RU2125055C1 - Thioformamide derivatives or their pharmacologically acceptable salts - Google Patents

Abstract

FIELD: organic chemistry, pharmacy. SUBSTANCE: invention relates to derivatives of thioformamide of the general formula (I)

where Y - a group of the formula -C(O)-, -CH(OH)-,

=N-O-Ph, O=C(Ph)-O

; Z means

; A means substituted or nonsubstituted imidazopyridyl; R¹, R², R³ and R⁴ - hydrogen or lower alkyl, or their pharmaceutically acceptable salts exhibiting high hypotensive properties. EFFECT: improved method of synthesis, enhanced pharmacological activity of compounds. 6 cl, 24 ex, 1 tbl

Description

 The present invention relates to a thioformamide derivative useful as a medicine.

 Hypertension is known as a disease that causes complications such as stroke or heart disease, which are high on the list of causes of death in Japan, as a result of which various studies have been carried out to prevent and treat it. The blood pressure regulation system is complex and therefore various types of antihypertensive drugs are used.

 Such antihypertensive agents include diuretics, β-blockers and ACE inhibitors. However, diuretics cause an undesirable effect in the form of hyperuricemia, exacerbation of diabetes mellitus, gout attacks, etc .; β-blockers - heart failure, bronchospasm, etc. ACE inhibitors - shortness of breath, cardiac slowdown, etc. Thus, antihypertensive agents of the prior art, respectively, cause undesirable effects, in particular heart disease, which complicates their use or makes it undesirable.

 In Japan, the number of patients with cardiac coronary artery disease reached the same level as in Europe and America, with the transition to a Western lifestyle, and it is estimated that there are a very significant number of patients with coronary heart disease (such as angina pectoris (angina pectoris ) or myocardial infarction), including diseases caused by hypertension.

 Although nitrite preparations and β-blockers are used as prophylactic and therapeutic agents for angina pectoris, nitrite preparations have the disadvantage that they cause tolerance in patients and are accompanied by undesirable effects, such as metemoglobinemia or ocular hypertension, while β-blockers are the cause, as mentioned above, of an undesirable effect, such as heart failure or bronchospasm. Therefore, caution is required in the use of these drugs.

 Meanwhile, the number of patients with asthma has recently increased, presumably due to changes in eating habits or environmental degradation caused by pollution of air, water, etc.

 Until recently, β-stimulants, methylxanthines, mast cell stabilizers and steroids have been used as prophylactic and therapeutic agents for asthma. However, β-stimulants cause arrhythmia, hypertension, headache, etc .; methylxanthines - gastrointestinal upsets or neuropathy; steroids - diabetes mellitus or osteoporosis. So, these medications sometimes cause serious unwanted effects and therefore require caution when prescribing them. Although mast cell stabilizers are not the cause of any undesirable effects, they have the disadvantages that their use for children and the elderly is difficult, as they can only be used as a dosage form for inhalation, that they are not effective against serious asthma and that they can only be used as a prophylactic.

 Under such circumstances, there is a need to develop a hypotensive agent or agent for the prevention and treatment of heart disease or asthma, which has various mechanisms of action and can be easily applied due to its safety and quality superior to the quality of drugs of the prior art.

 The inventors of the present invention have carried out intensive studies studying compounds useful as such drugs. As a result of the studies, they turned their attention to the activity of opening the ATP-sensitive potassium channel and conducted studies to find a compound having such activity.

 As a result of these studies, the authors of the present invention have found that thioformamide derivatives, which will be described below, can achieve the above goal. The present invention is made based on this discovery.

 Although thioformamide derivatives having activity as drugs are disclosed, for example, in Japanese Patent Publication No. 59150/1990 and Japanese Patent Laid-open Publication NN 63260/1991, 289543/1990, 286659/1990, 211566/1989, 273/1990, 308275 / 1989 and 258760/1990, the compounds of the present invention differ in structure.

 SUMMARY OF THE INVENTION

в которой
Y обозначает группу, представленную формулой -O-, группу, представленную формулой

, (где n - нуль или целое число от 1 до 2), группу, представленную формулой

группу, представленную формулой

(где R⁵ и R⁶ могут быть одинаковыми или различными и каждый обозначает водород, низший алкил, низший алкоксил, циано, цианоалкил, возможно защищенный карбоксил, возможно (необязательно) защищенный карбоксиалкил или ацил), группу, представленную формулой

(где R⁷ обозначает группу, представленную формулой -OR⁸, где R⁸ обозначает водород, циано, низший алкил, возможно замещенный арилалкил, возможно замещенный гетероарилалкил, возможно защищенный карбоксил или возможно защищенный карбоксиалкил), группу, представленную формулой

(где R⁹ и R¹⁰ могут быть одинаковыми или различными и каждый обозначает водород, циано, низший алкил, возможно замещенный арилалкил, возможно замещенный гетероарилалкил, возможно защищенный карбоксил, или возможно защищенный карбоксиалкил, или альтернативно R⁹ и R¹⁰ могут обозначать вместе с атомом азота, к которому они присоединены, циклическую группу), водород, циано, цианоалкил, низший алкил, возможно замещенный арилалкил, возможно замещенный гетероарилалкил, возможно защищенный карбоксил, или возможно защищенный карбоксиалкил), или группу, представленную формулой

{где R¹¹ и R¹² могут быть одинаковыми или различными и каждый обозначает водород, низший алкил, арил, арилалкил, цианоалкил, ацилалкил, возможно защищенный карбоксиалкил, группу, представленную формулой -(CH₂)_s-O-R¹³, [где R¹³ обозначает водород, низший алкил, возможно замещенный арилалкил, возможно замещенный гетероарилалкил, низший алкоксиалкил, ацил, карбамоил, алкилкарбамоил, возможно замещенный арилкарбамоил, возможно замещенный арилалкилкарбамоил, возможно замещенный арилалкилсульфинил, возможно замещенный гетероарилалкилсульфинил, возможно замещенный арилсульфонил, возможно замещенный гетероарилсульфонил, алкилсульфонил, возможно защищенный карбоксиалкил, аминоалкил, в котором амино- часть может быть замещена, или группу, представленную формулой

(где B обозначает серу, кислород или группу, представленную формулой =N-CN; и R¹⁶ и R¹⁷ могут быть одинаковыми или различными и каждый обозначает водород, циано, низший алкил, возможно замещенный арил, возможно замещенный гетероарил, возможно замещенный арилалкил, или возможно замещенный гетероарилалкил, или альтернативно R¹⁶ и R¹⁷ могут обозначать вместе с атомом азота, к которому они присоединены, циклическую группу); и s - нуль или целое число от 1 до 10], или группу, представленную формулой

[где R¹⁴ и R¹⁵ могут быть одинаковыми или различными и каждый обозначает водород, низший алкил, возможно замещенный арилалкил, возможно замещенный гетероарилалкил, низший алкоксиалкил, ацил, карбамоил, алкилкарбамоил, возможно замещенный арилкарбамоил, возможно замещенный арилалкилкарбамоил, возможно замещенный арилсульфонил, возможно замещенный гетероарилсульфонил, алкилсульфонил, возможно замещенный арилалкилсульфинил, возможно замещенный гетероарилалкилсульфинил, группу, представленную формулой

(где D обозначает серу, кислород или группу, представленную формулой = N-CN; и R¹⁸ и R¹⁹ могут быть одинаковыми или различными и каждый обозначает водород, циано, низший алкил, возможно замещенный арил, возможно замещенный гетероарил, возможно замещенный арилалкил или возможно замещенный гетероарилалкил, или альтернативно R¹⁸ и R¹⁹ могут обозначать вместе с атомом азота, к которому они присоединены, циклическую группу), возможно защищенный карбоксиалкил, или аминоалкил, в котором аминная часть может быть замещена, или, альтернативно R¹⁴ и R¹⁵ могут обозначать вместе с атомом азота, к которому они присоединены, циклическую группу; и t - нуль или целое число от 1 до 10]};
Z обозначает группу, представленную формулой -O-, группу, представленную формулой

(где m - нуль или целое число от 1 до 2) или группу, представленную формулой -(CH₂)_p - (где p - нуль или целое число от 1 до 2);
A обозначает арил, тиенил, фурил, бензофуразанил, пирролил, имидазолил, триазолил, тетразолил, пиридонил, пиразолил, изоксазолил, изотиазолил, оксазолил, бензимидазолил, имидазопиридил, имидазопиразинил, имидазопиримидинил, имидазопиридазинил, имидазоксазинил или имидазотиазинил, при условии, что каждая гетероарильная группа может иметь один или два заместителя, и незамещенный имидазолил исключается, когда Y обозначает группу, представленную формулой -O- или -S- или когда Z обозначает группу, представленную формулой -O- или -S-;
R¹ и R² могут быть одинаковыми или различными и каждый обозначает водород, низший алкил, возможно замещенный арилалкил, или возможно замещенный гетероарилалкил, или альтернативно R¹ и R² могут вместе обозначать бензольное кольцо;
R³ и R⁴ могут быть одинаковыми или различными и каждый обозначает водород, низший алкил, циклоалкил, низший алкокси, гидроксил, арил, арилалкил, гетероарил, или гетероарилалкил или альтернативно R³ и R⁴ могут обозначать вместе с атомом азота, к которому они присоединены, циклическую группу, которая может содержать атом кислорода, азота или серы.The present invention relates to a thioformamide derivative represented by the following general formula (I), or a pharmacologically acceptable salt thereof:

wherein
Y represents a group represented by the formula —O—, a group represented by the formula

, (where n is zero or an integer from 1 to 2), the group represented by the formula

a group represented by the formula

(where R ⁵ and R ⁶ may be the same or different and each represents hydrogen, lower alkyl, lower alkoxyl, cyano, cyanoalkyl, possibly protected carboxyl, optionally (optionally) protected carboxyalkyl or acyl), a group represented by the formula

(where R ⁷ represents a group represented by the formula —OR ⁸ , where R ⁸ represents hydrogen, cyano, lower alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, possibly protected carboxyl or possibly protected carboxyalkyl), a group represented by formula

(where R ⁹ and R ¹⁰ may be the same or different and each represents hydrogen, cyano, lower alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, possibly protected carboxyl, or possibly protected carboxyalkyl, or alternatively R ⁹ and R ¹⁰ may be together with the nitrogen atom to which they are attached, a cyclic group), hydrogen, cyano, cyanoalkyl, lower alkyl, possibly substituted arylalkyl, possibly substituted heteroarylalkyl, possibly protected carboxyl, or possibly protected carboxyalkyl), or pu represented by the formula

{where R ¹¹ and R ¹² may be the same or different and each represents hydrogen, lower alkyl, aryl, arylalkyl, cyanoalkyl, acylalkyl, possibly protected carboxyalkyl, a group represented by the formula - (CH ₂ ) _s —OR ¹³ , [where R ¹³ denotes hydrogen, lower alkyl, possibly substituted arylalkyl, possibly substituted heteroarylalkyl, lower alkoxyalkyl, acyl, carbamoyl, alkylcarbamoyl, possibly substituted arylcarbamoyl, possibly substituted arylalkylcarbamoyl, possibly substituted arylalkylsulphinyl, optionally substituted optionally substituted arylsulfonyl, possibly substituted heteroarylsulfonyl, alkylsulfonyl, optionally protected carboxyalkyl, aminoalkyl in which the amino moiety may be substituted, or a group represented by the formula

(where B is sulfur, oxygen or a group represented by the formula = N-CN; and R ¹⁶ and R ¹⁷ may be the same or different and each is hydrogen, cyano, lower alkyl, possibly substituted aryl, possibly substituted heteroaryl, possibly substituted arylalkyl, or optionally substituted heteroarylalkyl, or alternatively, R ¹⁶ and R ¹⁷ may, together with the nitrogen atom to which they are attached, ring group); and s is zero or an integer from 1 to 10], or a group represented by the formula

[where R ¹⁴ and R ¹⁵ may be the same or different and each represents hydrogen, lower alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, lower alkoxyalkyl, acyl, carbamoyl, alkylcarbamoyl, possibly substituted arylcarbamoyl, possibly substituted arylalkylcarbamoyl, possibly substituted substituted heteroaryl sulfonyl, alkyl sulfonyl, optionally substituted arylalkylsulfinyl, optionally substituted heteroarylalkylsulfinyl, a group represented by the formula

(where D is sulfur, oxygen or a group represented by the formula = N-CN; and R ¹⁸ and R ¹⁹ may be the same or different and each is hydrogen, cyano, lower alkyl, optionally substituted aryl, possibly substituted heteroaryl, possibly substituted arylalkyl, or optionally substituted heteroarylalkyl, or alternatively R ¹⁸ and R ¹⁹ may mean, together with the nitrogen atom to which they are attached, a cyclic group), possibly a protected carboxyalkyl, or aminoalkyl in which the amine moiety may be substituted, or alternatively R ¹⁴ and R ¹⁵ may boznachat together with the nitrogen atom to which they are attached, a cyclic group; and t is zero or an integer from 1 to 10]};
Z represents a group represented by the formula —O—, a group represented by the formula

(where m is zero or an integer from 1 to 2) or a group represented by the formula - (CH ₂ ) _p - (where p is zero or an integer from 1 to 2);
A denotes aryl, thienyl, furyl, benzofurazanil, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, pyridonyl, pyrazolyl, isoxazolyl, isothiazolyl, oxazolyl, benzimidazolyl, imidazopyridyl, imidazidazidazidazinidazidazidazidazinidazidazinidazidazinidazidazinidazidazinidazidazinidazidazinidazidazinidazido have one or two substituents, and unsubstituted imidazolyl is excluded when Y is a group represented by the formula —O— or —S— or when Z is a group represented by the formula —O— or —S—;
R ¹ and R ² may be the same or different and each represents hydrogen, lower alkyl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl, or alternatively R ¹ and R ² may together represent a benzene ring;
R ³ and R ⁴ may be the same or different and each represents hydrogen, lower alkyl, cycloalkyl, lower alkoxy, hydroxyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, or alternatively R ³ and R ⁴ may represent together with the nitrogen atom to which they attached, a cyclic group which may contain an oxygen, nitrogen or sulfur atom.

Lower alkyl specified in relation to R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ , is linear or branched alkyl having from 1 to 8 carbon atoms, examples thereof are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert. -butyl, pentyl (amyl), isopentyl, neopentyl, tert.-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2 trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl and octyl. Among these groups, methyl, ethyl, propyl and isopropyl are preferred, and methyl and ethyl are most preferred.

The lower alkoxy indicated in relation to R ³ and R ⁴ is a linear or branched alkoxy having from 1 to 8 carbon atoms, and examples thereof are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec. butoxy tert. -butoxy, 1-methylbutoxy, 2-methylbutoxy, 1,2-dimethylpropoxy and hexyloxy. Among these groups, methoxy and ethoxy are preferred, with methoxy being most preferred.

The cycloalkyl indicated in relation to R ³ and R ⁴ is cycloalkyl having from 3 to 8 carbon atoms, preferably from 3 to 7 carbon atoms and most preferably 5 or 6 carbon atoms.

The aryl indicated with respect to R ³ , R ⁴ , R ¹¹ , R ¹² , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ and A includes phenyl, naphthyl and tolyl.

The aryl group included in the arylalkyl specified in relation to R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ , is the same as the groups indicated above. An alkyl group (i.e., an alkylene group) included in an arylalkyl is a group having from 1 to 6 carbon atoms.

The heteroaryl indicated in relation to R ³ , R ⁴ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ is a heteroaryl derived from a 5- or 6-membered ring containing one or two heteroatoms selected from nitrogen, sulfur and oxygen atoms .

The heteroaryl group included in the heteroarylalkyl indicated in relation to R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹³ , R ¹⁴ and R ¹⁵ is the same as groups indicated above. An alkyl group (i.e., alkylene chain) included in heteroarylalkyl is a group having from 1 to 6 carbon atoms.

The arylalkylsulfinyl indicated with respect to R ¹³ , R ¹⁴ and R ¹⁵ is an arylalkylsulfinyl derived from any of the above arylalkyl groups.

The heteroarylalkylsulfinyl indicated with respect to R ¹³ , R ¹⁴ and R ¹⁵ is heteroarylalkylsulfinyl derived from any of the above heteroarylalkyl groups.

Arylsulfonyl indicated in relation to R ¹³ , R ¹⁴ and R ¹⁵ is an arylsulfonyl derivative from any of the above aryl groups.

Heteroarylsulfonyl indicated with respect to R ¹³ , R ¹⁴ and R ¹⁵ is heteroarylsulfonyl derived from any of the above heteroaryl groups.

Alkylsulfonyl indicated in relation to R ¹³ , R ¹⁴ and R ¹⁵ is an alkylsulfonyl derivative from any of the above lower alkyl groups.

As indicated above, R ¹⁴ and R ¹⁵ may together with the nitrogen atom to which they are attached represent a cyclic group. The cyclic group includes groups derived from piperidine and pyrazoline rings. The cyclic group may further contain an oxygen, nitrogen or sulfur atom, and examples of such a group are groups derived from morpholine and piperazine rings. The cyclic group is not limited to these groups. Alternatively, R ¹⁴ and R ¹⁵ can together represent an acyl group derived from a dicarboxylic acid, that is, they can form an imide group together with a nitrogen atom.

 Preferred examples of the substituent for the above aryl and heteroaryl include hydrogen, lower alkyl, halogen, nitro, lower alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, halo substituted lower alkyl, cyano, carboxyl, optionally protected, aryl, optionally substituted, and optionally substituted.

As indicated above, R ⁵ , R ⁶ , R ⁸ , R ^9, and R ¹⁰ may each represent a possibly protected carboxyl, and a protecting group suitable for this case includes lower alkyl groups such as methyl, ethyl and t-butyl; phenyl substituted lower alkyl groups in which the phenyl group may be substituted, such as p-methoxybenzyl, p-nitrobenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, trityl and phenethyl; halogenated lower alkyl groups such as 2,2,2-trichloroethyl and 2-iodoethyl; lower alkanoyloxy lower alkyl groups such as pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, butyroloxymethyl, valeryloxymethyl, 1-acetoxyethyl, 2-acetoxyethyl, 1-pivaloyloxyethyl and 2-pivaloyloxyethyl; higher alkanoyloxy lower alkyl groups such as palmitoyloxyethyl, heptadecanoyloxymethyl and 1-palmitoyloxyethyl; lower alkoxycarbonyloxy lower alkyl groups such as methoxycarbonyloxymethyl, 1- (butoxycarbonyloxy) ethyl and 1- (isopropoxycarbonyloxy) ethyl; carboxy lower alkyl groups such as carboxymethyl and 2-carboxyethyl; heterocyclic groups such as 3-phthalidyl; optionally substituted benzoyloxy lower alkyl groups such as 4-glycyloxybenzoyloxymethyl; (substituted dioxylene) lower alkyl groups such as (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl; cycloalkyl substituted lower alkanoyloxy lower alkyl groups such as 1-cyclohexylacetyloxyethyl; and cycloalkyloxycarbonyloxy lower alkyl groups such as 1-cyclohexyloxycarbonyloxyethyl. Further, the carboxyl group may be protected in the form of various acid amides. In short, the protecting group may be any group that can be removed by some means in vivo to give a free carboxyl group.

As indicated above, R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ may each represent a possibly protected carboxyalkyl, and the protecting group suitable for this case is the same as described above with respect to a possibly protected carboxyl. Further, an alkylene group included in a possibly protected carboxyalkyl is a group derived from any of the above alkyl groups.

(где R²⁰ и R²¹ могут быть одинаковыми или различными и каждый обозначает водород, циано, нитро, низший алкил, галоген, низший алкокси, алкилтио, алкилсульфинил, алкилсульфонил, галоидзамещенный низший алкил, возможно замещенный арил, возможно замещенный гетероарил или возможно защищенный карбоксил).Although imidazolyl indicated above with respect to A may be any, imidazolyl represented by the formula is preferred

(where R ²⁰ and R ²¹ may be the same or different and each represents hydrogen, cyano, nitro, lower alkyl, halogen, lower alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, halo substituted lower alkyl, optionally substituted aryl, possibly substituted heteroaryl or possibly protected carboxyl )

The imidazopyridyl indicated with respect to A may be imidazopyridyl derived from any imidazopyridine, and examples thereof include
(1) groups derived from imidazo / 1,2-a / pyridine, such as imidazo / 1,2-a / pyridin-2-yl, imidazo / 1,2-a / pyridin-3-yl, imidazo / 1 , 2-a / pyridin-5-yl, imidazo / 1,2-a / pyridin-6-yl, imidazo / 1,2-a / pyridin-7-yl and imidazo / 1,2-a / pyridin-8 -il;
(2) groups derived from imidazo / 1,5-a / pyridine, such as imidazo / 1,5-a / pyridin-1-yl, imidazo / 1,5-a / pyridin-3-yl, imidazo / 1 5-a / pyridin-5-yl, imidazo / 1,5-a / pyridin-6-yl, imidazo / 1,5-a / pyridin-7-yl and imidazo / 1,5-a / pyridin-8 -il;
(3) groups derived from imidazo / 4,5-b / pyridine, such as imidazo / 4,5-b / pyridin-1-yl, imidazo / 4,5-b / pyridin-2-yl, imidazo / 4 5-b / pyridin-3-yl, imidazo / 4,5-b / pyridin-5-yl, imidazo / 4,5-b / pyridin-6-yl and imidazo / 4,5-b / pyridin-7 -il;
(4) groups derived from imidazo / 4,5-c / pyridine, such as imidazo / 4,5-c / pyridin-1-yl, imidazo / 4,5-c / pyridin-2-yl, imidazo / 4 5-c / pyridin-3-yl, imidazo / 4,5-c / pyridin-4-yl, imidazo / 4,5-c / pyridin-6-yl and imidazo / 4,5-c / pyridin-7 -il.

