iii) dioxopiperazinyl and 2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl, substituted with C1-C3alkyl; or iv) heteroaryl rings containing 5-10 atoms selected from thiazole, triazole, 1H-imidazole, thiadiazole, oxazole, isoxazole, oxadiazole, benzodioxole, benzo(1,4)dioxepanyl, pyridine, pyrimidine, 1H-indole, 2,3-dihydrobenzo[b][1,4]dioxynil, which can be substituted with oine or two substitutes selected from: a) hydroxy; b) C1-C3alkyl (which can be substituted with one more two substitutes selected from: ) phenyl; ii) C1-C4alkoxycarbonyl; iii) naphthalenyl; iv) 2-methylthiazolyl) ; c) NHC(O)C1-C3alkyl; d) C1-C4alkoxycarbonyl; e) 1 -(tert-butoxycarbonyl)-2-phenylethyl; f) methoxybenzyl; g) phenyl which can be substuted with C1-C4alkoxy, halogen, methoxycarbonyl or >NHC(O)CH3; h) (methoxy-2-oxoethyl)carbamoyl; L denotes a group selected from: i) C(O)NH[C(R5aR5b)]w-; ii) -C(O)[C(R6aR6b)]x-; iii) -C(O)[C(R7aR7b)]yC(O)-; iv) -SO2[C(R8aR8b)]z-; R5a, R5b, R6a, R6b, R7a, R7b, R8a and R8b, each independently denotes: i) hydrogen; ii) C1-C3 linear alkyl which can be substituted with 1 or 2 halogen atoms; iii) phenyl which can be substituted with 1-2 substitutes selected from halogen and lower alkoxy; iv) heteroaryl rings selected from imidazolyl, imidazolyl substituted with methyl, benzo(1,4)oxazinyl, oxadiazolyl substituted with methyl; index n equals 0 or 1; indices w, x, y and z are each independently equal to a number from 1 to 3. The invention also relates to pharmaceutically acceptable salts of compounds of formula (I) and use of compounds of formula (I) to prepare a medicinal agent for treating protein tyrosine phosphatase beta-mediated conditions.

EFFECT: obtaining compounds of formula (I) as human protein tyrosine phosphatase beta (HPTP-β) inhibitors.

15 cl, 17 dwg, 13 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

and pharmaceutically acceptable salts and solvates thereof, in which R1 is an optionally substituted alkyl or similar, R2 is a group of formula: -Y-R5, where Y is -O- or S; R5 is a substituted alkyl (the substitute is an optionally substituted cycloalkyl or similar), a branched alkyl or similar; R4 is hydrogen or C1-10 alkyl; R3 is a group of formula: -C(=O)-Z-R6, where Z is -NR7- or -NR7-W-; R6 is an optionally substituted cycloalkyl or similar; R7 is hydrogen or C1-10 alkyl, W is C1-10 alkylene; X is =N- provided that a compound in which R2 is 2-(4-morpholino)ethoxy, 2-, 3- or 4-pyridylmethoxy, 1-methylpiperidinyl-2-methoxy, benzyloxy or 4-substituted benzyloxy is excluded; and R3 is N-(1-adamantyl)carbamoyl, N-(2-adamantyl)carbamoyl and N-(3-noradamantyl)carbamoyl. Said compound is an 11β-hydroxysteroid dehydrogenase type 1 inhibitor. The invention also relates to a pharmaceutical composition containing said compound as an active ingredient.

EFFECT: improved properties of the compound.

23 cl, 72 ex

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