 Preferred examples of the substituent for imidazopyridyl include cyano, nitro, lower alkyl, halogen, lower alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, halo substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl and possibly protected carboxyl.

The acyl indicated above with respect to R ⁵ , R ⁶ , R ¹³ , R ¹⁴ and R ¹⁵ may be an acyl derived from any of the aliphatic saturated monocarboxylic, aliphatic saturated dicarboxylic, aliphatic unsaturated carbonic, saturated and unsaturated carbocyclic carbon, heterocyclic carbon hydroxycarboxylic, alkoxycarboxylic and any other carboxylic acids. Examples of acyl include lower alkanoyl groups such as formyl, acetyl, propionionyl, butyryl, valeryl, isovaleryl and pivaloyl; aroyl groups such as benzoyl, toluene and naphthoyl; and heteroaroyl groups such as furoyl, nicotinoyl and isonicotinoyl.

The cyanoalkyl indicated above with respect to R ¹¹ and R ¹² is an alkyl group described above, in which one of the hydrogen atoms included in the alkyl group is replaced by a cyano group.

The acylalkyl indicated above with respect to R ¹¹ and R ¹² is an acylalkyl derived from any of the above lower alkyl groups by replacing one of the hydrogen atoms with an acyl group.

 A pharmacologically acceptable salt in accordance with the present invention includes salts of inorganic acids such as hydrochloride, hydrobromide, sulfate and phosphate; organic acid salts such as acetate, maleate, tartrate, methanesulfonate, benzenesulfonate and toluenesulfonate; and amino acid salts such as arginate, aspartate and glutamate.

 Further, the derivative according to the present invention can form a metal salt, such as a salt of sodium, potassium, calcium or magnesium. A pharmacologically acceptable salt in accordance with the present invention includes these metal salts.

 Further, derivatives in accordance with the present invention can be represented as geometric or optical isomers, depending on the substituent. The present invention includes these isomers.

 Typical processes for preparing the compounds of the present invention are described below.

 The method of obtaining 1.

может быть получено согласно следующему способу:

где
R¹, R², R⁴, A и Z имеют каждый вышеуказанное значение.A compound represented by general formula (I) in which R ³ is hydrogen, and Y is a group represented by formula

can be obtained according to the following method:

Where
R ¹ , R ² , R ⁴ , A and Z each have the above meaning.

 More specifically, the target compound (III) can be obtained by reacting a compound represented by general formula (II) with a compound represented by general formula (IV) in the presence of a base.

 The base includes alkali metal alkoxides, such as potassium t-butoxide; alkali metal hydrides such as sodium hydride; and organolithium compounds such as n-butyllithium.

 The solvent used in the above reaction is preferably an ether, such as tetrahydrofuran, a polar aprotic solvent, such as N, N-dimethylformamide, or a mixture thereof, although it may be any organic solvent which is inert under the conditions of this reaction.

The reaction temperature may range from -78 ^° C. to the reflux temperature of the solvent used.

 The method of obtaining 2.

, может быть получено согласно следующему способу:

где
R¹, R², R³, R⁴, A и Z каждый имеет вышеприведенные значения.A compound represented by general formula (I) in which Y is a group represented by formula

can be obtained according to the following method:

Where
R ¹ , R ² , R ³ , R ⁴ , A and Z each have the above meanings.

 More specifically, the target compound (VI) can be obtained by reducing the compound represented by the general formula (V) to a metal hydride complex or a metal hydride.

 The metal hydride complex includes sodium borohydride and aluminum lithium hydride, and diisobutyl aluminum hydride is preferably used as the metal hydride.

 The solvent used in the above reaction is preferably an alcohol, such as methanol, an ether, such as tetrahydrofuran, or a hydrocarbon, such as toluene, although it may be any organic solvent that is inert under the conditions of this reaction.

The reaction temperature may range from -78 ^o C to about 50 ^o C.

 Alternatively, the compound represented by general formula (VI) can also be prepared by reducing the compound represented by general formula (V) with aluminum alkoxide in an alcohol solvent. In this reaction, it is preferable to use isopropyl alcohol as a solvent and aluminum alkoxide as a reducing agent.

 The reaction temperature may range from room temperature to the reflux temperature of the solvent used.

 The method of obtaining 3.

(где R $\genfrac{}{}{0ex}{}{\text{13}}{\text{a}}$ обозначает ацил), может быть получено согласно следующему способу:

где
R¹, R², R³, R⁴, A, Z и R $\genfrac{}{}{0ex}{}{\text{13}}{\text{a}}$ каждый имеет вышеприведенные значения.A compound represented by general formula (I) in which Y is a group represented by formula

(where R $\genfrac{}{}{0ex}{}{\text{13}}{\text{a}}$ denotes acyl), can be obtained according to the following method:

Where
R ¹ , R ² , R ³ , R ⁴ , A, Z and R $\genfrac{}{}{0ex}{}{\text{13}}{\text{a}}$ each has the above meanings.

 More specifically, the target compound (VII) can be obtained by condensing a compound represented by the general formula (VI) with a compound represented by the general formula (VIII) or a reactive derivative thereof, in a conventional manner.

 Alternatively, a salt of compound (VIII) can be used and converted to compound (VIII) in the reaction system.

 The reactive derivative of compound (VIII) includes its acid halides and symmetric acid anhydrites. When compound (VIII) is used in the form of a free alcohol, a condensing agent is usually used with it.

 Preferred examples of the condensing agent include diphonylphosphoramide, N-hydroxybenzotriazole, N-hydroxysuccinamide, ethyl chloroformate, methanesulfonyl chloride, 1,3-dicyclohexylcarboniimide, 1,1'-carbonyldiimidazole, diethyl azodicarboxylate and dipyridyl disulfide.

 Further, the above condensation may be carried out in the presence of a base in some cases. The base used in this case is preferably an organic base such as diisopropylethylamine, triethylamine, pyridine, picoline, lutidine, N, N-dimethylaniline or 4-dimethylaminopyridine, or an inorganic base such as potassium carbonate or sodium hydroxide, although it may be any basis.

 The solvent used in this reaction is preferably an alcohol such as ethanol, an ether such as tetrahydrofuran, a hydrocarbon such as toluene, a halide solvent such as dichloromethane, a polar aprotic solvent such as ethyl acetate, N, N-dimethylformamide or acetonitrile or pyridine.

The reaction temperature may range from -20 ^° C. to the reflux temperature of the solvent used.

 The method of obtaining 4.

, может быть также получено следующим способом:
(Стадия 1)

где
R¹, R², A и Z каждый имеет вышеуказанные значения, R²² обозначает низший алкил или бензил: и Q обозначает уходящую или удаляемую группу.A compound represented by general formula (I) in which Y is a group represented by formula

can also be obtained in the following way:
(Stage 1)

Where
R ¹ , R ² , A and Z each have the above meanings, R ²² is lower alkyl or benzyl: and Q is a leaving or leaving group.

 More specifically, the target compound (X) can be obtained by reacting a compound represented by general formula (II), first with carbon disulfide, and then with a compound represented by general formula (IX) in the presence of a base.

 The leaving group indicated with respect to Q is preferably halogen or methanesulfonyloxy.

 Preferred examples of the base include alkali metal alkoxides, such as potassium t-butoxide; alkali metal hydrides such as sodium hydride; and organolithium compounds such as n-butyllithium.

 The solvent used in the reaction is preferably an ether, such as tetrahydrofuran, a polar aprotic solvent, such as N, N-dimethylformamide or a mixture thereof, although it may be any organic solvent inert under the reaction conditions.

где
R¹, R², R³, R⁴, R²², A и Z каждый имеет вышеуказанные значения.(Stage 2)

Where
R ¹ , R ² , R ³ , R ⁴ , R ²² , A and Z each have the above meanings.

 The target compound (XI) can be obtained by reacting a compound represented by general formula (X) with a compound represented by general formula (XII), usually in excess, in the presence or absence of a solvent, and, if necessary, under pressure.

 When the use of a solvent is meant in the above reaction, the solvent is preferably an alcohol, such as ethanol, an ether, such as tetrahydrofuran, or a hydrocarbon, such as toluene, although it may be any organic solvent which is inert under the reaction conditions.

 The reaction temperature may range from room temperature to the reflux temperature of the solvent.

It is useful that R ²² —SH formed during the reaction is captured in the form of a heavy metal by adding, for example, mercury chloride to the reaction system.

 The method of obtaining 5.

может быть получено следующим способом

где
R¹, R², R³, R⁴, R⁷, A и Z каждый имеет вышеуказанные значения.A compound represented by general formula (I) in which Y is a group represented by formula

can be obtained in the following way

Where
R ¹ , R ² , R ³ , R ⁴ , R ⁷ , A and Z each have the above meanings.

 More specifically, the target compound (XIV) can be obtained by condensing the produced thioformamide represented by the general formula (XI) with the compound represented by the general formula (XIII) or its acid addition salt (acid addition salt) in the presence of a base.

 The base is preferably pyridine or an inorganic base such as sodium acetate.

 The solvent used in the reaction is preferably an alcohol, such as methanol, pyridine or water, although it may be any organic solvent which is inert under the reaction conditions.

The reaction temperature can range from about 0 ^° C. to the reflux temperature of the solvent used.

 Learning Method 6.

может быть получено также следующим способом

где
R¹, R², R³, R⁴, R⁷, A и Z каждый имеет вышеуказанные значения.A compound represented by general formula (I) in which Y is a group represented by formula

can also be obtained in the following way

Where
R ¹ , R ² , R ³ , R ⁴ , R ⁷ , A and Z each have the above meanings.

 More specifically, the target compound (XIV) can be obtained by condensation of a thioformamide derivative represented by the general formula (XI) with a compound represented by the general formula (XIII) or an acid addition salt thereof in the presence of a Lewis acid.

 The Lewis acid is preferably titanium tetrachloride.

 The solvent used in the reaction is preferably a halide organic solvent, such as dichloromethane, although it may be any organic solvent which is inert under the reaction conditions.

The reaction temperature can range from about 0 ^° C. to the reflux temperature of the solvent used.

 The method of obtaining 7.

(где R¹⁵ имеет вышеуказанное значение), может быть получено следующим способом:

где
R¹, R², R³, R⁴, R¹⁵, A и Z каждый имеет вышеуказанные значения.A compound represented by general formula (I) in which Y is a group represented by formula

(where R ¹⁵ has the above meaning), can be obtained in the following way:

Where
R ¹ , R ² , R ³ , R ⁴ , R ¹⁵ , A and Z each have the above meanings.

 More specifically, the target compound (XV) can be obtained by reducing the thioformamide derivative (XIV) 'obtained by method 6 under ordinary conditions.

 This reduction can be carried out in a conventional manner, for example, by a method using a metal hydride complex or catalytic hydrogenation.

 The metal hydride complex includes sodium cyanohydroborate and sodium borohydride.

The solvent used in this case is preferably an ether, such as tetrahydrofuran, or an alcohol, such as methanol. Preferably, the reaction temperature is between about −20 ^° C. and about 50 ^° C.

 Catalytic hydrogenation can be carried out using a conventional catalyst such as platinum / carbon, platinum oxide, Raney nickel or rhodium / alumina.

The solvent used in the catalytic hydrogenation is preferably an alcohol, such as methanol, a hydrocarbon, such as toluene, an ether, such as tetrahydrofuran, N, N-dimethylformamide or ethyl acetate. Preferably, the reaction temperature is between 0 ^° C. and the reflux temperature of the solvent used.

 The method of obtaining 8.

(где R⁵ и R⁶ каждый имеет вышеуказанные значения), может быть получено следующим способом:

где
R¹ , R², R³, R⁴, R⁵, R⁶, A и Z каждый имеет вышеуказанные значения; R²³ представляет низший алкил; R²⁴ представляет фенил; и Hal представляет галоген.A compound represented by general formula (I) in which Y is a group represented by formula

(where R ⁵ and R ⁶ each have the above meanings) can be obtained in the following way:

Where
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A and Z each have the above meanings; R ²³ represents lower alkyl; R ²⁴ represents phenyl; and Hal is halogen.

 More specifically, the target compound (XVI) can be obtained by reacting a compound represented by general formula (XI) with a compound represented by general formula (XVII) or (XVIII) according to the Wittig reaction under ordinary conditions.

 Preferred examples of the base used in this reaction include alkali metal hydrides such as sodium hydride; organolithium compounds such as n-butyllithium; and alkali metal alkoxides such as potassium t-butoxide.

 The solvent used in the reaction is preferably an ether, such as tetrahydrofuran, or a polar aprotic solvent, such as N, N-dimethylformamide, although it may be any solvent inert under the reaction conditions.

The reaction temperature may range from about -78 ^° C. to the reflux temperature of the solvent used.

When at least one of R ³ and R ⁴ is hydrogen, it is sometimes desirable that the thiofamide group of compound (XI) be protected by a compound represented by the general formula: R ²² —Q (where R ²² and Q each have the above meanings) before reaction with compound (XVII) or (XVIII).

 The method of obtaining 9.

/где R $\genfrac{}{}{0ex}{}{\text{11}}{\text{a}}$ и R $\genfrac{}{}{0ex}{}{\text{12}}{\text{a}}$ имеют те же значения, что и указанные выше в отношении R¹¹ и R¹², соответственно при условии, что группы, представленные формулой

(где R¹⁴ и R¹⁵ каждый имеет вышеуказанные значения) и -OR¹³ (где R¹³ имеет вышеуказанные значения) исключены/, может быть получено следующим способом:

где
R¹, R², R³, R⁴, R⁵, R⁶, R $\genfrac{}{}{0ex}{}{\text{11}}{\text{a}}$ ,R $\genfrac{}{}{0ex}{}{\text{12}}{\text{a}}$ , A и Z каждый имеет вышеуказанные значения.A compound represented by general formula (I) in which Y is a group represented by formula

/ where R $\genfrac{}{}{0ex}{}{\text{eleven}}{\text{a}}$ and R $\genfrac{}{}{0ex}{}{\text{12}}{\text{a}}$ have the same meanings as above with respect to R ¹¹ and R ¹² , respectively, provided that the groups represented by the formula

(where R ¹⁴ and R ¹⁵ each have the above meanings) and -OR ¹³ (where R ¹³ has the above meanings) are excluded /, can be obtained in the following way:

Where
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R $\genfrac{}{}{0ex}{}{\text{eleven}}{\text{a}}$ , R $\genfrac{}{}{0ex}{}{\text{12}}{\text{a}}$ , A and Z each have the above meanings.

 More specifically, the target compound (XIX) can be obtained by catalytic hydrogenation of a compound represented by the general formula (XVI) under ordinary conditions.

 The catalyst used in the hydrogenation process includes palladium / carbon, platinum oxide, Raney nickel and rhodium / alumina.

 Preferred examples of the solvent used in the reaction include alcohols such as methanol, hydrocarbons such as toluene, ethers such as tetrahydrofuran, N, N-dimethylformamide and ethyl acetate.

The reaction temperature can range from about 0 ^° C. to the reflux temperature of the solvent used.

 The method of obtaining 10.

(где n есть целое число от 0 до 2), может быть получено следующим способом:

где
R¹, R², R²², A, Z, Q и n каждый имеет вышеуказанные значения.A compound represented by general formula (I) in which Y is a group represented by formula

(where n is an integer from 0 to 2), can be obtained in the following way:

Where
R ¹ , R ² , R ²² , A, Z, Q and n each have the above meanings.

 More specifically, the target compound (XXI) can be obtained by reacting a compound represented by general formula (XX), first with carbon disulfide, and then with a compound represented by general formula (IX) in the presence of a base.

 The leaving group indicated with respect to Q is preferably halogen or methanesulfonyloxy.

 Preferred examples of the base include alkali metal alkoxides, such as potassium t-butoxide, and alkali metal dialkylamides, such as lithium diisopropylamide.

 The solvent used in the reaction is preferably an ether, such as tetrahydrofuran, which can be used together with hexamethylphosphoramide as a co-solvent in some cases.

Preferably, the reaction temperature is between about −78 ^° C. and the reflux temperature of the solvent used.

где
R¹, R², R³, R⁴, R²², A, Z и n каждый имеет вышеуказанные значения.

Where
R ¹ , R ² , R ³ , R ⁴ , R ²² , A, Z and n each have the above meanings.

 More specifically, the target compound (XXII) can be obtained by reacting the compound (XXI) obtained in stage 1, with a compound represented by General formula (XII).

 The solvent used in the reaction is preferably an alcohol, such as ethanol, an ether, such as tetrahydrofuran, or a hydrocarbon, such as toluene, although it may be any organic solvent which is inert under the reaction conditions.

 Preferably, the reaction temperature is between room temperature and the reflux temperature of the solvent used.

It is useful that R ²² —SH formed during the reaction is pressed in the form of a heavy metal salt by adding, for example, mercury chloride to the reaction system.

 The method of obtaining 11.

где
R¹, R², R³, R⁴, A, Y и Z каждый имеет вышеуказанные значения.The compound represented by general formula (I) having an asymmetric carbon atom can be obtained as an optically active substance in the following way:

Where
R ¹ , R ² , R ³ , R ⁴ , A, Y and Z each have the above meanings.

 When the thioformamide derivative represented by the general formula (I) has basic properties, the optically active substance (I ′) can be obtained by reacting the derivative with an optically active acid, such as dibenzoyl tartaric acid, to form a diastereoisomeric acid mixture, subjecting the mixture to fractional crystallization using a suitable solvent to obtain a pure diastereoisomeric salt, and neutralizing this diastereomeric salt.

 Further, the optically active substance (I ') can also be obtained by reacting a thioformamide derivative represented by the general formula (I) with an optically active optical separation reagent (such as optically active hydrazine) to form a diastereoisomeric mixture, and separating the diastereoisomeric mixture using column chromatography or fractional crystallization to obtain a pure diastereomer from an optically active reagent.

 Further, the optically active substance (I ') can also be obtained by direct separation of the thioformamide derivative represented by the general formula (I) by chromatography using a chiral column.

 Further, the optically active substance (I ') can also be obtained by subjecting the thioformamide derivative represented by the general formula (I) to kinetic separation using an asymmetric reducing agent and oxidizing the resulting diastereomeric product in the usual manner.

 The effect of the invention.

 Examples of pharmacological experiments are described below to illustrate the effects of the invention.

 (1) Vasohypotonic activity on a sample of rat aorta.

 The compounds of the present invention were tested for vasohypotonic activity using an aorta removed from a rat.

 Experimental method.

The thoracic aorta was quickly removed from a male SD rat weighing 250-400 g, and a spiral specimen was prepared from the aorta. This spiral sample was vertically suspended in an OrganWann filled with a Krebs-Hensleit solution at 30 ^° C, through which a gas mixture consisting of 95% oxygen and 5% carbon dioxide was passed. The change in sample voltage was measured isotonically under a load of 1 g.

 After the tension of the sample was stabilized, 20 mM KCl was added to the bath. After the tension has stabilized, the test compound is cumulatively added to Organwanna to determine relaxation.

The amount of relaxation, i.e. activity to slow the occurrence of tension, was determined by taking the tension that occurs when adding KCl, up to 100% and counting the value of the IC ₅₀ . The IC ₅₀ values determined in this way are shown in the table.

 (2) Activity regarding the potential (latent) duration of action on the right ventricular papillary muscle of the guinea pig.

 The compounds of the invention were tested for the potassium channel activation effect using the right ventricular papillary guinea pig muscle.

 Experimental method.

The potential duration of action at 90% repolarization (hereinafter abbreviated as APD ₉₀ ) reflects the output current of potassium. A compound having a potassium channel activation effect can activate an outgoing potassium channel, reducing APD ₉₀ (see Proc. Natl. Acad. Sci., USA, 85, 8360 - 8364 (1988)).

Hartley male guinea pigs weighing 300 to 500 g were used. The guinea pig was sacrificed by bloodletting, the papillary muscle was completely removed from its right ventricle and fixed in Organwan. The surface of the papillary muscle was washed with a Tyrode solution at 36 ± 0.5 ^° C, through which an oxygen / carbon dioxide mixture was passed. The resulting sample was stimulated by applying a 1 Hz square wave pulse to it to record the action potential using the glass microelectrode method.

 After the action potential stabilized, the sample was washed with Tyrode solutions containing each of the test compounds for 30 minutes to determine the dose-response curve.

The ratio (percentage) of APD ₉₀ detected at each concentration of the test compound in the Tyrode solution to the initial APD ₉₀ detected before administration of the compound was calculated to determine the concentration of the compound (-log M) at which the APD ₉₀ was reduced by 50% of the initial value. The compound concentrations thus determined are presented in the table as IC ₅₀ values.

 (3) Antihypertensive activity and activity to increase coronary blood flow in an anesthetized dog with an open chest.

 The compounds of the present invention were tested for antihypertensive activity and activity to increase coronary blood flow by using an anesthetized dog with an open chest.

 Experimental method.

 Used an adult hybrid dog. The dog's chest was opened under inhalation anesthesia using enfluran / laughing gas. An electromagnetic flowmeter sensor was installed on the envelope branch (ramus circumflexes) of the left coronary artery to determine coronary blood flow. Blood pressure was determined by placing the tip of the pressure sensor with a catheter in the aortic arch (arcus aortae).

 Each test compound was administered intravenously at a dose of 3 μg / kg through a catheter inserted into the femoral vein.

 Antihypertensive activity and activity to increase coronary blood flow for each compound are shown in the table as a change in blood pressure and coronary blood flow compared with those before administration of the compound.

 (4) Antihypertensive effect on a spontaneously hypertensive rat in a state of awakening.

 The compounds of the present invention were tested for antihypertensive activity by oral administration into spontaneously hypertensive rats (SHR).

 Experimental method.

 Systolic pressure of spontaneously male hypertensive rats (weight: 260 - 360 g), which were not fed for 12 hours, was determined bloodlessly by the tail cuff method. Each drug was suspended in a 0.5% aqueous solution of methylcellulose and orally administered at a dose of 1 mg / kg. Control rats were given only solvent.

 The blood pressure in rats 2 hours after drug administration is shown in the table, and the blood pressure before administration is taken as 100.

 The experimental results.

The results of the above experimental examples (1) to (13) are shown in the table. Compounds 1 to 13 are as follows:
compound 1
(-) - 1- (imidazo / 1,2-a / pyridin-6-yl) -N-methyl-2-oxocyclohexanecarbothioamide
compound 2
(-) - N-ethyl-1- (imidazo / 1,2-a / pyridin-6-yl) -2-oxocyclohexanecarbothioamide
compound 3
(-) - N-methyl-1- (2-methylimidazo / 1,2-a / pyridin-6-yl) -2-oxocyclohexanecarbothioamide
compound 4
(-) - 2-benzoyloxy-1- (imidazo / 1,2-a / pyridin-6-yl) -2-N-methylcyclohexanecarbothioamide
compound 5
2-benzyloxy-1- (imidazo / 1,2-a / pyridin-6-yl) -N-methyl-cyclohexanecarbothioamide
compound 6
anti-2-benzyloxyimino-1- (imidazo / 1,2-a / pyridin-6-yl) -N-methylcyclohexanecarbothioamide
compound 7
2-benzylamino-1- (imidazo / 1,2-a / pyridin-6-yl) -N- methylcyclohexanecarbothioamide
compound 8
2- (imidazo / 1,2-a / pyridin-6-yl) -N-methyltetrahydrothiopyran-2-carbothioamide-1-oxide
compound 9
2-benzoyloxy-N-methyl-1- (4-nitroimidazol-1-yl) cyclohexanecarbothioamide
compound 10
2-benzyloxy-N-methyl-1- (4-nitroimidazol-1-yl) cyclohexanecarbothioamide
compound 11
anti-2-benzyloxyimino-N-methyl-1- (4-nitroimidazol-1-yl) cyclohexanecarbothioamide
compound 12
(-) - 1- (2-trifluoromethylimidazo / 1,2-a / pyridin-6-yl) -N-methyl-2-oxocyclohexanecarbothioamide
compound 13
(-) - 2- (2-methylimidazo / 1,2-a / pyridin-6-yl) -N-methyltetrahydrothiopyran-2-carbothioamide-1-oxide
As can be seen from the results of pharmacological experiments, the compounds according to the present invention can activate the potassium channel of smooth muscle, thereby relaxing the smooth blood muscle and thus exhibiting activity in increasing coronary blood flow and hypotensive activity. Accordingly, the compounds of the present invention are effective as a potassium channel opening agent, and due to this activity, they can be used as a medicine.

 Thus, the compounds of the present invention are effective in the prevention and treatment of ischemic heart diseases such as angina pectoris and hypertension.

 Furthermore, the compounds of the present invention are less toxic and have a large safety margin, which makes them valuable in this sense as well.

 The compound of the present invention is administered as a therapeutic and prophylactic agent for the aforementioned diseases in the form of a tablet, powder, granule, capsule, syrup or inhalation. Although the dose of the compound varies depending on the severity of the symptom, age and type of illness, the daily dose for an adult is from about 0.1 to 1000 mg, preferably from 1 to 500 mg, and can be administered in one or more doses per day.

 When the compound of the present invention is administered by injection, the dose is usually from 1 to 3000 μg / kg, preferably from about 3 to 1000 μg / kg.

 The pharmaceutical preparations of the present invention are prepared using conventional carriers in the usual manner.

 More specifically, a solid preparation for oral administration in accordance with the present invention is prepared by adding a filler and, if necessary, a binder, disintegrator, lubricant, coloring and / or modifying substances to the active ingredient, and molding the resulting mixture into tablets, coated tablets, granules, powder or capsules in the usual way.

 Examples of excipients include lactose, grain starch, sucrose, glucose, sorbitol, crystalline cellulose, and silicon dioxide; examples of a binder include polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, acacia, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxymethyl cellulose, calcium citrate, dextrin and pectin; examples of a lubricant include magnesium stearate, talc, polyethylene glycol, silica and hydrogenated vegetable oil; examples of a coloring agent include approved pharmaceutical additives, and examples of modifying agents include cocoa powder, peppermint, aromatic powder, peppermint oil, borneol, and powdered brown tree bark. Of course, tablets, granules can be suitably coated with sugar, gelatin or the like, if necessary.

 An injection solution in accordance with the present invention is prepared by adding, if necessary, to the active ingredient a pH regulator, a buffer, a stabilizer and / or a solubilizing agent and formulating the mixture into an injection for subcutaneous, intramuscular or intravenous administration in the usual way.

 Example.

 Below will be described examples in accordance with the present invention, although there is no need to say that the present invention is not limited to them.

 Preparative examples will be given that describe the preparation of the starting material preparations used in the preparation of the target compounds of the present invention.

 In the following preparative examples and examples, Me is methyl and Et is ethyl.

 Preparative example 1.

49,35 г магния добавляли к 500 мл тетрагидрофурана, и к полученной смеси прикапывали 11,4 мл бромэтана при комнатной температуре при перемешивании в атмосфере азота для приготовления реактива Гриньяра. Полученную реакционную смесь охлаждали водой и в эту реакционную смесь в течение приблизительно одного часа по каплям прибавляли раствор 100 г 6-бромимидазо/1,2-a/пиридина и 102 мл бромэтана в 1 л тетрагидрофурана. После окончания прикапывания полученную смесь нагревали с обратным холодильником в течение 30 минут.2- (Imidazo / 1,2-a / pyridin-6-yl) cyclohexanone

49.35 g of magnesium was added to 500 ml of tetrahydrofuran, and 11.4 ml of bromoethane was added dropwise to the resulting mixture at room temperature with stirring under a nitrogen atmosphere to prepare the Grignard reagent. The resulting reaction mixture was cooled with water, and a solution of 100 g of 6-bromimidazo / 1,2-a / pyridine and 102 ml of bromoethane in 1 L of tetrahydrofuran was added dropwise to the reaction mixture over approximately one hour. After completion of the dropping, the resulting mixture was heated under reflux for 30 minutes.

 The resulting reaction mixture was cooled with ice, followed by the dropwise addition of a solution of 263 g of 2-methoxycyclohexanone in 200 ml of tetrahydrofuran. After completion of the dropping, the resulting mixture was stirred at room temperature for 3 hours.

 The resulting reaction mixture was again cooled with ice and quenched by the addition of a saturated aqueous solution of ammonium chloride. The resulting mixture was acidified with 6 N. hydrochloric acid. The aqueous phase was washed with ethyl acetate, made basic with concentrated aqueous ammonia and extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove the solvent, giving 122.5 g of a brown oil.

 To this oil was added portionwise 300 ml of concentrated sulfuric acid. The resulting mixture was shaken at room temperature vigorously enough to give a brown solution, which took about 2 hours. The resulting brown solution was poured onto ice and the resulting mixture was basified with concentrated aqueous ammonia and extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove the solvent. The obtained residue was purified by silica gel column chromatography (solvent: dichloromethane / methanol (50: 1-30: 1)) and the obtained solid was washed thoroughly with ether to obtain 63.46 g of the main compound as a light ocher powder.

 Next, the washings were concentrated and purified chromatographically on a silica gel column / solvent: dichloromethane / methanol (30: 1) /. The resulting solid was washed with ether to give 6.83 g of the main compound as a pale ocher powder. Thus, a total of 70.29 g of the title compound was obtained (yield: 65%).

Mp ( ^o C): 120 - 121.5.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.76 - 1.12 (4H, m), 2.16 - 2.28 (1H, m), 2.29 - 2.38 (1H, m ), 2.44 - 2.62 (2H, m), 3.59 (1H, dd, J = 5.5, 12.4 Hz), 6.95 (1H, dd, J = 1.6, 9 , 3 Hz), 7.52 (1H, dd, J = 0.5, 1.3 Hz), 7.57 (1H, d, J = 9.3 Hz), 7.60 (1H, d, J = 1.3 Hz), 7.94 (1H, dd, J = 0.5, 1.3 Hz).

 Preparative example 2.

7,70 мл (0,103 моль) этилбромида прикапывали к суспензии 32,08 г (1,32 моль) металлической магниевой стружки в 350 мл тетрагидрофурана в атмосфере азота. Как только было замечено образование этилмагнийбромида, к полученной смеси по каплям добавляли раствор 69,52 г (0,329 моль) 6-бром-2-метилимидазо-/1,2-a/пиридина и 66,0 мл (0,880 моль) этилбромида в 700 мл тетрагидрофурана в течение часа с такой скоростью, чтобы продолжалось спонтанное мягкое дефлегмирование. После окончания прикапывания полученную смесь нагревали с обратным холодильником в течение 30 минут и охлаждали льдом. К реакционной смеси добавляли раствор 171,1 г (1,34 моль) 2-метоксициклогексанона в 150 мл тетрагидрофурана в течение 30 минут с такой скоростью, чтобы температура основной массы смеси не превышала 30^oC. Полученную смесь встряхивали при комнатной температуре в течение 3 часов, охлаждали льдом и подкисляли добавлением насыщенного водного раствора хлорида аммония и 6 н. хлористоводородной кислоты в указанном порядке. Полученную кислую водную фазу промывали этилацетатом, подщелачивали концентрированным водным аммиаком и экстрагировали хлороформом. Органическую фазу промывали насыщенным водным раствором поваренной соли, сушили над безводным сульфатом магния и концентрировали в вакууме.2- (2-Methylimidazo / 1,2-a / pyridin-6-yl) cyclohexanone

7.70 ml (0.103 mol) of ethyl bromide were added dropwise to a suspension of 32.08 g (1.32 mol) of magnesium metal shavings in 350 ml of tetrahydrofuran in a nitrogen atmosphere. Once the formation of ethyl magnesium bromide was observed, a solution of 69.52 g (0.329 mol) of 6-bromo-2-methylimidazo- / 1,2-a / pyridine and 66.0 ml (0.880 mol) of ethyl bromide in 700 were added dropwise to the resulting mixture. ml of tetrahydrofuran for an hour at such a rate that continued spontaneous mild reflux. After the completion of the dropping, the resulting mixture was heated under reflux for 30 minutes and cooled with ice. A solution of 171.1 g (1.34 mol) of 2-methoxycyclohexanone in 150 ml of tetrahydrofuran was added to the reaction mixture over 30 minutes at such a rate that the temperature of the bulk of the mixture did not exceed 30 ^° C. The resulting mixture was shaken at room temperature for 3 hours, cooled with ice and acidified by adding a saturated aqueous solution of ammonium chloride and 6 N. hydrochloric acid in that order. The resulting acidic aqueous phase was washed with ethyl acetate, made basic with concentrated aqueous ammonia and extracted with chloroform. The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo.

 To the resulting crude 2-methoxy-2- (2-methylimidazo- / 1,2-a / pyridin-6-yl) cyclohexanone (73.7 g), 200 ml of concentrated sulfuric acid was added portionwise over 30 minutes, cooling the resulting mixture suitably in a water bath. The resulting reddish-purple liquid was stirred at room temperature for 16 hours.

 The resulting reaction mixture was poured onto ice, cooling with ice. The resulting mixture was made basic with concentrated aqueous ammonia and extracted with dichloromethane. The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue (62.3 g) was purified by silica gel column chromatography (solvent: dichloromethane / methanol (50: 1)) to obtain 51 g of a yellow crystal. The crystals were recrystallized from dichloromethane / ethyl acetate to obtain 18.85 g of the main compound as colorless crystals. Next, the mother liquor (26.7 g) was triturated with ether to obtain 16.89 g of the title compound as a light brown powder. Thus, a total of 35.74 g of the title compound was obtained (yield: 48%).

T. pl. ( ^o C): 147 - 148.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.76 - 2.08 (4H, m), 2.16 - 2.24 (1H, m), 2.31 (1H, m), 2, 44 (3H, d, J = 0.9 Hz), 2.46 - 2.60 (2H, m), 3.57 (1H, dd, J = 12.4, 5.4 Hz), 6.90 (1H, dd, J = 9.3, 1.6 Hz), 7.27 (1H, br s), 7.45 (1H, d, J = 9.2 Hz), 7.84 (1H , dd, J = 1.6, 0.8 Hz).

 Preparative example 3.

2,50 г 2-Гидрокси-1-(имидазо/1,2-a/пиридин-6-ил)-N- метилциклогексанкарботиоамида (M-форма) суспендировали в 45 мл N,N-диметилформамида с последующим добавлением 1,32 г безводного карбоната калия и 1,29 мл 4-метоксибензилхлорида. Полученную смесь перемешивали при комнатной температуре в течение 10 часов.2- (Imidazo / 1,2-a / pyridin-6-yl) -2 - ((4-methoxybenzylthio) (methylimino) methyl) cyclohexanol

2.50 g of 2-Hydroxy-1- (imidazo / 1,2-a / pyridin-6-yl) -N-methylcyclohexanecarbothioamide (M-form) was suspended in 45 ml of N, N-dimethylformamide followed by 1.32 g anhydrous potassium carbonate and 1.29 ml of 4-methoxybenzyl chloride. The resulting mixture was stirred at room temperature for 10 hours.

 The resulting reaction mixture was concentrated, then water was added. The resulting mixture was filtered to obtain an insoluble material. This material was washed with 50% aqueous ethanol and ether sequentially to obtain 3.19 g of the title compound as a slightly yellow powder (yield: 90%).

T. pl. ( ^o C): 203 - 206 (decomp.).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.36 - 1.70 (5H, m), 1.83 - 1.90 (1H, m), 2.59 - 2.68 (1H, m ), 3.33 (1H, d, J = 12.3 Hz), 3.55 (3H, m), 3.72 (3H, s), 3.75 (1H, d, J = 12.3 Hz ), 4.37 (1H, ddd, J = 2.7, 2.9, 10.1 Hz), 6.53 - 6.57 (2H, m), 6.68 - 6.73 (2H, m ), 7.49-7.56 (3H, m), 7.61 (1H, m), 8.74 (1H, br s).

 Preparative example 4.

1,04 г (2-Имидазо/1,2-a/пиридин-6-ил)-2-((4-метоксибензилтио) (метилимино))метил)циклогексанола суспендировали в 25 мл тетрагидрофурана. Полученную суспензию охлаждали до -60^oC с последующим добавлением сразу 300 мг т-бутоксида калия. Полученную смесь перемешивали при -60^oC в течение 2,5 часов с последующим добавлением 0,32 мл бензилбромида. Температуру полученной смеси постепенно поднимали до 0^oC в течение приблизительно одного часа, и полученную смесь перемешивали при 0^oC в течение 2 часов, затем добавляли воду. Полученную смесь экстрагировали хлороформом. Органическую фазу сушили над безводным сульфатом магния и перегоняли для удаления растворителя. Остаток очищали хроматографически на колонках с силикагелем /растворитель: дихлорметан/метанол (50:1)/, получая 500 мг указанного в заголовке соединения в виде бледно-желтого масла (выход: 39%).2-Benhzylcoxy-1- (imidazo / 1,2-a / pyridin-6-yl) -1 - ((4-methoxybenzylthio) (methylimino) methyl) cyclohexane

1.04 g of (2-Imidazo / 1,2-a / pyridin-6-yl) -2 - ((4-methoxybenzylthio) (methylimino)) methyl) cyclohexanol was suspended in 25 ml of tetrahydrofuran. The resulting suspension was cooled to -60 ^o C, followed by the addition of immediately 300 mg of potassium t-butoxide. The resulting mixture was stirred at -60 ^° C for 2.5 hours, followed by the addition of 0.32 ml of benzyl bromide. The temperature of the resulting mixture was gradually raised to 0 ^° C. over about one hour, and the resulting mixture was stirred at 0 ^° C. for 2 hours, then water was added. The resulting mixture was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography (solvent: dichloromethane / methanol (50: 1)) to obtain 500 mg of the title compound as a pale yellow oil (yield: 39%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.14 - 1.28 (1H, m), 1.45 - 1.76 (3H, m), 1.88 - 2.02 (2H, m ), 2.19 (1H, dt, J = 3.5, 12.7 Hz), 3.35 (1H, d, J = 12.3 Hz), 3.60 (3H, s), 3.70 (3H, s), 3.72 (1H, d, J = 12.3 Hz), 4.07 (1H, d, J = 11.7 Hz), 4.35 (1H, br s), 4 41 (1H, d, J = 11.7 Hz), 6.51-6.56 (2H, m), 6.64-6.68 (2H, m), 6.83 (2H, dd, J = 1.5, 8.4 Hz), 7.04 - 7.17 (4H, m), 7.46 (2H, t, J = 4.4 Hz), 7.61 (1H, d, J = 1.3 Hz), 7.98 (1H, m).

 Preparative example 5.

1,97 г 6-бромидазо/1,2-a/пиридина суспендировали в 40 мл безводного эфира. Полученную суспензию охлаждали до -70^oC и перемешивали в атмосфере азота с последующим добавлением 6,9 мл 1,6 М раствора н-бутиллития в гексане. Полученную смесь перемешивали в течение одного часа, затем добавляли сразу 1,5 мл N,N-диметилформамида. Через час температуру смеси повышали до комнатной температуры, и полученную смесь перемешивали в течение 30 минут.6-imidazo / 1,2-a / pyridinecarbaldehyde

1.97 g of 6-bromidazo / 1,2-a / pyridine was suspended in 40 ml of anhydrous ether. The resulting suspension was cooled to -70 ^° C. and stirred under nitrogen, followed by the addition of 6.9 ml of a 1.6 M solution of n-butyllithium in hexane. The resulting mixture was stirred for one hour, then 1.5 ml of N, N-dimethylformamide was immediately added. After one hour, the temperature of the mixture was raised to room temperature, and the resulting mixture was stirred for 30 minutes.

 Ice water was added to the mixture, and the resulting mixture was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled in vacuo to remove the solvent. Ether was added to the resulting residue, and the resulting mixture was filtered to obtain insoluble material. Thus, 0.43 g of the title compound was obtained as a light brown powder. Next, the filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography / solvent: dichloromethane / methanol (50: 1) /, to obtain 0.47 g of the compound indicated in the workpiece as a pale yellow solid. Thus, a total of 0.90 g of the target compound was obtained (yield: 62%).

Mp ( ^o C): 151 - 153.5.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.66 (1H, dd, J = 1.6, 9.3 Hz), 7.71 (1H, d, J = 9.3 Hz), 7 74 (1H, dd, J = 0.9, 1.3 Hz), 7.77 (1H, d, J = 1.3 Hz), 8.70 (1H, ddd, J = 0.5, 0 9, 1.6 Hz), 9.96 (1H, d, J = 0.5 Hz).

 Preparative example 6.

0,90 г 6-имидазо/1,2-a/пиридинкарбальдегида, полученного в препаративном примере 5, растворяли в 20 мл метанола. Полученный раствор перемешивали при охлаждении льдом, затем к нему добавляли 90 мг боргидрида натрия. Полученную смесь перемешивали в течение 50 минут с последующим добавлением воды. Полученную смесь экстрагировали хлороформом. Органическую фазу сушили над безводным сульфатом магния и перегоняли для удаления растворителя. Полученный остаток очищали хроматографией на колонке с силикагелем /растворитель: дихлорметан/метанол (от 30 : 1 до 10 : 1)/, получая 0,52 г указанного в заготовке соединения в виде слабо оранжево-желтого твердого тела (выход: 57%).(Imidazo / 1,2-a / pyridin-6-yl) methanol

0.90 g of 6-imidazo / 1,2-a / pyridinecarbaldehyde obtained in Preparative Example 5 was dissolved in 20 ml of methanol. The resulting solution was stirred under ice cooling, then 90 mg of sodium borohydride was added thereto. The resulting mixture was stirred for 50 minutes, followed by the addition of water. The resulting mixture was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove the solvent. The obtained residue was purified by silica gel column chromatography / solvent: dichloromethane / methanol (30: 1 to 10: 1) /, to obtain 0.52 g of the compound indicated in the workpiece as a slightly orange-yellow solid (yield: 57%).

Mp ( ^o C): 106 - 107.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.69 (2H, d, J = 0.9 Hz), 7.12 (1H, dd, J = 1.6, 9.3 Hz), 7 , 50 (1H, d, J = 9.3 Hz), 7.52 (1H, dd, J = 0.5, 1.3 Hz), 7.58 (1H, d, J = 1.3 Hz) 8.10 (1H, ddd, J = 0.5 0.9, 1.6 Hz).

 Preparative example 7.

11,23 г (имидазо/1,2-a/пиридин-6-ил)метанола, полученного в препаративном примере 6, растворяли в 170 мл хлороформа, а затем добавляли по каплям 11,1 мл тионилхлорида при комнатной температуре при перемешивании. Спустя час, отгоняли растворитель. Таким образом получали сырой 6-хлорметилимидазо/1,2-a/пиридин-гидрохлорид в виде светло-коричневого порошка.6 - ((4-Chlorobutyl) thiomethyl) imidazo / 1,2-a / pyridine

11.23 g of (imidazo / 1,2-a / pyridin-6-yl) methanol obtained in Preparative Example 6 was dissolved in 170 ml of chloroform, and then 11.1 ml of thionyl chloride was added dropwise at room temperature with stirring. After an hour, the solvent was distilled off. Thus, crude 6-chloromethylimidazo / 1,2-a / pyridine hydrochloride was obtained in the form of a light brown powder.

 The powder was added to a mixture containing 40 ml of methanol and 40 ml of ethanol, followed by the addition of 6.92 g of thiourea. The resulting mixture was heated under reflux for 4 hours, cooled, allowed to stand, and distilled to remove the solvent. Thus, crude S - ((imidazo / 1,2-a / pyridin-6-yl) methylisothiourea-dihydrochloride was obtained in the form of a light brown powder.

 This powder was dissolved in 40 ml of water, followed by the addition of 15.2 ml of 10 N. an aqueous solution of sodium hydroxide. The resulting mixture was heated under reflux for 2 hours and cooled with ice. 9.1 ml of 10 N were successively added to the mixture. an aqueous solution of sodium hydroxide, 11.4 ml of 1-bromo-4-chlorobutane and 40 ml of ethanol. The resulting mixture was stirred at room temperature for 2 hours.

 Water was added to the mixture, and then extracted with ethyl acetate. The organic phase was extracted with dilute hydrochloric acid. The aqueous phase was made basic with potassium carbonate and extracted again with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove the solvent. The resulting residue was purified by silica gel column chromatography (solvent: dichloromethane / methanol (50: 1)) to obtain 11.79 g of the title compound as a slightly brown oil (overall yield: 61%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.70 - 1.79 (2H, m), 1.82 - 1.90 (2H, m), 2.46 (2H, t, J = 7 , 1 Hz), 3.53 (2H, t, J = 6.2 Hz), 3.69 (2H, d, J = 0.4 Hz), 7.20 (1H, dd., J = 1, 6, 9.3 Hz), 7.54 (1H, dd., J = 0.5, 1.1 Hz), 7.59 (1H, d., J = 9.3 Hz), 7.62 ( 1H, d, J = 1.1 Hz), 8.05 (1H, ddd, J = 0.4, 0.5, 1.6 Hz).

 Preparative example 8.

11,79 г 6-((4-хлорбутил)тиометил)имидазо/1,2-a/пиридина, полученного в препаративном примере 7, растворяли в 160 мл дихлорметана. Полученный раствор охлаждали льдом с последующим добавлением 7,99 г м-хлорпербензойной кислоты в течение приблизительно 40 минут. Полученную смесь перемешивали. Через 30 минут к ней добавляли еще 0,4 г м-хлорпербензойной кислоты. Полученную смесь дополнительно перемешивали в течение одного часа, а затем к ней добавляли водный раствор тиосульфата натрия. Полученную смесь энергично перемешивали при комнатной температуре в течение 30 минут и экстрагировали хлороформом. Органическую фазу промывали водным раствором карбоната калия, сушили над безводным сульфатом магния и перегоняли для удаления растворителя. Полученный остаток очищали хроматографией на колонке с силикагелем /растворитель: дихлорметан/метанол (от 30 : 1 до 10 : 1)/, получая 9,51 г указанного в заголовке соединения в виде темно-кремового масла (выход: 76%).6 - ((- Chlorobutyl) sulfinylmethyl) imidazo / 1,2-a / pyridine

11.79 g of 6 - ((4-chlorobutyl) thiomethyl) imidazo / 1,2-a / pyridine obtained in Preparation Example 7 was dissolved in 160 ml of dichloromethane. The resulting solution was cooled with ice, followed by the addition of 7.99 g of m-chloroperbenzoic acid over about 40 minutes. The resulting mixture was stirred. After 30 minutes, another 0.4 g of m-chloroperbenzoic acid was added to it. The resulting mixture was further stirred for one hour, and then an aqueous solution of sodium thiosulfate was added to it. The resulting mixture was vigorously stirred at room temperature for 30 minutes and extracted with chloroform. The organic phase was washed with an aqueous solution of potassium carbonate, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The resulting residue was purified by silica gel column chromatography / solvent: dichloromethane / methanol (30: 1 to 10: 1) /, to give 9.51 g of the title compound as a dark cream oil (yield: 76%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.85 - 2.04 (4H, m), 2.64 (2H, dd, J = 6.8, 7.7 Hz), 3.58 (2H t, J = 6.0 Hz), 3.87 (1H, d, J = 13.4 Hz), 3.98 (1H, d, J = 13.4 Hz), 7.07 (1H , dd, J = 1.6, 9.2 Hz), 7.60 (1H, dd, J = 0.7, 1.2 Hz), 7.64 (1H, d, J = 9.2 Hz) 7.66 (1H, d, J = 1.2 Hz); 8.19 (1H, dd, J = 0.7, 1.6 Hz).

 Preparative example 9.

8,68 г т-бутоксида калия добавляли к 80 мл смеси /4:1 (об./об.)/ тетрагидрофурана и гексаметилфосфорного триамида с последующим охлаждением льдом. В полученную смесь по каплям добавляли раствор 9,51 г 6-((4-хлорбутил)-сульфинилметил)имидазо/1,2-a/пиридина, полученного в препаративном примере 8, в 30 мл смеси /4:1 (об./об.)/ тетрагидрофурана и гексаметилфосфорного триамида. Полученную смесь перемешивали в течение одного часа, после чего к ней добавляли ледяную воду. Полученную смесь экстрагировали хлороформом. Органическую фазу сушили над безводным сульфатом магния и перегоняли для удаления растворителя. Полученное масло отверждали, давая ему постоять, с последующим добавлением эфира. Полученную смесь фильтровали, получая 5,84 г указанного в заголовке соединения в виде темно-кремового порошка (выход: 71%). ЯМР-спектроскопический анализ этого порошка показал, что порошок представляет собой смесь, содержащую два диастереометра в соотношении приблизительно 2:1.2- (Imidazo / 1,2-a / pyridin-6-yl) tetrahydrothiopyran 1-oxide

8.68 g of potassium t-butoxide was added to 80 ml of a mixture of 4: 1 (v / v) / tetrahydrofuran and hexamethylphosphoric triamide, followed by ice cooling. To the resulting mixture was added dropwise a solution of 9.51 g of 6 - ((4-chlorobutyl) -sulfinylmethyl) imidazo / 1,2-a / pyridine obtained in Preparation Example 8 in 30 ml of a mixture of 4: 1 (v / v) vol.) / tetrahydrofuran and hexamethylphosphoric triamide. The resulting mixture was stirred for one hour, after which ice water was added to it. The resulting mixture was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove the solvent. The resulting oil was solidified, allowing it to stand, followed by the addition of ether. The resulting mixture was filtered to give 5.84 g of the title compound as a dark cream powder (yield: 71%). NMR spectroscopic analysis of this powder showed that the powder is a mixture containing two diastereometers in a ratio of approximately 2: 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.53 - 2.45 (5H, m), 2.56 - 2.81 (2H, m), 3.16 - 3.61 (2H, m ), 7.09 - 7.17 (full 1H, d, J = 1.8, 9.3 Hz), 7.56 - 7.67 (3H, m), 8.17 - 8.19 (1H , m).

 Preparative example 10.

84,0 мл (0,736 моль) 2-хлорциклогексанона и 92,54 г (0,670 моль) карбоната калия добавляли к суспензии 75,16 г (0.665 моль) 4-нитроимидазола в 1 л ацетонитрила. Полученную смесь нагревали с обратным холодильником в течение 18 часов и охлаждали, давая ей постоять, после чего к ней добавляли воду. Полученную смесь экстрагировали этилацетатом. Полученную органическую фазу промывали насыщенным водным раствором поваренной соли, сушили над безводным сульфатом магния и концентрировали в вакууме. Полученный остаток порошковали этилацетатом, получая 86,46 г указанного в заголовке соединения в виде светло-коричневого порошка (выход: 62%).2- (4-Nitroimidazol-1-yl) cyclohexanone

84.0 ml (0.736 mol) of 2-chlorocyclohexanone and 92.54 g (0.670 mol) of potassium carbonate were added to a suspension of 75.16 g (0.665 mol) of 4-nitroimidazole in 1 L of acetonitrile. The resulting mixture was heated under reflux for 18 hours and cooled, allowing it to stand, after which water was added to it. The resulting mixture was extracted with ethyl acetate. The resulting organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was triturated with ethyl acetate to give 86.46 g of the title compound as a light brown powder (yield: 62%).

T. pl. ( ^o C): 122 - 123.

¹ H-NMR (400 MHz, CDCl ₃ ) δ /: 1.81 (1H, qt, J = 13.4, 3.8 Hz), 1.94 (1H, m), 2.12 ( 1H, qd J = 12.8, 3.4 Hz), 2.18 (1H, m), 2.27 (1H, m), 2.53 (1H, tdd, J = 13.8 , 6.2, 0.7 Hz), 2.60 (1H, m), 2.70 (1H, q.s., J = 13.9, 2.2 Hz), 4.90 (1H, dd ., J = 13.0, 5.7 Hz), 7.42 (1H, d, J = 1.6 Hz), 7.77 (1H, d. J = 1.6 Hz).

 Preparative example 11.

40,0 мл (395 ммоль) циклогексеноксида и 86,37 г (625 ммоль) карбоната калия добавляли к суспензии 50,08 г (443 ммоль) 4-нитроимидазола в 800 мл N, N-диметилформамида. Полученную смесь перемешивали при нагревании при 100^oC в течение 3 дней и 20 часов, получая желтовато-коричневую суспензию. Эту суспензию охлаждали, давая ей постоять, и фильтровали для удаления нерастворимых веществ. Фильтрат концентрировали в вакууме. Добавляли воду к полученному остатку для образования кристаллического осадка. Кристаллический осадок удаляли фильтрованием и промывали водой. Полученный сырой кристалл растворяли в хлороформе, и полученный раствор промывали насыщенным водным раствором поваренной соли. Органическую фазу сушили над безводным сульфатом магния и концентрировали в вакууме. В ходе концентрирования начинали осаждаться кристаллы. Кристаллы удаляли фильтрованием, получая 53,26 г указанного в заголовке соединения в виде бесцветных кристаллов. Далее, фильтрат перекристаллизовывали из дихлорметан/изопропилового эфира, получая 5,14 г целевого соединения в виде светло-коричневых кристаллов. Таким образом, всего получено 58,30 г целевого соединения (выход: 70%).2- (4-Nitroimidazol-1-yl) cyclohexanol

40.0 ml (395 mmol) of cyclohexene oxide and 86.37 g (625 mmol) of potassium carbonate were added to a suspension of 50.08 g (443 mmol) of 4-nitroimidazole in 800 ml of N, N-dimethylformamide. The resulting mixture was stirred under heating at 100 ^° C. for 3 days and 20 hours to give a tan suspension. This suspension was cooled, allowing it to stand, and filtered to remove insoluble substances. The filtrate was concentrated in vacuo. Water was added to the resulting residue to form a crystalline precipitate. The crystalline precipitate was removed by filtration and washed with water. The resulting crude crystal was dissolved in chloroform, and the resulting solution was washed with a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo. During concentration, crystals began to precipitate. The crystals were removed by filtration to obtain 53.26 g of the title compound as colorless crystals. Further, the filtrate was recrystallized from dichloromethane / isopropyl ether, to obtain 5.14 g of the target compound as light brown crystals. Thus, a total of 58.30 g of the target compound was obtained (yield: 70%).

T. pl. ( ^o C): 150 - 151.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.36 - 1.54 (3H, m), 1.76 (1H, m), 1.84 - 1.98 (2H, m), 2, 12-2.26 (2H, m), 3.18 (1H, d, J = 4.2 Hz), disappeared with the addition of D ₂ O, 3.71 (1H, m, when D ₂ O was added, td. J = 9.9, 4.5 Hz), 3.79 (1H, ddd, J = 12.3, 9.5, 3.8 Hz), 4.47 (1H, d, J = 1.6 Hz ), 7.79 (1H, d, J = 1.6 Hz).

 Preparative example 12.

Раствор 19,0 мл (218 ммоль) оксалилхлорида в 250 мл дихлорметана охлаждали в бане из сухого льда и метанола. В вышеуказанный раствор в течение 10 минут по каплям добавляли раствор 27,0 мл (380 ммоль) диметилсульфоксида в 90 мл дихлорметана с такой скоростью, чтобы температура основной массы раствора поддерживалась в пределах от -60 до -50^oC. Полученную смесь далее перемешивали в течение 4 минут, получая бесцветный раствор. В бесцветный раствор по каплям добавляли раствор 31,92 г (151 ммоль) 2-(4-нитроимидазол-1-ил)циклогексанола, полученного в препаративном примере 11, в смеси, содержащей 240 мл дихлорметана и 30 мл диметилсульфоксида, в течение 7 минут с такой скоростью, чтобы температура основной массы не превышала -50^oC. Полученную смесь далее перемешивали в течение 15 минут. В полученную смесь в течение 7 минут прикапывали 80,0 мл (570 ммоль) триэтиламина с такой скоростью, чтобы температура основной массы не превышала -50^oC. Полученную смесь далее перемешивали в течение 7 минут и после этого убирали баню из сухого льда и метанола. Через 30 минут температура основной массы достигала +10^oC. К полученной в результате смеси добавляли насыщенный водный раствор кислого карбоната натрия, и полученную смесь оставляли стоять для расслоения жидкость-жидкость. Органическую фазу концентрировали в вакууме, полученный остаток растворяли в этилацетате. Далее, водную фазу экстрагировали этилацетатом, и этилацетатную фазу объединяли с этилацетатным раствором, полученным ранее. Полученную смесь промывали насыщенным водным раствором поваренной соли. Органическую фазу сушили над безводным сульфатом магния и концентрировали в вакууме, получая 33,9 г сырых кристаллов. Сырые кристаллы перекристаллизовывали из дихлорметана/этилацетата, получая 26,53 г целевого соединения в виде бесцветного кристалла. Далее, маточный раствор перекристаллизовывали из дихлорметана/диизопропилового эфира, получая 2,52 г целевого соединения в виде светлых желтовато-коричневых кристаллов. Таким образом, всего получали 29,05 г целевого соединения (выход: 92%).2- (4-Nitroimidazol-1-yl) cyclohexanone

A solution of 19.0 ml (218 mmol) of oxalyl chloride in 250 ml of dichloromethane was cooled in a bath of dry ice and methanol. A solution of 27.0 ml (380 mmol) of dimethyl sulfoxide in 90 ml of dichloromethane was added dropwise to the above solution over 10 minutes, so that the temperature of the bulk of the solution was maintained between -60 and -50 ^° C. The resulting mixture was further stirred in for 4 minutes, obtaining a colorless solution. To a colorless solution, a solution of 31.92 g (151 mmol) of 2- (4-nitroimidazol-1-yl) cyclohexanol obtained in Preparative Example 11 in a mixture containing 240 ml of dichloromethane and 30 ml of dimethyl sulfoxide was added dropwise over 7 minutes at such a speed that the temperature of the bulk did not exceed -50 ^o C. The resulting mixture was further stirred for 15 minutes. 80.0 ml (570 mmol) of triethylamine were added dropwise into the resulting mixture for 7 minutes so that the temperature of the bulk did not exceed -50 ^o C. The resulting mixture was further stirred for 7 minutes and then the bath was removed from dry ice and methanol . After 30 minutes, the temperature of the bulk reached +10 ^° C. A saturated aqueous solution of sodium hydrogencarbonate was added to the resulting mixture, and the resulting mixture was left to stand for liquid-liquid separation. The organic phase was concentrated in vacuo, the resulting residue was dissolved in ethyl acetate. Next, the aqueous phase was extracted with ethyl acetate, and the ethyl acetate phase was combined with the ethyl acetate solution obtained previously. The resulting mixture was washed with saturated aqueous sodium chloride. The organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo to give 33.9 g of crude crystals. The crude crystals were recrystallized from dichloromethane / ethyl acetate, to give 26.53 g of the target compound as a colorless crystal. Next, the mother liquor was recrystallized from dichloromethane / diisopropyl ether to give 2.52 g of the target compound as light tan crystals. Thus, a total of 29.05 g of the target compound was obtained (yield: 92%).

 Preparative example 13.

21,7 мл (160 ммоль) 4-метоксибензилхлорида и 32,94 г (238 ммоль) карбоната калия добавляли к раствору 45,23 г (159 ммоль) 2-гидрокси-N-метил-1-(4-нитроимидазол-1-ил)циклогексанкарботиоамида (L-форма), полученного в примере 17, в 300 мл N,N-диметилформамида. Полученную смесь перемешивали при комнатной температуре в течение 17 часов, получая желтовато-коричневую суспензию. К этой суспензии добавляли воду и поваренную соль, и полученную смесь экстрагировали этилацетатом. Органическую фазу промывали насыщенным водным раствором поваренной соли, сушили над безводным сульфатом магния и концентрировали в вакууме. Полученный остаток (65,5 г) перекристаллизовывали из дихлорметана/этилацетата, получая 42,78 г указанного в заголовке соединения в виде светлых желтовато-коричневых кристаллов (выход: 66%).2 - ((4-Methoxybenzylthio) (methylimino) methyl) -2- (4-nitroimidazol-1-yl) cyclohexanol

21.7 ml (160 mmol) of 4-methoxybenzyl chloride and 32.94 g (238 mmol) of potassium carbonate were added to a solution of 45.23 g (159 mmol) of 2-hydroxy-N-methyl-1- (4-nitroimidazole-1- il) cyclohexanecarbothioamide (L-form) obtained in Example 17 in 300 ml of N, N-dimethylformamide. The resulting mixture was stirred at room temperature for 17 hours to give a tan suspension. Water and sodium chloride were added to this suspension, and the resulting mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue (65.5 g) was recrystallized from dichloromethane / ethyl acetate to give 42.78 g of the title compound as light tan crystals (yield: 66%).

T. pl. ( ^o C): 135 - 136.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.28 - 1.48 (3H, m), 1.56 - 1.76 (3H, m), 1.90 (1H, m), 2, 63 (1H, m), 3.44 (1H, d, J = 12.5 Hz), 3.58 (3H, s), 3.74 (1H, d, J = 12.5 Hz), 3, 77 (3H, s), 4.38 (1H, dt, J = 11.0, 3.1 Hz when adding D ₂ O, dd, J = 11.3, 3.6 Hz), 4.78 (1H , b.s. disappeared when D ₂ O was added), 6.74 (2H, d, J = 8.6 Hz), 6.85 (2H, d, J = 8.6 Hz), 7.99 (1H d, J = 1.6 Hz), 8.27 (1H, d, D = 1.6 Hz).

 Preparative example 14.

Раствор 42,76 г (106 ммоль) 2-((4-метоксибензилтио)(метилмино)метил- 2-(4-нитроимидазол-1-ил)циклогексанола, полученного в препаративном примере 13, в 300 мл тетрагидрофурана по каплям добавляли к суспензии 5,13 г (60%-ная дисперсия в минеральном масле, 128 ммоль) гидрида натрия в 60 мл тетрагидрофурана в атмосфере азота при комнатной температуре в течение 20 минут. Полученную смесь далее перемешивали при 50^oC в течение 10 минут с последующим добавлением 13,2 мл (111 ммоль) бензилбромида при 50^oC. Полученную смесь перемешивали при 50^oC в течение одного часа и затем в условиях дефлегмации при нагревании в течение 20 часов. Полученную коричневую суспензию оставляли охлаждаться и наливали в нее ледяную воду. Полученную смесь экстрагировали этилацетатом. Полученную органическую фазу промывали насыщенным водным раствором поваренной соли, сушили над безводным сульфатом магния и концентрировали в вакууме. Полученный остаток (55,8 г) очищали хроматографией на колонке с силикагелем /растворитель: бензол/ацетон (от 25 : 1 до 5 : 1)/, получая 6,15 г указанного в заголовке соединения в виде коричневого масла (выход: 12%).2-Benzyloxy-1 - ((4-methoxybenzylthio) (methylimino) methyl) - 1- (4-nitroimidazol-1-yl) cyclohexane

A solution of 42.76 g (106 mmol) of 2 - ((4-methoxybenzylthio) (methylmino) methyl- 2- (4-nitroimidazol-1-yl) cyclohexanol obtained in Preparation Example 13 in 300 ml of tetrahydrofuran was added dropwise to the suspension 5.13 g (60% dispersion in mineral oil, 128 mmol) of sodium hydride in 60 ml of tetrahydrofuran in a nitrogen atmosphere at room temperature for 20 minutes, and the resulting mixture was further stirred at 50 ^° C. for 10 minutes, followed by 13 2 ml (111 mmol) of benzyl bromide at 50 ^o C. The resulting mixture was stirred at 50 ^o C for one hour and then at under reflux under heating for 20 hours. The resulting brown suspension was allowed to cool and ice water was poured into it. The resulting mixture was extracted with ethyl acetate. The resulting organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The obtained residue (55 , 8 g) was purified by silica gel column chromatography / solvent: benzene / acetone (25: 1 to 5: 1) /, to obtain 6.15 g of the title compound as a brown oil (yield: 12%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.28 - 1.49 (2H, m), 1.49 - 1.60 (1H, m), 1.60 - 1.78 (2H, m ), 1.91 (1H, m), 2.19 (1H, ddd, J = 12.8, 8.8, 2.9 Hz), 2.39 (1H, m), 3.58 (3H, s), 3.59 (1H, d, J = 19.4 Hz), 3.76 (1H, d, J = 19.4 Hz), 3.77 (3H, s), 4.24 (1H, d, J = 11.4 Hz), 4.29 (1H, dd, J = 6.9, 2.5 Hz), 4.53 (1H, d, J = 11.4 Hz), 6.75 ( 2H, d, J = 8.8 Hz), 6.91 (2H, d, J = 8.8 Hz), 7.08 (2H, dd, J = 7.5, 1.8 Hz), 7, 22 - 7.32 (3H, m), 7.61 (1H, d, J = 1.1 Hz), 7.69 (1H, d, J = 1.1 Hz).

 Preparative example 15.

6,9 г магния добавляли к 120 мл тетрагидрофурана, и полученную смесь перемешивали в атмосфере азота. К образовавшейся смеси добавляли 1,6 мл бромэтана по каплям при комнатной температуре с получением реактива Гриньяра. К вышеуказанной реакционной смеси прикапывали раствор 18,9 г 6-бром-2-трифторметилимидазо/1,2-a/пиридина и 14,4 мл бромэтана в 120 мл тетрагидрофурана. По окончании прикапывания полученную смесь нагревали с обратным холодильником в течение 30 минут и затем охлаждали льдом. К полученной смеси по каплям добавляли 36,2 мл 2-метоксициклогексана. Полученную смесь перемешивали при комнатной температуре в течение 3 часов и охлаждали снова льдом с последующим добавлением насыщенного водного раствора хлорида аммония. Полученную смесь экстрагировали хлороформом. Органическую фазу сушили над безводным сульфатом магния и перегоняли для удаления растворителя с получением коричневого масла.2- (2- (Trifluoromethylimidazo / 1,2-a / -pyridin-6-yl) -cyclohexanone

6.9 g of magnesium was added to 120 ml of tetrahydrofuran, and the resulting mixture was stirred under nitrogen. To the resulting mixture was added 1.6 ml of bromoethane dropwise at room temperature to give Grignard reagent. To the above reaction mixture was added dropwise a solution of 18.9 g of 6-bromo-2-trifluoromethylimidazo / 1,2-a / pyridine and 14.4 ml of bromoethane in 120 ml of tetrahydrofuran. Upon completion of the dropping, the resulting mixture was heated under reflux for 30 minutes and then cooled with ice. To the resulting mixture was added dropwise 36.2 ml of 2-methoxycyclohexane. The resulting mixture was stirred at room temperature for 3 hours and cooled again with ice, followed by the addition of a saturated aqueous solution of ammonium chloride. The resulting mixture was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove the solvent to obtain a brown oil.

 To this oil was added portionwise 70 ml of concentrated sulfuric acid. The resulting mixture was stirred at room temperature for 2 hours and poured onto ice. The resulting mixture was made basic with concentrated aqueous ammonia and extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography / solvent: n-hexane / ethyl acetate (2: 1 to 1: 1) / and the obtained solid was washed with ether to obtain 10.18 g of the title compound as a slightly yellow powder (yield: 51%).

T. pl. ( ^o C): 166.5 - 169.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.76 - 2.03 (3H, m), 2.07 (1H, m), 2.24 (1H, m), 2.35 (1H, m), 2.46 - 2.62 (2H, m), 3.62 (1H, dd, J = 5.3, 12.4 Hz), 7.09 (1H, dd, J = 1.6 Hz , 9.3 Hz), 7.62 (1H, d, J = 9.3 Hz), 7.82 (1H, m), 7.98 (1H, m).

 Preparative example 16.

В атмосфере азота 78,56 г магния добавляли к 2 л тетрагидрофурана и 0,3 г иода, и 18 мл бромэтана добавляли к полученной смеси для получения реактива Гриньяра. К вышеуказанной реакционной смеси медленно добавляли по каплям раствор 170,5 г 6-бром-2-метилимидазо/1,2-a/пиридина и 162 мл бромэтана в 500 мл тетрагидрофурана. По окончания прикапывания полученную смесь нагревали с обратным холодильником в течение 30 минут и затем охлаждали льдом. Формальдегид генерировался с помощью нагревания контейнера, содержащего 242 г параформальдегида, до 200^oC и вводился в реакционную смесь с использованием струи азота. Через 30 минут к образовавшейся смеси добавляли разбавленную хлористоводородную кислоту, и полученную смесь фильтровали для удаления нерастворимых веществ. Фильтрат подщелачивали концентрировали водным аммиаком и экстрагировали хлороформом. Органическую фазу сушили над безводным сульфатом магния и перегоняли для удаления растворителя. Остаток очищали хроматографией на колонке с силикагелем /растворитель: дихлорметан/метанол (от 30:1 до 10:1)/, получая 120 г целевого соединения в виде бледно-желтого твердого вещества (выход: 91,9%).2-Methylmidazo / 1,2-a / pyridin-6-methanol

Under nitrogen atmosphere, 78.56 g of magnesium was added to 2 L of tetrahydrofuran and 0.3 g of iodine, and 18 ml of bromoethane was added to the resulting mixture to obtain the Grignard reagent. To the above reaction mixture, a solution of 170.5 g of 6-bromo-2-methylimidazo / 1,2-a / pyridine and 162 ml of bromoethane in 500 ml of tetrahydrofuran was slowly added dropwise. Upon completion of the dropping, the resulting mixture was heated under reflux for 30 minutes and then cooled with ice. Formaldehyde was generated by heating a container containing 242 g of paraformaldehyde to 200 ^° C. and introduced into the reaction mixture using a stream of nitrogen. After 30 minutes, dilute hydrochloric acid was added to the resulting mixture, and the resulting mixture was filtered to remove insoluble matter. The filtrate was made basic, concentrated with aqueous ammonia and extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography (solvent: dichloromethane / methanol (30: 1 to 10: 1)) to obtain 120 g of the target compound as a pale yellow solid (yield: 91.9%).

T. pl. ( ^o C): 136 - 137
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.8 (1H, broad), 2.43 (3H, d, J = 0.9 Hz), 4.66 (2H, s), 7, 06 (1H, dd, J = 1.6 Hz, 9.2 Hz), 7.27 (1H, s), 7.39 (1H, d, J = 9.2 Hz), 7.99 (1H, m).

 Preparative example 17.

6,80 г 2-метилимидазо/1,2-a/пиридин-6-метанола, полученного в препаративном примере 16, растворяли в 90 мл хлороформа, и затем по каплям добавляли к полученному раствору 6,1 мл тионилхлорида при перемешивании при комнатной температуре. Через два часа растворитель отгоняли. Получали сырой 6-хорметил-2-метилимидазо/1,2-a/пиридин-гидрохлорид в виде коричневого масла.6 - ((4-Chlorobetyl) thiomethyl) -2-methylimidazo / 1,2-a / pyridine

6.80 g of 2-methylimidazo / 1,2-a / pyridin-6-methanol obtained in Preparation 16 was dissolved in 90 ml of chloroform, and then 6.1 ml of thionyl chloride was added dropwise to the resulting solution with stirring at room temperature. . After two hours, the solvent was distilled off. The crude 6-chloromethyl-2-methylimidazo / 1,2-a / pyridine hydrochloride was obtained as a brown oil.

 The oil was dissolved in a mixture containing 40 ml of methanol and 40 ml of ethanol, followed by the addition of 3.8 g of thiourea. The resulting mixture was heated under reflux for 3.5 hours and then cooled, allowing it to stand. The resulting mixture was distilled to remove the solvent, obtaining crude S - ((2-methylimidazo / 1,2-a / pyridin-6-yl) methyl) isothiourea-dihydrochloride as a light orange-yellow amorphous substance.

 To this substance was added 40 ml of water and 8.4 ml of 10 N. an aqueous solution of sodium hydroxide. The resulting mixture was heated under reflux for one hour and cooled with ice, followed by the addition of 5.8 ml of 10 N. an aqueous solution of sodium hydroxide, 5.0 ml of 1-bromo-4-holorbutane and 2.2 ml of ethanol in that order. The resulting mixture was stirred at room temperature for 2 hours, then water was added to it. The resulting mixture was extracted with ethyl acetate, and the organic phase was extracted with diluted hydrochloric acid. The aqueous phase was made basic with potassium carbonate and extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography / solvent: dichloromethane / methanol (100: 1 to 50: 1) /, to give 4.95 g of the title compound as a yellow oil (yield: 44%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ /: 1.69 - 1.79 (2H, m), 1.81 - 1.89 (2H, m), 2.45 (3H, d, J = 0.9 Hz), 2.50 (2H, t, J = 7.1 Hz), 3.53 (2H, t, J = 7.1 Hz), 3.67 (2H, s), 7.14 (1H, dd, J = 1.8 Hz, 9.3 Hz), 7.29 (1H, s), 7.47 (1H, d, J = 9.3 Hz), 7.95 (1H, m )

 Preparative example 18.

4,95 г 6-((4-хлорбутил)тиометил)-2-метилимидазо/1,2-a/-пиридина, полученного в препаративном примере 17, растворяли в 50 мл дихлорметана с последующим охлаждением полученного раствора льдом. В образовавшийся раствор по каплям добавляли в течение 20 минут раствор 3,18 г м-хлорпербензойной кислоты в 20 мл дихлорметана. Через один час в полученную смесь еще добавляли 0,16 г м-хлорпербензойной кислоты. Полученную смесь дополнительно перемешивали в течение 30 минут, затем к ней добавляли водный раствор тиосульфата натрия. Полученную смесь энергично перемешивали при комнатной температуре в течение 15 минут, и затем к ней добавляли водный раствор карбоната калия. Полученную смесь экстрагировали дихлорметаном. Органическую фазу сушили над безводным карбонатом калия и перегоняли для удаления растворителя. Остаток очищали хроматографией на колонке с силикагелем /растворитель: дихрометан/ метанол (от 50 : 1 до 30 : 1)/, получая 4,18 г указанного в заголовке соединения в виде бледно-розового твердого тела (выход: 79 %).6 - ((4-Chlorobutyl) sulfinylmethyl) -2-methylimidazo / 1,2-a / pyridine

4.95 g of 6 - ((4-chlorobutyl) thiomethyl) -2-methylimidazo / 1,2-a / pyridine obtained in Preparative Example 17 was dissolved in 50 ml of dichloromethane, followed by cooling of the resulting solution with ice. A solution of 3.18 g of m-chloroperbenzoic acid in 20 ml of dichloromethane was added dropwise to the resulting solution over 20 minutes. After one hour, 0.16 g of m-chloroperbenzoic acid was added to the resulting mixture. The resulting mixture was further stirred for 30 minutes, then an aqueous solution of sodium thiosulfate was added to it. The resulting mixture was vigorously stirred at room temperature for 15 minutes, and then an aqueous solution of potassium carbonate was added to it. The resulting mixture was extracted with dichloromethane. The organic phase was dried over anhydrous potassium carbonate and distilled to remove the solvent. The residue was purified by silica gel column chromatography (solvent: dichromethane / methanol (50: 1 to 30: 1)) to obtain 4.18 g of the title compound as a pale pink solid (yield: 79%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.83 - 2.03 (4H, m), 2.46 (3H, d, J = 0.9 Hz), 2.66 (2H, m) 3.57 (2H, m), 3.86 (1H, d, J = 13.6 Hz), 3.96 (1H, d, J = 13.6 Hz), 7.02 (1H, dd, J = 1.8 Hz, 9.3 Hz), 7.35 (1H, m), 7.52 (1H, d, J = 9.3 Hz), 8.08 (1H, m).

 Example 1

13,00 г 2-(имидазо/1,2-a/пиридин-6-ил)циклогексанона, полученного в препаративном примере 1, суспендировали в 200 мл безводного тетрагидрофурана с последующим добавлением 7,50 г т-бутоксида калия при охлаждении льдом. Полученную смесь перемешивали один час. К смеси добавляли раствор 4,88 г метилизоцианата в 10 мл тетрагидрофурана с последующим добавлением 20 мл N, N-диметилформамида. Полученную смесь перемешивали при комнатной температуре в течение 45 минут и выливали в насыщенный водный раствор хлорида аммония, и полученную смесь экстрагировали хлороформом. Органическую фазу сушили над безводным сульфатом магния и перегоняли для удаления растворителя.1- (Imidazo / 1,2-a / pyridin-6-yl) -N-methyl-2-oxo-cyclohexanecarbothioamide

13.00 g of 2- (imidazo / 1,2-a / pyridin-6-yl) cyclohexanone obtained in Preparative Example 1 was suspended in 200 ml of anhydrous tetrahydrofuran, followed by the addition of 7.50 g of potassium t-butoxide under ice-cooling. The resulting mixture was stirred for one hour. To the mixture was added a solution of 4.88 g of methyl isocyanate in 10 ml of tetrahydrofuran, followed by 20 ml of N, N-dimethylformamide. The resulting mixture was stirred at room temperature for 45 minutes and poured into a saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove the solvent.

 The resulting solid was washed with a mixture of chloroform and ethyl acetate to obtain 12.53 g of the title compound as a slightly yellow powder (yield: 72%).

T. pl. ( ^o C): 241-243 (decomp.).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.74 - 1.86 (1H, m), 1.88 - 1.96 (2H, m), 1.98 - 2.09 (1H, m ), 2.30 - 2.64 (2H, m), 2.79 (2H, t, J = 6.2 Hz), 3.18 (3H, d, J = 4.8 Hz), 7.01 (1H, dd, J = 2.0, 9.7 Hz), 7.52 - 7.57 (2H, m), 7.62 (1H, d, J = 1.1 Hz), 8.05 ( 1H, dd, J = 0.9, 2.0 Hz), 8.96 (1H, broad).

 Example 2

5,60 г 1-(имидазо/1,2-a/пиридин-6-ил)-N-метил-2- оксоциклогексанкарботиоамида, полученного в примере 1, суспендировали в 130 мл смеси ацетона и воды /3 : 1 (об./об.)/ с последующим добавлением раствора 7,34 г моногидрата (+)-дибензоил-D-винной кислоты в 20 мл смеси воды с ацетоном /3 : 1 (об./об. )/. Полученную смесь перемешивали при комнатной температуре в течение 30 минут с получением осадка. Осадок удаляли фильтрованием и промывали ацетоном, получая 5,85 г белого порошка. Порошок растворяли в 100 мл смеси этанола и воды /5 : 1 (об./об.)/ при нагревании. К полученному раствору добавляли воду до тех пор, пока раствор не становился мутным. Полученную смесь оставляли стоять при комнатной температуре с образованием осадка. Этот осадок удаляли фильтрованием. Получали 3,33 г белых игловидных кристаллов. Кристаллы перекристаллизовывали из 300 мл смеси этанола и воды /3 : 5 (об./об.)/, получая еще 2,52 г белых игловидных кристаллов, которые перекристаллизовывали снова из 150 мл смеси этанола с водой /3 : 5 (об./об.)/, получая 2,15 г белых игольчатых кристаллов. Кристаллы добавляли к разбавленному водному аммиаку, и полученную смесь экстрагировали хлороформом. Органическую фазу сушили над безводным сульфатом магния и перегоняли для удаления растворителя, получая кристаллический остаток. Этот кристаллический остаток перекристаллизовывали из ацетонитрила, получая 0,32 г указанного в заголовке соединения в виде пластинчатых кристаллов (выход: 6%).(-) - 1- (Imidazo / 1,2-a / pyridin-6-yl) -N-methyl-2-oxo-cyclohexanecarbothioamide

5.60 g of 1- (imidazo / 1,2-a / pyridin-6-yl) -N-methyl-2-oxocyclohexanecarbothioamide obtained in Example 1 was suspended in 130 ml of a mixture of acetone and water / 3: 1 (vol. /ob.)/ followed by the addition of a solution of 7.34 g of (+) - dibenzoyl-D-tartaric acid monohydrate in 20 ml of a mixture of water with acetone / 3: 1 (v / v) /. The resulting mixture was stirred at room temperature for 30 minutes to obtain a precipitate. The precipitate was removed by filtration and washed with acetone to give 5.85 g of a white powder. The powder was dissolved in 100 ml of a mixture of ethanol and water / 5: 1 (vol./about.) / With heating. Water was added to the resulting solution until the solution became cloudy. The resulting mixture was allowed to stand at room temperature to form a precipitate. This precipitate was removed by filtration. Received 3.33 g of white needle-shaped crystals. The crystals were recrystallized from 300 ml of a mixture of ethanol and water / 3: 5 (vol./about.) /, Obtaining another 2.52 g of white needle-shaped crystals, which were recrystallized again from 150 ml of a mixture of ethanol with water / 3: 5 (vol./ vol.) /, receiving 2.15 g of white needle crystals. The crystals were added to diluted aqueous ammonia, and the resulting mixture was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove the solvent, obtaining a crystalline residue. This crystalline residue was recrystallized from acetonitrile to give 0.32 g of the title compound as plate crystals (yield: 6%).

 The optical purity of this product, determined by high performance liquid chromatography using a chiral column, was 100%.

 Characterization of high performance liquid chromatography.

 Column: Hiracel (registered trademark) (product of the company Deicel Chemical Industries, Ltd.) (250 mm x 4.6 mm inner diameter.).

 Solvent: n-hexane / 2-propanol / 3: 2 (v / v) /.

 Flow rate: 1.0 ml / min.

 Detection: UV detector (254 nm).

Retention time: 10.2 min (retention time of racemic modification was 7.8 and 10.2 minutes)
T. pl. ( ^o C): 225-227 (decomp.).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.74 - 1.86 (1H, m), 1.87 - 1.97 (2H, m), 1.98 - 2.09 (1H, m ), 2.30 - 2.64 (2H, m), 2.79 (2H, t, J = 6.0 Hz), 3.18 (3H, d, J = 4.8 Hz), 7.01 (1H, dd, J = 2.0, 9.5 Hz), 7.54 (1H, d, J = 9.5 Hz), 7.54 (1H, d, J = 0.9, 1.3 Hz), 7.62 (1H, d, J = 1.3 Hz), 8.04 (1H, d, J = 0.9, 2.0 Hz), 8.94 - 9.03 (1H, br .).

-236^o (C = 1,0, метанол).Specific rotation:

-236 ^° (C = 1.0, methanol).

 Example 3

5,00 г (23,4 ммоль) 2-(имидазо/1,2-a/пиридин-6-ил)циклогексанона, полученного в препаративном примере 1, растворяли в 50 мл сухого тетрагидрофурана. Полученный раствор охлаждали до 0^oC, а затем добавляли к нему т-бутоксид калия. Полученную смесь перемешивали в течение 30 минут с последующим медленным добавлением по каплям раствора 2,45 г N-этилизоцианата в 5 мл полученной смеси. Температуру полученной смеси постепенно повышали до комнатной, и образовавшуюся в результате смесь оставляли на ночь перемешиваться с получением кристаллического осадка. Этот кристаллический осадок отделяли фильтрованием и промывали этилацетатом, получая 4,8 г целевого соединения в виде белых кристаллов (выход: 72%).Ethyl-1- (imidazo / 1,2-a / pyridin-6-yl) -2-oxocyclohexanecarbothioamide

5.00 g (23.4 mmol) of 2- (imidazo / 1,2-a / pyridin-6-yl) cyclohexanone obtained in Preparation Example 1 was dissolved in 50 ml of dry tetrahydrofuran. The resulting solution was cooled to 0 ^° C., and then potassium t-butoxide was added thereto. The resulting mixture was stirred for 30 minutes, followed by a slow dropwise addition of a solution of 2.45 g of N-ethyl isocyanate in 5 ml of the resulting mixture. The temperature of the resulting mixture was gradually raised to room temperature, and the resulting mixture was allowed to stir overnight to obtain a crystalline precipitate. This crystalline precipitate was separated by filtration and washed with ethyl acetate, to obtain 4.8 g of the target compound as white crystals (yield: 72%).

T. pl. ( ^o C): 176 (decomp.).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.24 (3H, t, J = 7.3 Hz), 1.74 - 2.10 (4H, m), 2.50 - 2.62 ( 2H, m), 2.70 - 2.84 (2H, m), 3.59 - 3.76 (2H, m), 7.01 (1H, dd, J = 1.9 Hz, 9.6 Hz ), 7.50 - 7.58 (2H, m), 7.62 (1H, d, J = 1.3 Hz), 8.05 - 8.08 (1H, m), 8.75 (1H, lat. s.).

 Example 4

1,43 г рацемической модификации, приготовленной в примере 3, и 2,06 г (+)-дибензоил-D-винной кислоты-моногидрата растворяли в 10 мл смеси воды и ацетона (3:1) при нагревании. Полученный раствор медленно охлаждали, получая 1,5 г кристаллического осадка. Этот осадок извлекали фильтрованием, снова растворяли в 7 мл смеси воды и ацетона (3:1) и перекристаллизовывали из нее с получением 1,0 г кристаллов. Эти кристаллы растворяли в водном растворе бикарбоната натрия, и полученный раствор экстрагировали хлороформом, получая свободное соединение. Данное соединение перекристаллизовывали из этилацетата, получая 210 мг целевого соединения.(-) - N-Ethyl-1- (imidazo / 1,2-a / pyridin-6-yl) -2-oxocyclohexanecarbothioamide and (+) - N-ethyl-1- (imidose- / 1,2-a / pyridin-6-yl) -2-oxocyclohexanecarbothioamide

1.43 g of the racemic modification prepared in Example 3 and 2.06 g of (+) - dibenzoyl-D-tartaric acid monohydrate were dissolved in 10 ml of a mixture of water and acetone (3: 1) with heating. The resulting solution was slowly cooled, yielding 1.5 g of a crystalline precipitate. This precipitate was recovered by filtration, redissolved in 7 ml of a mixture of water and acetone (3: 1) and recrystallized from it to obtain 1.0 g of crystals. These crystals were dissolved in an aqueous sodium bicarbonate solution, and the resulting solution was extracted with chloroform to give the free compound. This compound was recrystallized from ethyl acetate to give 210 mg of the target compound.

 The optical purity of this product, determined by high performance liquid chromatography using a chiral column, was 100%.

 Characterization of high performance liquid chromatography.

 Column: Hiracel (registered trademark) (product of Daicel Chemical Industries Ltd.) (250 mm x 4.6 mm inner diameter).

 Solvent: n-hexane / 2-propanol / diethylamine (60: 300: 1).

 Flow rate: 0.5 ml / min.

 Detection: UV detector (254 nm).

 Retention time: 16.7 minutes (retention time of the racemic modification was 14.2 and 16.7 minutes).

T. pl. ( ^o C): 208 (decomp.).

- 262,6^o (C = 1,0, этанол).Specific rotation:

- 262.6 ^o (C = 1.0, ethanol).

 Example 5

В атмосфере азота раствор 35,79 г (0,157 моль) 2-(2-метилимидазо/1,2-a/пиридин-6-ил)циклогексанона, приготовленного в препаративном примере 2, в 550 мл тетрагидрофурана охлаждали льдом, а затем к нему добавляли 19,55 г (0,174 моль) т-бутоксида калия. Полученный желтый раствор перемешивали при охлаждении льдом в течение одного часа, а затем к нему добавляли раствор 11,8 мл (0,173 моль) метилизоцианата в 50 мл тетрагидрофурана и 60 мл N,N-диметилформамида в этом порядке. Полученную реакционную смесь перемешивали при охлаждении льдом один час с последующим добавлением насыщенного водного раствора хлорида аммония. Полученную смесь экстрагировали хлороформом. Органическую фазу промывали насыщенным водным раствором поваренной соли, сушили над безводным сульфатом магния и концентрировали в вакууме. В ходе концентрирования начинали осаждаться кристаллы. Кристаллы выделяли фильтрованием. Было получено 37,09 г целевого соединения в виде бесцветных кристаллов. Далее, маточную жидкость (14,5 г) очищали хроматографией на колонке с силикагелем /растворитель: дихлорметан/метанол (100:3)/ и перекристаллизовывали из дихлорметана/этилацетата с получением 3,21 г целевого соединения в виде бледно-розового кристалла. Таким образом, всего было получено 40,3 г целевого соединения (выход: 85%).N-Methyl-1- (2-methylimidazo / 1,2-a / pyridin-6-yl) -2-oxocyclohexanecarbothioamide

In a nitrogen atmosphere, a solution of 35.79 g (0.157 mol) of 2- (2-methylimidazo / 1,2-a / pyridin-6-yl) cyclohexanone prepared in Preparative Example 2 in 550 ml of tetrahydrofuran was cooled with ice, and then to it 19.55 g (0.174 mol) of potassium t-butoxide was added. The resulting yellow solution was stirred under ice cooling for one hour, and then a solution of 11.8 ml (0.173 mol) of methyl isocyanate in 50 ml of tetrahydrofuran and 60 ml of N, N-dimethylformamide was added to it. The resulting reaction mixture was stirred under ice cooling for one hour, followed by the addition of a saturated aqueous solution of ammonium chloride. The resulting mixture was extracted with chloroform. The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. During concentration, crystals began to precipitate. The crystals were isolated by filtration. Received 37.09 g of the target compound as colorless crystals. Next, the mother liquor (14.5 g) was purified by silica gel column chromatography (solvent: dichloromethane / methanol (100: 3)) and recrystallized from dichloromethane / ethyl acetate to obtain 3.21 g of the target compound as a pale pink crystal. Thus, a total of 40.3 g of the target compound was obtained (yield: 85%).

T. pl. ( ^o C): 217-220 (decomp.).

¹ H-NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ /: 1.58 - 1.82 (3H, m), 1.88 - 2.02 (1H, m), 2.22 (1H, m) 2.31 (3H, d, J = 0.7 Hz), 2.40 (1H, dt, J = 13.6, 3.5 Hz), 3.00 (1H, m), 3.01 ( 3H, d, J = 4.4 Hz), 3.13 (1H, ddd, J = 13.6, 11.5, 6.4 Hz), 7.16 (1H, dd, J = 9.5, 1.8 Hz), 7.32 (1H, d, J = 9.5 Hz), 9.67 (1H, br.), 8.24 (1H, dd, J = 2.0, 0.9 Hz ), 9.80 (1H, brd, J = 4.4 Hz).

 Example 6

Раствор 20,26 г (53,8 ммоль) (+)-дибензоил-D-винной кислоты-моногидрата в 110 мл смеси ацетона и воды (4:1) добавляли к раствору 16,21 г (53,8 ммоль) (±)-N-метил-1-(2-метилимидазо/1,2-a/ пиридин-6-ил)-2-оксоциклогексанкарботиоамида, приготовленного в примере 5, в 900 мл смеси ацетона и воды (4:1). Полученную смесь оставляли стоять при комнатой температуре на 2 часа, получая (+)-N-метил-1-(2- метилимидазо/1,2-a/пиридин-6-ил)-2-оксоциклогексанкарботиоамид (+)-дибензоил-D-винной кислоты в виде бесцветных призматических кристаллов. Кристаллы (14,6 г, 95% или выше) отфильтровывали.(-) - N-Methyl-1- (2-methylimidazo / 1,2-a / pyridin-6-yl) -2-oxocyclohexanecarbothioamide

A solution of 20.26 g (53.8 mmol) of (+) - dibenzoyl-D-tartaric acid monohydrate in 110 ml of a mixture of acetone and water (4: 1) was added to the solution of 16.21 g (53.8 mmol) (± ) -N-methyl-1- (2-methylimidazo / 1,2-a / pyridin-6-yl) -2-oxocyclohexanecarbothioamide prepared in Example 5 in 900 ml of a mixture of acetone and water (4: 1). The resulting mixture was allowed to stand at room temperature for 2 hours to obtain (+) - N-methyl-1- (2-methylimidazo / 1,2-a / pyridin-6-yl) -2-oxocyclohexanecarbothioamide (+) - dibenzoyl-D -varic acid in the form of colorless prismatic crystals. Crystals (14.6 g, 95% or higher) were filtered off.

 The filtrate was concentrated in vacuo, and the resulting residue was dissolved in 900 ml of a mixture of ethanol and water (9: 1) under reflux. The resulting solution was left to stand for 12 hours, obtaining colorless needle crystals (20.4 g). The crystal was isolated by filtration and dissolved again in 900 ml of a mixture of ethanol and water (9: 1) under reflux. The resulting solution was cooled, allowing it to stand for 2 hours, and colorless needle crystals were obtained. These crystals were isolated by filtration. Thus, 14.17 g (98%) of (-) - N-methyl-1- (2-methylimidazo / 1,2-a / pyridin-6-yl) -2-oxocyclohexanecarbothioamide (+) - dibenzoyl-D were obtained guilty acid.

 To a suspension of 14.17 g (21.5 mmol) of the salt prepared above in 200 ml of water was added 100 ml of 1 N. an aqueous solution of sodium hydroxide. The resulting mixture was stirred at room temperature for 5 minutes, obtaining a colorless solution, which was extracted with chloroform. The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. During the concentration, precipitation of crystals began. The resulting crystals were recovered by filtration. Thus, 5.22 g of the target compound was obtained in the form of colorless crystals (yield: 32%, optical purity: 99%).

 The optical yield was determined using high performance liquid chromatography using a chiral column.

 Characterization of liquid chromatography.

 Column: Hiracel (registered trademark) (product of the company Deicel Chemical Industries, Ltd.) (250 mm x 4.6 mm inner diameter.).

 Eluent: n-hexane / 2-propanol / 4.1 (v / v) /.

 Column temperature: room temperature.

 Flow rate: 1 ml / min.

 Detection: UV detector (254 nm).

 Retention time: 16 min (retention times of racemic modification were 14 and 16 minutes).

Mp ( ^o C): 219 - 222 (decomp.).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.79 (1H, m), 1.90 (2H, quint, J = 6.4 Hz), 2.00 (1H, m), 2.43 (3H, d, J = 0.9 Hz), 2.55 (2H, m), 2.80 (2H, m), 3.16 (3H, d, J = 4.8 Hz), 6.96 (1H, dd, J = 9.5, 2.0 Hz), 7.30 (1H, br s), 7.43 (1H, br d, J = 9.5 Hz), 7.96 ( 1H, dd, J = 2.0, 0.9 Hz), 8.98 (1H, br s).

-218^o (C = 1,09, метанол).Specific rotation:

-218 ^o (C = 1.09, methanol).

 Example 7

Суспензию 14,6 г (22,1 ммоль) (+)-N-метил-1-(2-метилимидазо/1,2-a/ пиридин-6-ил)-2-оксоциклогексанкарботиоамида (+)-дибензоил-D-винной кислоты, отфильтрованного в примере 6, в 1 л смеси метанола и воды (9:1) нагревали с обратным холодильником в течение 30 минут и охлаждали, давая постоять 90 минут. Полученную в результате суспензию фильтровали, получая кристаллы.(+) - N-Methyl-1- (2-methylimidazo / 1,2-a / pyridin-6-yl) -2-oxocyclocarbothioamide

Suspension 14.6 g (22.1 mmol) (+) - N-methyl-1- (2-methylimidazo / 1,2-a / pyridin-6-yl) -2-oxocyclohexanecarbothioamide (+) - dibenzoyl-D- tartaric acid, filtered in example 6, in 1 l of a mixture of methanol and water (9: 1) was heated under reflux for 30 minutes and cooled, allowing to stand for 90 minutes. The resulting suspension was filtered to give crystals.

 To a suspension of 12.02 g (18.2 mmol) of the obtained salt in 200 ml of water was added 100 ml of 1 N. an aqueous solution of sodium hydroxide. The resulting mixture was stirred at room temperature for 5 minutes, obtaining a colorless solution, which was extracted with chloroform. The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. During concentration, crystals began to precipitate. The crystals thus formed were recovered by filtration. 4.30 g of the target compound were obtained as colorless crystals (yield: 27%, optical purity: 99%).

 Optical purity was determined using high performance liquid chromatography using a chiral column.

 Characterization of liquid chromatography.

 Column: Hiracel (registered trademark) (product of the company Deicel Chemical Industries, Ltd.) (250 mm x 4.6 mm inner diameter).

 Eluent: n-hexane / 2-propanol / 4: 1 (v / v) /.

 Column temperature: room temperature.

 Flow rate: 1 ml / min.

 Detection: UV detector (254 nm).

 Retention time: 14 min (retention times of racemic modification were 14 and 16 minutes).

T. pl. ( ^o C): 219 - 222 (decomp.).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.78 (1H, m), 1.91 (2H, quint, J = 6.3 Hz), 2.00 (1H, m), 2.43 (3H, d, J = 0.7 Hz), 2.56 (2H, m), 2.80 (2H, m), 3.16 (3H, d, J = 4.6 Hz), 6.96 (1H, dd, J = 9.4, 1.9 Hz), 7.30 (1H, br s), 7.42 (1H, br d, J = 9.5 Hz), 7.96 ( 1H, dd, J = 2.0, 0.9 Hz), 9.00 (1H, br s).

-227^o (C = 1,03, метанол).Specific rotation:

-227 ^o (C = 1.03, methanol).

 Example 8

24,9 г 1-имидазо/1,2-a/пиридин-6-ил)-N-метил-2- оксоциклогексанкарботиомида, полученного в примере 1, суспендировали в 280 мл метанола. Полученную суспензию охлаждали льдом с последующим добавлением 1,27 г боргидрата натрия. Полученную смесь перемешивали в течение 30 минут.2-Hydroxy-1- (imidazo / 1,2-a / pyridin-6-yl) -N-methyl-cyclohexanecarbothioamide (M-form)

24.9 g of 1-imidazo / 1,2-a / pyridin-6-yl) -N-methyl-2-oxocyclohexanecarbothiomide obtained in Example 1 was suspended in 280 ml of methanol. The resulting suspension was cooled with ice, followed by the addition of 1.27 g of sodium borohydrate. The resulting mixture was stirred for 30 minutes.

 The reaction mixture was analyzed by thin-layer chromatography on silica gel / developer: benzene / ethyl acetate / methanol (10: 10: 1) /, and it was found that the reaction product consists of a low polar diastereomer (L-form) as a minor component and a highly polar diastereomer (M-form) as the main component.

 Water was added to the reaction mixture, and the resulting mixture was filtered to isolate insoluble material. Thus, 15.12 g of the target compound was obtained in the form of a pure diastereomer as a pale yellow powder (yield: 62%).

T. pl. ( ^o C): 231 - 233 (decomp.).

¹ H-NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ: 1.27 - 1.41 (3H, m), 1.52 - 1.71 (2H, m), 1.92 - 2.01 (1H , m), 2.16 - 2.26 (1H, m), 2.47 - 2.56 (1H, m), 2.92 (3H, d, J = 4.4 Hz), 4.59 - 4.68 (1H, m), 4.88 - 4.97 (1H, m), 7.32 (1H, dd, J = 1.8, 9.5 Hz), 7.44 (1H, d, J = 9.5 Hz), 7.51 (1H, d, J = 1.3 Hz), 7.95 (1H, m), 8.63 (1H, m), 9.21 - 9.28 ( 1H, m).

 Example 9

500 мг 2-гидрокси-1-(имидазо/1,2-a/пиридин-6-ил)-N- метилциклогексанкарботиамида (M-форма), приготовленного в примере 8, суспендировали в 5 мл N, N-диметилформамида с последующей добавкой 470 мг бензойного ангидрида, 0,29 мл триэтиламина и каталитического количества 4-диметиламинопиридина. Полученную смесь перемешивали при комнатной температуре в течение 2 часов, затем к ней добавляли воду. Образовавшуюся смесь экстрагировали этилацетатом. Органическую фазу промывали водой и насыщенным водным раствором поваренной соли, сушили над безводным сульфатом магния и перегоняли для удаления растворителя. Остаток очищали и перегоняли для удаления растворителя. Остаток очищали хроматографически в колонке с силикагелем /растворитель: дихлорметан/метанол (30 : 1)/, и полученное твердое вещество перекристаллизовывали из смеси хлороформ/эфир, получая 40 мг целевого соединения в виде белого порошка (выход: 6%).2-Benzoyloxy-1- (imidazo / 1,2-a / pyridin-6-yl) -N-methyl-cyclohexanecarbothioamide

500 mg of 2-hydroxy-1- (imidazo / 1,2-a / pyridin-6-yl) -N-methylcyclohexanecarbothiamide (M-form) prepared in Example 8 was suspended in 5 ml of N, N-dimethylformamide, followed by addition 470 mg of benzoic anhydride, 0.29 ml of triethylamine and a catalytic amount of 4-dimethylaminopyridine. The resulting mixture was stirred at room temperature for 2 hours, then water was added to it. The resulting mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified and distilled to remove the solvent. The residue was purified by silica gel column chromatography (solvent: dichloromethane / methanol (30: 1)), and the resulting solid was recrystallized from chloroform / ether to obtain 40 mg of the target compound as a white powder (yield: 6%).

T. pl. ( ^o C): 273 - 274 (decomp.).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.38 - 1.76 (4H, m), 1.90 - 2.02 (1H, m), 2.35 - 2.51 (2H, m ), 2.69 - 2.78 (1H, m), 3.04 (3H, d, J = 4.8 Hz), 6.19 (1H, dd, J = 3.5, 8.8 Hz) , 7.31 (1H, dd, J = 1.8, 9.5 Hz), 7.35 - 7.45 (3H, m), 7.50 - 7.56 (2H, m), 7.60 (1H, m), 7.46 (1H, d, J = 1.1 Hz), 7.81 - 7.86 (2H, m), 8.59 (1H, m).

 Example 10

Суспензию 1,00 г (-)-1-имидазо/1,2-a/пиридин-6-ил)-N-метил-2- оксоциклогексанкарботиоамида (97%), приготовленного в примере 2, в 20 мл метанола охлаждали льдом с последующим добавлением 53 мг боргидрида натрия. Полученную смесь перемешивали в течение 30 минут.(-) - 2-Hydroxy-1- (imidazo / 1,2-a / pyridin-6-yl) -N-methylcyclohexanecarbothioamide (M-form)

A suspension of 1.00 g of (-) - 1-imidazo / 1,2-a / pyridin-6-yl) -N-methyl-2-oxocyclohexanecarbothioamide (97%) prepared in Example 2 in 20 ml of methanol was cooled with ice with subsequent addition of 53 mg of sodium borohydride. The resulting mixture was stirred for 30 minutes.

 The reaction mixture was analyzed by thin layer chromatography on silica gel / developer: benzene / ethyl acetate / methanol (10: 10: 1) /, and it was found that the reaction product consisted of a low polar diastereomer (L-form) as a minor component and a highly polar diastereomer (M-form) as the main component.

 Water was added to the reaction mixture, and the resulting mixture was filtered to extract insoluble material. Thus, 0.61 g of the target compound was obtained in the form of a pure diastereomer as a white powder (yield: 60%).

T. pl. ( ^o C): 244-246 (decomp.).

¹ H-NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ: 1.26 - 1.40 (3H, m), 1.52 - 1.72 (2H, m), 1.93 - 2.02 (1H , m), 2.15 - 2.25 (1H, m), 2.47 - 2.55 (1H, m), 2.92 (3H, d.J = 4.4 Hz), 4.60 - 4.66 (1H, m), 4.88 - 4.94 (1H, m), 7.32 (1H, dd, J = 1.8, 9.5 Hz), 7.44 (1H, d, J = 9.5 Hz), 7.51 (1H, d, J = 1.3 Hz), 7.96 (1H, m), 8.63 (1H, m), 9.20 - 9.30 ( 1H, m).

-44^o (C = 0,68, N,N-диметилформамид).Specific rotation:

-44 ^° (C = 0.68, N, N-dimethylformamide).

 Example 11

400 мг (-)-2-Гидрокси-1-(имидазо/1,2-a/пиридин-6-ил)- метилциклогексанкарботиоамида (M-форма), полученного в примере 10, суспендировали в 10 мл N, N-диметилформамида с последующим добавлением 0,24 мл триэтиламина, 380 мг бензойного ангидрида и каталитического количества 4-пирролидинпиридина. Полученную смесь перемешивали при комнатной температуре в течение 2 часов, затем к ней добавляли насыщенный раствор бикарбоната натрия. Полученную смесь экстрагировали этилацетатом. Органическую фазу промывали последовательно водой и насыщенным водным раствором поваренной соли, сушили над безводным сульфатом магния и перегоняли для удаления растворителя. Остаток очищали хроматографией на колонке с силикагелем /растворитель: дихлорметан/метанол (от 50 : 1 до 30 : 1)/ и полученное твердое вещество перекристаллизовывали из дихлорметана/эфира, получая 380 мг указанного в заголовке соединения в виде игольчатых кристаллов (выход: 69%).(-) - 2-Benzoyloxy-1- (imidazo / 1,2-a / pyridin-6-yl) -N-methylcyclohexanecarbothioamide

400 mg of (-) - 2-Hydroxy-1- (imidazo / 1,2-a / pyridin-6-yl) methylcyclohexanecarbothioamide (M-form) obtained in Example 10 was suspended in 10 ml of N, N-dimethylformamide with followed by the addition of 0.24 ml of triethylamine, 380 mg of benzoic anhydride and a catalytic amount of 4-pyrrolidine pyridine. The resulting mixture was stirred at room temperature for 2 hours, then a saturated sodium bicarbonate solution was added thereto. The resulting mixture was extracted with ethyl acetate. The organic phase was washed successively with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography / solvent: dichloromethane / methanol (50: 1 to 30: 1) / and the resulting solid was recrystallized from dichloromethane / ether to give 380 mg of the title compound as needle crystals (yield: 69% )

 The optical purity of the above product was 98% and was determined by high performance liquid chromatography using a chiral column.

 Characterization of high performance liquid chromatography.

 Column: Hiracel (registered trademark) (product of the company Deicel Chemical Industries, Ltd.) (250 mm x 4.6 mm inner diameter).

 Solvent: n-hexane / 2-propanol / 4: 1 (v / v) /.

 Flow rate: 0.5 ml / min.

 Detection: UV detector (254 nm).

 Retention time: 11.2 minutes (retention times of the racemic modification were 8.8 and 11.2 minutes).

T. pl. ( ^o C): 231.5 - 233 (decomp.).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.39 - 1.51 (1H, m), 1.56 - 1.76 (3H, m), 1.91 - 2.01 (1H, m ), 2.35 - 2.51 (2H, m), 2.70 - 2.78 (1H, m), 3.05 (3H, d, J = 4.6 Hz), 6.19 (1H, dd, J = 3.5, 8.6 Hz), 7.34 (1H, dd, J = 1.8, 9.5 Hz), 7.36 - 7.41 (2H, m), 7.42 - 7.48 (1H, m), 7.50 - 7.56 (2H, m), 7.58 (1H, m), 7.63 (1H, d, J = 1.3 Hz), 7, 82-7.86 (2H, m); 8.55 (1H, m).

-238^o (C = 0,5, метанол).Specific rotation:

-238 ^o (C = 0.5, methanol).

 Example 12

500 мг 2-бензилокси-1-(имидазо/1,2-a/пиридин-6-ил)-1-((4- метоксибензилтио)(метилимино)метил)циклогексан, приготовленного в препаративном примере 4, растворяли в 5 мл дихлорметана с последующим добавлением 1 мл анизола. Полученную смесь охлаждали льдом с последующим постепенным добавлением 5 мл трифторуксусной кислоты. Полученную смесь перемешивали один час, затем к ней добавляли насыщенный водный раствор бикарбоната натрия. Полученную смесь экстрагировали хлороформом. Органическую фазу сушили над безводным сульфатом натрия и перегоняли для удаления растворителя. Полученный остаток очищали хроматографией на колонке с силикагелем /растворитель: дихлорметан/метанол (50: 1)/. Полученное масло кристаллизовали из эфира, и полученные кристаллы извлекали фильтрованием. Таким образом, было получено 300 мг целевого соединения в виде белого порошка (выход: 79%).2-Benzyloxy-1- (imidazo / 1,2-a / pyridin-6-yl) -N- methylcyclohexanecarbothioamide

500 mg of 2-benzyloxy-1- (imidazo / 1,2-a / pyridin-6-yl) -1 - ((4-methoxybenzylthio) (methylimino) methyl) cyclohexane prepared in Preparation Example 4 was dissolved in 5 ml of dichloromethane followed by the addition of 1 ml of anisole. The resulting mixture was cooled with ice, followed by the gradual addition of 5 ml of trifluoroacetic acid. The resulting mixture was stirred for one hour, then a saturated aqueous solution of sodium bicarbonate was added to it. The resulting mixture was extracted with chloroform. The organic phase was dried over anhydrous sodium sulfate and distilled to remove the solvent. The obtained residue was purified by silica gel column chromatography / solvent: dichloromethane / methanol (50: 1) /. The resulting oil was crystallized from ether, and the obtained crystals were recovered by filtration. Thus, 300 mg of the target compound was obtained in the form of a white powder (yield: 79%).

T. pl. ( ^o C): 196 - 198.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.98 - 1.11 (1H, m), 1.43 - 1.60 (2H, m), 1.71 - 1.83 (2H, m ), 2.14 - 2.22 (1H, m), 2.38 - 2.46 (1H, m), 2.63 (1H, dt, J = 3.3, 13.5 Hz), 3, 03 (3H, d, J = 4.8 Hz), 4.32 (1H, dd, J = 4.4, 11.7 Hz), 4.43 (1H, d, J = 11.2 Hz), 4.71 (1H, d, J = 11.2 Hz), 7.21 (1H, dd, J = 1.8, 9.5 Hz), 7.24 - 7.36 (5H, m), 7 54 (1H, broad), 7.55 (1H, dd, J = 0.9, 1.3 Hz), 7.58 (1H, d, J = 9.5 Hz), 7.63 (1H d, J = 1.3 Hz), 8.80 (1H, dd, J = 0.9, 1.8 Hz).

 Example 13

600 мг 1-(имидазо/1,2-a/пиридин-6-ил)-N-метил-2-оксогексанкарботиоамида, приготовленного в примере 1, растворяли в 5 мл пиридина с последующим добавлением 730 мг O-бензилгидроксиламина-гидрохлорида. Полученную смесь перемешивали при 80^oC в атмосфере азота в течение 13 часов, затем к ней добавляли водный раствор карбоната калия. Полученную смесь экстрагировали хлороформом. Органическую фазу сушили над безводным сульфатом магния и перегоняли для удаления растворителя. Полученный остаток очищали хроматографически на колонке с силикагелем /растворитель: дихлорметан/метанол (от 100:1 до 50:1)/, и полученное масло кристаллизовали из эфира. Образовавшиеся кристаллы извлекали фильтрованием. Таким образом получали 610 мг целевого соединения в виде белого похожего на ленты кристаллов (выход: 74%).Anti-2-benzyloxyimino-1- (imidazo / 1,2-a / pyridin-6-yl) -N-methylcyclohexanecarbothioamide

600 mg of 1- (imidazo / 1,2-a / pyridin-6-yl) -N-methyl-2-oxohexanecarbothioamide prepared in Example 1 was dissolved in 5 ml of pyridine, followed by the addition of 730 mg of O-benzylhydroxylamine hydrochloride. The resulting mixture was stirred at 80 ^° C. under nitrogen for 13 hours, then an aqueous solution of potassium carbonate was added to it. The resulting mixture was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove the solvent. The obtained residue was purified by silica gel column chromatography / solvent: dichloromethane / methanol (100: 1 to 50: 1) /, and the resulting oil was crystallized from ether. The resulting crystals were recovered by filtration. Thus, 610 mg of the target compound was obtained in the form of a white ribbon-like crystal (yield: 74%).

T. pl. ( ^o C): 159 - 161.5.

¹ H-NMR (400 MHz, CDCL ₃ ) δ: 1.50 - 1.79 (3H, m), 1.83 - 1.94 (1H, m), 2.15 - 2.27 (2H, m ), 2.88 - 3.01 (2H, m), 3.05 (3H, d, J = 4.9 Hz), 5.06 (2H, s), 6.91 (1H, dd, J = 1.8, 9.5 Hz), 7.25 - 7.30 (2H, m), 7.32 - 7.44 (5H, m), 7.57 (1H, d, J = 1.3 Hz ), 7.80 (1H, dd, J = 0.9, 1.8 Hz), 8.24 (1H, broad).

 Example 14

1,50 г 1-(имидао/1,2-a/пиридин-6-ил)-N-метил-2- оксоциклогексанкарботиоамида, приготовленного в примере 1, и 2,35 г бензиламина растворяли в 20 мл дихлорметана. Полученный раствор охлаждали до 0^oC.2-Benzylamino-1- (imidazo / 1,2-a / pyridin-6-yl) -N-methyl-cyclohexanecarbothioamide

1.50 g of 1- (imidao / 1,2-a / pyridin-6-yl) -N-methyl-2-oxocyclohexanecarbothioamide prepared in Example 1 and 2.35 g of benzylamine were dissolved in 20 ml of dichloromethane. The resulting solution was cooled to 0 ^o C.

5.5 ml of a solution (1 mmol / ml) of TiCl ₄ in dichloromethane was slowly added dropwise into the solution prepared above, and the temperature of the resulting mixture was raised to room temperature. The resulting mixture was stirred for 2 hours, followed by the addition of an aqueous solution of sodium bicarbonate. The resulting mixture was filtered through celite to remove insoluble particles. The filtrate was extracted three times with chloroform. The combined organic phases were dried over sodium sulfate and distilled in vacuo to remove the solvent to give an oil. The oil as such (without purification) was dissolved in 10 ml of a mixture of dichloromethane with methanol (1: 1), followed by the addition of 350 mg of NaBH ₃ CN at room temperature. Acetic acid was added to the resulting solution to adjust the pH to 3. The resulting solution was stirred for one hour, followed by the addition of sodium bicarbonate solution. The resulting mixture was extracted three times with chloroform. The combined organic phases were dried over sodium sulfate and distilled in vacuo to remove the solvent to give an oil. This oil was purified by silica gel column chromatography (solvent: dichloromethane / methanol (50: 1)) to obtain 950 mg of the target compound (yield: 45%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.19 - 1.33 (1H, m), 1.43 - 1.78 (4H, m), 2.05 - 2.13 (1H, m ), 2.37 - 2.56 (2H, m), 3.70 (3H, d, J = 4 Hz), 3.55 (1H, dd, J = 4 Hz, 12 Hz), 3.64 ( 1H, d, J = 12 Hz), 3.90 (1H, d, J = 12 Hz), 7.22 - 7.31 (4H, m), 7.31 - 7.38 (2H, m), 7.52 - 7.57 (2H, m), 7.61 (1H, d, J = 1.61 Hz), 8.70 (1H, br.s.), 8.98 (1H, s).

 Example 15

3,00 г 2-(имидазо/1,2-a/пиридин-6-ил)-тетрагидротиопирана 1-оксида, приготовленного в препаративном примере 9, суспендировали в 40 мл смеси тетрагидрофурана с гексаметилфосфорным триамидом /4:1 (об./об.)/. Полученную суспензию охлаждали льдом с последующим добавлением 1,58 г т-бутоксида калия. Полученную смесь перемешивали один час, затем к ней прикапывали 1,5 мл дисульфид углерода. Полученную смесь перемешивали 30 минут и затем к ней прикапывали 2,4 мл метилиодида. Полученную смесь перемешивали при комнатной температуре в течение 1,5 часов с последующим добавлением ледяной воды. Полученную смесь экстрагировали этилацетатом, органическую фазу промывали водой и насыщенным водным раствором поваренной соли, сушили над безводным сульфатом магния и перегоняли для удаления растворителя.2- (Imidazo / 1,2-a / pyridin-6-yl) -N-methyltetrahydrothiopyran-2-carbothioamide 1-oxide

3.00 g of 2- (imidazo / 1,2-a / pyridin-6-yl) -tetrahydrothiopyran 1-oxide prepared in Preparative Example 9 was suspended in 40 ml of a mixture of tetrahydrofuran with hexamethylphosphoric triamide / 4: 1 (v / v) about.)/. The resulting suspension was cooled with ice, followed by the addition of 1.58 g of potassium t-butoxide. The resulting mixture was stirred for one hour, then 1.5 ml of carbon disulfide was added dropwise to it. The resulting mixture was stirred for 30 minutes and then 2.4 ml of methyl iodide were added dropwise to it. The resulting mixture was stirred at room temperature for 1.5 hours, followed by the addition of ice water. The resulting mixture was extracted with ethyl acetate, the organic phase was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and distilled to remove the solvent.

 The resulting red oil was dissolved in 10 ml of methanol, then 10 ml of a 40% solution of methylamine in methanol was added to the solution. The resulting mixture was stirred at room temperature for 1.5 hours and concentrated. The residue was purified by silica gel column chromatography / solvent: dichloromethane / methanol (20: 1 to 10: 1) / and crystallized from ethyl acetate to obtain 160 mg of the target compound as a slightly yellow powder (yield: 4%).

T. pl. ( ^o C): about 235 (decomp.).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.56 - 1.84 (3H, m), 2.09 - 2.25 (2H, m), 2.65 - 2.75 (1H, m ), 3.01 - 3.08 (1H, m), 3.28 (3H, d, J = 4.8 Hz), 3.92 - 4.03 (1H, m), 6.94 - 7, 00 (1H, m), 7.17 - 7.22 (1H, m), 7.42 (1H, m), 7.54 (1H, d, J = 1.3 Hz), 8.08 (1H , m), 9.74 - 9.83 (1H, broad).

 Example 16

В атмосфере азота суспензию 76,40 г (0,365 моль) 2-(4-нитроимидазол-1-ил)-циклогексанона, приготовленного в препаративном примере 10, в 1,2 л тетрагидрофурана охлаждали льдом с последующим добавлением 45,16 г (0,402 моль) т-бутоксида калия. Полученную красновато-пурпурную реакционную смесь перемешивали при охлаждении льдом в течение одного часа с последующим добавлением раствора 27,5 мл (0,402 моль) метилизоцианата в 100 мл тетрагидрофурана и 300 мл диметилформамида в этом порядке. Реакционную смесь перемешивали один раз, при этом ее температура повышалась до комнатной. К полученной смеси последовательно добавляли насыщенный водный раствор хлорида аммония и воду с последующей экстракцией хлороформом. Органическую фазу промывали насыщенным водным раствором поваренной соли, сушили над безводным сульфатом магния и концентрировали в вакууме. Остаток порошковали хлороформом, получая 46,93 г указанного в заголовке соединения в виде светло-коричневого порошка. Маточную жидкость концентрировали в вакууме и остаток порошковали хлороформом снова, получая 9,97 г целевого соединения в виде светло-коричневого порошка. Далее, маточную жидкость концентрировали в вакууме и остаток порошковали этилацетатом, получая 3,24 г целевого соединения в виде коричневого порошка. Таким образом, было получено всего 60,14 г целевого соединения (выход: 58%).N-Methyl-1- (4-nitroimidazol-1-yl) -2-oxocyclohexanecarbothioamide

In a nitrogen atmosphere, a suspension of 76.40 g (0.365 mol) of 2- (4-nitroimidazol-1-yl) -cyclohexanone prepared in Preparation Example 10 in 1.2 L of tetrahydrofuran was ice-cooled, followed by 45.16 g (0.402 mol) ) potassium t-butoxide. The resulting reddish-purple reaction mixture was stirred under ice cooling for one hour, followed by the addition of a solution of 27.5 ml (0.402 mol) of methyl isocyanate in 100 ml of tetrahydrofuran and 300 ml of dimethylformamide in this order. The reaction mixture was stirred once, while its temperature rose to room temperature. A saturated aqueous solution of ammonium chloride and water were successively added to the resulting mixture, followed by extraction with chloroform. The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was triturated with chloroform to obtain 46.93 g of the title compound as a light brown powder. The mother liquor was concentrated in vacuo and the residue was triturated with chloroform again to obtain 9.97 g of the target compound as a light brown powder. Next, the mother liquor was concentrated in vacuo and the residue was triturated with ethyl acetate to obtain 3.24 g of the target compound as a brown powder. Thus, a total of 60.14 g of the target compound was obtained (yield: 58%).

T. pl. ( ^o C): 205 - 208 (decomp.).

¹ H-NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ: / 1.58 - 1.78 (2H, m), 1.86 (1H, m), 1.98 (1H, m), 2.50 - 2.62 (2H, m), 3.07 (3H, d, J = 3.5 Hz), 3.08 - 3.18 (2H, m), 7.79 (1H, d, J = 1 6 Hz), 8.25 (1H, d, J = 1.6 Hz), 10.48 (1H, br s).

 Example 17

Суспензию 56,89 г (202 ммоль) N-метил-1-(4-нитроимидазол-1-ил)- 2-оксоциклогексанкарботиоамида, приготовленного в примере 16, в 160 мл метанола охлаждали льдом. К полученной суспензии порциями в течение 3 минут добавляли 2,68 г (70,8 ммоль) боргидрида натрия таким образом, что температура основной массы не превышала 10^oC. Полученную смесь перемешивали при охлаждении льдом в течение 30 минут с последующим добавлением насыщенного водного раствора хлорида аммония и воды в указанном порядке. Полученную смесь экстрагировали этилацетатом. Органическую фазу промывали насыщенным водным раствором поваренной соли и сушили над безводным сульфатом магния. Образовавшуюся органическую фазу анализировали хроматографией на колонке с силикагелем /проявитель: бензол/этилацетат (1:2)/, при этом было установлено, что продукт этой стадии состоит из низкополярного диастереомера (L-форма, R_f : 0,41) и высокополярного диастереомера (M-форма, R_f : 0,29) в соотношении 2: 1. Органическую фазу концентрировали. В ходе концентрирования начиналось выпадение кристаллов. Образовавшиеся таким образом кристаллы извлекали фильтрованием. Таким образом было получено целевое соединение в форме диастереомера в виде бледно-желтого кристалла (выход: 50%).2-Hydroxy-N-methyl-1- (4-nitroimidazol-1-yl) -cyclohexanecarbothioamide (L-form)

A suspension of 56.89 g (202 mmol) of N-methyl-1- (4-nitroimidazol-1-yl) - 2-oxocyclohexanecarbothioamide prepared in Example 16 in 160 ml of methanol was ice-cooled. To the resulting suspension, 2.68 g (70.8 mmol) of sodium borohydride was added in portions over 3 minutes so that the temperature of the bulk did not exceed 10 ^° C. The resulting mixture was stirred under ice-cooling for 30 minutes, followed by the addition of a saturated aqueous solution ammonium chloride and water in that order. The resulting mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The resulting organic phase was analyzed by silica gel column chromatography / developer: benzene / ethyl acetate (1: 2) /, and it was found that the product of this step consists of a low-polar diastereomer (L-form, R _f : 0.41) and a high-polar diastereomer (M-form, R _f : 0.29) in a ratio of 2: 1. The organic phase was concentrated. During the concentration, precipitation of crystals began. The crystals thus formed were recovered by filtration. Thus, the desired compound was obtained in the form of a diastereomer in the form of a pale yellow crystal (yield: 50%).

T. pl. ( ^o C): 198 - 201 (decomp.).

¹ H-NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ: 1.06 (1H, m), 1.28 - 1.48 (2H, m), 1.52 (1H, m), 1.60 ( 1H, m), 1.83 (1H, m), 2.45 (1H, m), 2.55 (1H, m), 2.99 (3H, s), 4.64 (1H, m, at adding D ₂ O, dd, J = 10.3, 3.5 Hz), 5.87 (1H, br., disappeared when adding D ₂ O), 8.12 (1H, d, J = 1.1 Hz ), 8.54 (1H, d, J = 1.1 Hz), 9.48 (1H, br.s., disappeared with the addition of D ₂ O).

 Example 18

К суспензии 4,99 г (17,5 ммоль) 2-гидрокси-N-метил-1-(4- нитроимидазол-1-ил)циклогексанкарботиоамида (L-форма), приготовленного в примере 17, в 50 мл дихлорметана добавляли 2,7 мл (19,4 ммоль) триэтиламина, 4,38 г (19,4 ммоль) бензойного ангидрида и 215 мг (1,8 ммоль) N,N-диметиламинопиридина. Полученную смесь перемешивали при комнатной температуре в течение 14 часов, получая оранжевый раствор, затем к нему добавляли насыщенный раствор бикарбоната натрия. Полученную смесь экстрагировали этилацетатом. Органическую фазу промывали последовательно водой и насыщенным водным раствором поваренной соли, сушили над безводным сульфатом магния и концентрировали в вакууме. Остаток (7,5 г) очищали хроматографически на колонке с силикагелем /растворитель: дихлорметан/ацетон (от 20:1 до 5:1)/ и перекристаллизовывали из дихлорметана/диизопропилового эфира, получая 3,15 г целевого соединения в виде бледно-желтых кристаллов (выход: 46%).2-Benzoyloxy-N-methyl-1- (4-nitroimidazol-1-yl) -cyclohexanecarbothioamide

To a suspension of 4.99 g (17.5 mmol) of 2-hydroxy-N-methyl-1- (4-nitroimidazol-1-yl) cyclohexanecarbothioamide (L-form) prepared in Example 17, 2 were added to 50 ml of dichloromethane. 7 ml (19.4 mmol) of triethylamine, 4.38 g (19.4 mmol) of benzoic anhydride and 215 mg (1.8 mmol) of N, N-dimethylaminopyridine. The resulting mixture was stirred at room temperature for 14 hours to give an orange solution, then a saturated sodium bicarbonate solution was added thereto. The resulting mixture was extracted with ethyl acetate. The organic phase was washed successively with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue (7.5 g) was purified by silica gel column chromatography / solvent: dichloromethane / acetone (20: 1 to 5: 1) / and recrystallized from dichloromethane / diisopropyl ether to obtain 3.15 g of the target compound as pale yellow crystals (yield: 46%).

T. pl. ( ^o C): 209 - 210.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.32 (1H, m), 1.56 - 1.88 (4H, m), 2.34 (1H, brd, J = 13.2, 4.2 Hz), 2.56 (1H, broad d, J = 15.2 Hz), 3.00 (1H, ddd, J = 15.3, 12.5, 3.1 Hz), 3.11 (3H, d, J = 4.8 Hz), 6.27 (1H, dd, J = 10.8, 3.8 Hz), 7.46 (2H, t, J = 7 , 7 Hz), 7.59 (1H, t, J = 7.5 Hz), 7.75 (1H, br s), 7.89 (2H, d, J = 7.9 Hz), 7, 95 (1H, d, J = 1.3 Hz), 8.21 (1H, d, J = 1.3 Hz).

 Example 19

6,15 г (12,4 ммоль) 2-бензилокси-1-((4-метоксибензилтио)(метил)- 1-(4-нитроимидазол-1-ил)циклогексан, приготовленного в препаративном примере 14, растворяли в 25 мл трифторуксусной кислоты при охлаждении льдом с последующим добавлением 5 мл анизола. Полученную смесь перемешивали при 0^oC в течение 10 минут, получая темно-коричневый раствор, который выливали на смесь, содержащую водный раствор бикарбоната натрия и лед. Полученную смесь экстрагировали этилацетатом. Органическую фазу промывали насыщенным водным раствором поваренной соли, сушили над безводным сульфатом магния и концентрировали в вакууме. Остаток (8,02 г) очищали хроматографией на колонке с силикагелем /растворитель: дихлорметан/ацетон (40:1)/ и перекристаллизовывали из дихлорметана/диизопропилового эфира, получая 3,14 г целевого соединения в виде бесцветных кристаллов (выход: 67%).2-Benzyloxy-N-methyl-1- (4-nitroimidazol-1-yl) -cyclohexanecarbothioimide

6.15 g (12.4 mmol) of 2-benzyloxy-1 - ((4-methoxybenzylthio) (methyl) - 1- (4-nitroimidazol-1-yl) cyclohexane prepared in Preparation Example 14 was dissolved in 25 ml of trifluoroacetic acid under ice cooling, followed by the addition of 5 ml of anisole.The resulting mixture was stirred at 0 ^° C. for 10 minutes to give a dark brown solution, which was poured onto a mixture containing aqueous sodium bicarbonate and ice.The mixture was extracted with ethyl acetate. saturated aqueous sodium chloride solution, dried over bezve magnesium sulfate and concentrated in vacuo.The residue (8.02 g) was purified by silica gel column chromatography / solvent: dichloromethane / acetone (40: 1) / and recrystallized from dichloromethane / diisopropyl ether to obtain 3.14 g of the target compound as colorless crystals (yield: 67%).

T. pl. ( ^o C): 165 - 166.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.98 (1H, qt, J = 13.5, 3.4 Hz), 1.38 (1H, qd, J = 12 6, 3.7 Hz), 1.50 (1H, sq.t. J = 12.9, 3.7 Hz), 1.70 (1H, m), 1.76 (1H, m), 2 14 (1H, m), 2.37 (1H, d.c. J = 15.4, 2.7 Hz), 2.97 (1H, ddd, J = 15.5, 13.8, 3, 8 Hz), 3.14 (3H, d, J = 4.8 Hz), 4.50 (1H, d, J = 10.8 Hz), 4.65 (1H, dd, J = 12.0, 4.3 Hz), 4.67 (1H, d, J = 10.8 Hz), 7.22 (2H, dd, J = 7.6, 1.7 Hz), 7.28 - 7.36 ( 3H, m), 7.65 (1H, br.s), 7.88 (1H, d, J = 1.6 Hz), 8.10 (1H, d, J = 1.6 Hz).

 Example 20

К суспензии 6,06 г (21,5 ммоль) N-метил-1-(4-нитроимидазол-1-ил)- 2-оксоциклогексанкарботиоамида, приготовленного в примере 16, в 50 мл пиридина добавляли 10,01 г (62,7 ммоль) O-бензилгидроксиламина- гидрохлорида. Полученную смесь перемешивали при нагревании при 100^oC в течение 19 часов и охлаждали, давая ей постоять. К образовавшейся в результате смеси добавляли насыщенный водный раствор бикарбоната натрия с последующей экстракцией этилацетатом. Органическую фазу промывали насыщенным водным раствором поваренной соли, сушили над безводным сульфатом магния и концентрировали в вакууме. Остаток (12,9 г) очищали хроматографически на колонке с силикагелем /растворитель: дихлорметан/ацетон (от 30:1 до 5:1)/ и перекристаллизовывали из дихлорметана/этилацетата, получая 2,27 г целевого соединения в виде бесцветных кристаллов (выход: 275 г).Anti-2-benzyloxyimino-N-methyl-1- (4-nitroimidazol-1-yl) cyclohexanecarbothioamide

To a suspension of 6.06 g (21.5 mmol) of N-methyl-1- (4-nitroimidazol-1-yl) - 2-oxocyclohexanecarbothioamide prepared in Example 16, 10.01 g (62.7) were added to 50 ml of pyridine mmol) O-benzylhydroxylamine hydrochloride. The resulting mixture was stirred under heating at 100 ^° C. for 19 hours and cooled to allow it to stand. A saturated aqueous sodium bicarbonate solution was added to the resulting mixture, followed by extraction with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue (12.9 g) was purified by silica gel column chromatography / solvent: dichloromethane / acetone (30: 1 to 5: 1) / and recrystallized from dichloromethane / ethyl acetate to obtain 2.27 g of the target compound as colorless crystals (yield : 275 g).

T. pl. ( ^o C): 175 - 177.

¹ H-NMR (400 MHz, CDCl ₂ ) δ: 1.58 - 1.76 (3H, m), 1.84 (1H, m), 2.39 (1H, ddd, J = 14.1, 8 4, 3.5 Hz), 2.49 (1H, ddd, J = 15.6, 8.3, 5.0 Hz), 2.73 (1H, m), 2.92 (1H, m) , 3.02 (3H, d, J = 4.8 Hz), 5.10 (2H, AB square J = 12.3 Hz), 7.29 (2H, m), 7.36 - 7.41 (3H, m), 7.39 (1H, d, J = 1.6 Hz), 7.70 (1H, d, J = 1.6 Hz), 8.08 (1H, br s).

 Example 21

К суспензии 6,0 г 2-(2-трифторметилимидазо/1,2-a/пиридин- 6-ил)циклогексанона, приготовленного в препаративном примере 15, в 70 мл тетрагидрофурана добавляли при охлаждении льдом 2,63 г т-бутоксида калия. Полученную смесь перемешивали один час с последующим добавлением раствора 1,7 г метилизотиоцианата в 5 мл тетрагидрофурана. Затем к полученной смеси добавляли 7 мл N,N-диметилформамида. Через час реакционную смесь выливали в насыщенный водный раствор хлорида аммиака и затем экстрагировали хлороформом. Органическую фазу сушили над безводным сульфатом магния и перегоняли для удаления растворителя. Остаток очищали хроматографией на колонке с силикагелем /растворитель: дихлорметан/метанол (50 : 1)/, и полученное твердое вещество промывали эфиром, получая 5,99 г целевого соединения в виде белого порошка (выход: 79%).1- (2-Trifluoromethylimidazo / 1,2-a / pyridin-6-yl) -R-methyl-2-oxocyclohexanecarbothioamide

To a suspension of 6.0 g of 2- (2-trifluoromethylimidazo / 1,2-a / pyridin-6-yl) cyclohexanone prepared in Preparative Example 15 in 70 ml of tetrahydrofuran was added 2.63 g of potassium t-butoxide under ice-cooling. The resulting mixture was stirred for one hour, followed by the addition of a solution of 1.7 g of methylisothiocyanate in 5 ml of tetrahydrofuran. Then, 7 ml of N, N-dimethylformamide was added to the resulting mixture. After one hour, the reaction mixture was poured into a saturated aqueous solution of ammonia chloride and then extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography / solvent: dichloromethane / methanol (50: 1) /, and the obtained solid was washed with ether to obtain 5.99 g of the target compound as a white powder (yield: 79%).

T. pl. (0 ^o C): 116 - 120.

¹ H-NMR (400 MHz, CDCl ₂ ) δ: 1.76 - 2.12 (4H, m), 2.51 - 2.63 (2H, m), 2.69 (1H, m), 2 81 (1H, m), 3.18 (3H, d, J = 4.8 Hz), 7.15 (1H, dd, J = 2.0, 9.7 Hz), 7.61 (1H, d, J = 9.7 Hz), 7.86 (1H, s), 8.08 (1H, m), 8.79 (1H, broad).

 Example 22

1-(2-Трифторметилимидазо/1,2-a/пиридин-6-ил)-N-метил-2- оксоциклогексанкарботиоамид, приготовленный в примере 21, подвергали препаративной хроматографии с использованием оптически активной колонки для проведения оптического разделения.(-) - 1- (2-Trifluoromethylimidazo / 1,2-a / pyridin-6-yl) -N-methyl-2-oxocyclohexanecarbothioamide

The 1- (2-Trifluoromethylimidazo / 1,2-a / pyridin-6-yl) -N-methyl-2-oxocyclohexanecarbothioamide prepared in Example 21 was subjected to preparative chromatography using an optically active column for optical separation.

 Characterization of preparative chromatography.

 Column: Hiracel (registered trademark), (product of the company Deicel Chemical Industries, Ltd.), (250 mm x 20 mm inner dia.).

 Solvent: n-hexane / 2-propanol (3: 1 (v / v)).

 Flow rate: 6 ml / min.

 Detection: UV detector (254 nm).

 Peak for preparatory purposes: a later peak between two peaks.

 The solid obtained by preparative chromatography was recrystallized from n-hexane / ethyl acetate to give the title compound as white crystals.

 The optical purity of this product, determined by high performance liquid chromatography using a chiral column, was 99%.

 Characterization of high performance liquid chromatography.

 Column: Hiracel (registered trademark), (product of the company Deicel Chemical Industries, Ltd.), (250 mm x 4.6 mm inner diameter).

 Solvent: n-hexane / 2-propanol (3: 1 (v / v)).

 Flow rate: 1.0 ml / min.

 Detection: UV detector (254 nm).

 Retention time: 20.0 min (retention times of racemic modification were 12.8 and 20.0 minutes).

T. pl. ( ^o C): 184 - 186.

-229^o (C = 1,02, метанол).Specific rotation:

-229 ^° (C = 1.02, methanol).

 Example 23

3,86 г т-бутоксида калия растворяли в 30 мл смеси (1 : 1 (об./об.)) тетрагидрофурана и гексаметилфосфорного триамида. Полученный раствор охлаждали льдом с последующим добавлением по каплям раствора 3,68 г 6-((4-хлорбутил)сульфинилметил)-2- метилимидазо/1,2-a/пиридина, приготовленного в перепаративном примере 18, в 30 мл смеси (1 : 1 (об./об.)) тетрагидрофурана и гексаметилфосфорного триамида. Через 1,5 часа в полученную смесь прикапывали 3,45 мл дисульфида углерода с последующим перемешиванием образовавшейся смеси при +10^oC. Через 1,5 часа в смесь прикапывали 3,57 мл метилиодида, и полученную смесь перемешивали при комнатной температуре в течение 1,5 часов и выливали в ледяную воду. Полученную смесь экстрагировали этилацетатом. Органическую фазу промывали водой и насыщенным водным раствором поваренной соли, сушили над безводным сульфатом магния и перегоняли для удаления растворителя, получая коричневое твердое вещество.2- (2-Methylimidazo / 1,2-a / pyridin-6-yl) -N-methyltetrahydrothiopyran-2-carbothioamide 1-oxide

3.86 g of potassium t-butoxide was dissolved in 30 ml of a mixture (1: 1 (v / v)) of tetrahydrofuran and hexamethylphosphoric triamide. The resulting solution was cooled with ice, followed by the dropwise addition of a solution of 3.68 g of 6 - ((4-chlorobutyl) sulfinylmethyl) -2-methylimidazo / 1,2-a / pyridine, prepared in the reparative Example 18, in 30 ml of a mixture (1: 1 (v / v)) tetrahydrofuran and hexamethylphosphoric triamide. After 1.5 hours, 3.45 ml of carbon disulfide was added dropwise to the resulting mixture, followed by stirring of the resulting mixture at + 10 ^° C. After 1.5 hours, 3.57 ml of methyl iodide was added dropwise to the mixture, and the resulting mixture was stirred at room temperature for 1 , 5 hours and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and distilled to remove the solvent to obtain a brown solid.

 This solid was dissolved in 10 ml of methanol, 10 ml of a 40% solution of methylamine in methanol was added to the solution. The resulting mixture was stirred at room temperature for one hour and distilled to remove the solvent. The residue was purified by silica gel column chromatography (solvent: dichloromethane / methanol (20: 1)), and the obtained solid was washed with ether to obtain 160 mg of the target compound as a white powder (yield: 3%).

T. pl. ( ^o C): 227 - 231.

¹ H-NMR (400 MHz, CDCl ₂ ) δ: 1.55 - 1.81 (3H, m), 2.08 - 2.24 (2H, m), 2.42 (3H, d, J = 0 , 7 Hz), 2.71 (1H, m), 3.04 (1H, m), 3.23 (3H, d, J = 4.8 Hz), 3.88 (1H, m), 6, 91 (1H, d, J = 9.5 Hz), 7.03 (1H, dd, J = 2.0 Hz, 9.5 Hz), 7.24 (1H, s), 8.29 (1H, s), 9.39 (1H, broad).

 Example 24

2-(2-Метилимидазо/1,2-a/пиридин-6-ил)-N-метилтетрагидротиопиран- 2-карботиоамид 1-оксид, приготовленный в примере 20, подвергали препаративной хроматографии с использованием оптически активной колонки для проведения оптического разделения.(-) - 2- (2-Methylimidazo / 1,2-a / pyridin-6-yl) -N-methyltetrahydrothiopyran-2-carbothioamide 1-oxide

2- (2-Methylimidazo / 1,2-a / pyridin-6-yl) -N-methyltetrahydrothiopyran-2-carbothioamide 1-oxide prepared in Example 20 was subjected to preparative chromatography using an optically active column for optical separation.

 Characterization of preparative chromatography.

 Column: Hiracel (registered trademark), (product of the company Deicel Chemical Industries, Ltd.), (750 mm x 50 mm inner dia.).

 Solvent: n-hexane / 2-propanol / diethylamine (750: 250: 1).

 Flow rate: 100 ml / min.

 Detection: UV detector (254 nm).

 Peak for preparatory purposes: a later peak between two peaks.

 The solid obtained by preparative chromatography was purified by silica gel column chromatography (solvent: dichloromethane / methanol (10: 1)) and recrystallized from aqueous ethanol to give the title compound as white crystals.

 The optical purity of this product, determined by high performance liquid chromatography using a chiral column, was 100%.

 Characterization of high performance liquid chromatography.

 Column: Hiracel (registered trademark), (product of the company Deicel Chemical Industries, Ltd.), (250 mm x 4.6 mm inner diameter).

 Solvent: n-hexane / 2-propanol / diethylamine (750: 250: 1).

 Flow rate: 0.7 ml / min.

 Detection: UV detector (254 nm).

 Retention time: 19.4 minutes (retention times of racemic modification were 14.5 and 19.4 minutes).

T. pl. ( ^o C): 219 - 223 (decomp.).

-352^o (C = 1,02, метанол).Specific rotation:

-352 ^° (C = 1.02, methanol).

Claims (6)

1. Derivatives of thioformamide of General formula I

in which y represents a group of formulas:

CH (OH),

Z is —CH ₂ -;
A represents unsubstituted or substituted imidazopyridyl;
R ¹ , R ² , R ³ and R ⁴ independently represent hydrogen or lower alkyl,
or their pharmacologically acceptable salts.  2. The thioformamide derivatives according to claim 1, wherein the imidazopyridyl group is an imidazo [1,2-a] pyridin-6-yl, or pharmacologically acceptable salts thereof. 3. The thioformamide derivatives of claim 1, wherein the optionally substituted imidazopyridyl group is
imidazo [1,2-a] pyridyl group selected from the group consisting of imidazo [1,2-a] pyridin-2-yl, imidazo [1,2-a] pyridin-3-yl, imidazo [1, 2-a] pyridin-5-yl, imidazo [1,2-a] pyridin-6-yl, imidazo [1,2-a] pyridin-7-yl, imidazo [1,2-a] pyridin-8 -ila;
imidazo [1,5-a] pyridyl group selected from the group consisting of imidazo [1,5-a] pyridin-1-yl, imidazo [1,5-a] pyridin-3-yl, imidazo [1 , 5-a] pyridin-5-yl, imidazo [1,5-a] pyridin-6-yl, imidazo [1,5-a] pyridin-7-yl, and imidazo [1,2-a] pyridine -8-silt;
imidazo [4,5-b] pyridyl group selected from the group consisting of imidazo [4,5-b] pyridin-1-yl, imidazo [4,5-b] pyridin-2-yl, imidazo [4, 5-b] pyridin-3-yl, imidazo [4,5-b] pyridin-5-yl, imidazo [4,5-b] pyridin-6-yl and imidazo [4,5-b] pyridin-7 -ila; or
imidazo [4,5-c] pyridyl group selected from the group consisting of imidazo [4,5-c] pyridin-1-yl, imidazo [4,5-c] pyridin-2-yl, imidazo [4 , 5-c] pyridin-3-yl, imidazo [4,5-c] pyridin-4-yl, imidazo [4,5-c] pyridin-6-yl, and imidazo [4,5-c] pyridin-7-yl,
or their pharmacologically acceptable salts. 4. The thioformamide derivatives of claim 1, wherein Y is CH (OH) -, Z is —CH ₂ -, R ¹ , R ² and R ³ are hydrogen atoms, R ⁴ is methyl, and A is imidazopyridyl, or pharmacologically acceptable salts.  5. The derivatives of thioformamide according to claim 1 or their pharmacologically acceptable salts having the ability to activate the output of potassium ions through the tubule.  6. Derivatives of thioformamide according to claim 1 or their pharmacologically acceptable salts having antihypertensive activity.

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