New amide derivatives and pharmaceutical composition, promoting insulin secretion and increases sensitivity to insulin

 

(57) Abstract:

The invention relates to new amide derivatives of General formula (I) or their salts, where a means thiazolidin, imidazoline, triazoline, benzimidazolyl, benzothiazolyl, thiadiazolyl, imidazopyridine or imidazothiazole; X is a bond, -NR5-, -NR5CO-, -NR5CONH-, NR5SO2-, -NR5C(= NH)NH-; R1means H, lower alkyl, aryl, pyridyl, thienyl, furyl, thiazolyl, benzimidazolyl, imidazopyridine, triazolyl, thiadiazolyl, imidazolyl, imidazothiazoles, benzothiazolyl, cyclohexyl, which may be optionally substituted with halogen, lower alkyl, -OH, -CN, -NO2, -CF3, -NH2, -O-lower alkyl, and the Deputy of the lower alkyl may be substituted by phenyl, naphthyl, fullam, tanila or pyridium;2a, R2bmean H or lower alkyl; R3means hydrogen or lower alkyl; R4a, R4bmean H or HE, or taken together form a group =O or =N-O-lower alkyl; R5means H or lower alkyl. Disclosed are also a number of specific compounds and pharmaceutical composition, promoting insulin secretion and increases sensitivity to insulin. The invention can be used in kachestvenie relates to pharmaceutical preparations in particular to pharmaceutical compositions containing the new amide derivative or its salt and a pharmaceutically acceptable carrier.

Diabetes is a disease that is accompanied by continuous hyperglycemic condition and allegedly the result of many factors related to the environment, and genetic factors. The main controlling factor in blood sugar is insulin, and it is known that hyperglycemia seen in case of lack of insulin, or in cases, when there is excessive there are other factors inhibition of insulin action (such as genetic factors, lack of exercise, obesity and stress).

There are two types of diabetes; diabetes is divided into insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes (NIDDM). It is argued that 95% or more of patients with diabetes Japanese have non-insulin-dependent type of diabetes, and because of changes in lifestyle there is a problem of increasing the number of such patients.

With regard to the treatment of diabetes, diet therapy, therapeutic exercise and positive trend in obesity are mostly done in mild cases, is such as sulfonylureas, and means that can help increase sensitivity to insulin). In severe cases is the introduction of insulin therapy. However, it is believed that the above-mentioned effects on insulin secretion and effect on the increased susceptibility to insulin have a completely different mechanism of action; if connections are made with both types of such impact, it should be expected that they will be therapies for diabetes with a new mechanism of action, with exceptionally high utility and with the ability to implement more stringent control of blood sugar. In the literature was described BRL 35135 - [methyl-(4-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)phenoxy)acetate] as the compounds having both types of such impact (Br. J. Clin. Pharmacol., 42, 291-300, 1966), but its effect is insufficient and has already terminated its improvement as medicines.

On the other hand, in the European patent 611003 described substituted derivatives phenylsulfanyl the following General formula and States that they are useful in the treatment of obesity, hyperglycemia, etc. due to their selective stimulatory effect on3-adrenaline receptor of human rights. However, in the absence of susceptibility to insulin.

< / BR>
(refer to the above patent for the values of the substituents in the formula).

The authors of the present invention conducted intensive study of compounds which promoting effects on insulin secretion and action, increasing sensitivity to insulin, and found that some new amide derivatives have both types of effects: promoting positive effect on insulin secretion and reinforcing effect on susceptibility to insulin, which leads to the achievement of the objective of the present invention.

Thus, the present invention relates to amide derivative of General formula (I) or salts thereof and to pharmaceutical compositions comprising the above-mentioned amide derivative or its salt and a pharmaceutically acceptable carrier, particularly a pharmaceutical composition as a therapeutic agent for the treatment of diabetes, since this compound has a promoting effect on insulin secretion and action, increasing sensitivity to insulin.

< / BR>
where a means of heteroaryl;

X is a bond, O, S, -NR5-, -NR5CO-, -NR5CONH-, -NR5SO2- or-NR5
R2a, R2bmean H or lower alkyl and may be the same or different;

R3means hydrogen or lower alkyl;

R4a, R4bmean H or HE, may be the same or different, or4aand R4btogether form a group =O or =N~O-lower alkyl and

R5means H or lower alkyl, hereinafter the same.

For compound (I) of the present invention particularly preferred compounds are amide derivatives, And in which means thiazolidin, imidazoline, triazoline, benzimidazolyl, benzothiazolyl, thiadiazolyl, imidazopyridine or imidazothiazole and X represents a bond, O, S, or-NR5- or their salts; amide derivatives, And in which means thiazolidin or imidazoline, X is-NR5-, a R1means lower alkyl, substituted by an optionally substituted aryl, or optionally substituted aryl, or their salts.

Especially preferred are the following compounds:

(S)-2-(2-benzylamino-4-thiazol-4-yl)-4'-[2-[(2-hydroxy-3-phenoxypropan)amino]ethyl]acetanilide;

(S)-2-[2-(3-foronline)-4-thiazol-4-yl)-4'-[2-[(2-hydroxy-3-phenoxypropan)amino]ethyl]acetanilide;

(S)-2-(2-aniline-4-thiazol-4-yl)-4'-{ 2-[(2-hydroxy-3-phenoxyphenyl

and their salts.

The present invention also relates to a pharmaceutical composition comprising the amide derivative or its salt and a pharmaceutically acceptable carrier, particularly to farm aseptically composition as a therapeutic tool for the treatment of diabetes.

As a consequence describe the compound (I) of the present invention.

The term "lower" in the General formula means normal or branched carbon chain with carbon atoms of 1 to 6, unless otherwise noted.

"Lower alkyl" is preferably a lower alkyl having from 1 to 4 carbon atoms, more preferred are methyl, ethyl or propyl. "Lower alkenyl" preferably means vinyl. "Lower quinil" preferably means ethinyl.

By "aryl" refers to aromatic hydrocarbon having from 6 to 14 carbon atoms, and preferred is phenyl or naphthyl. Under the "cycloalkyl" refers to a saturated hydrocarbon having 3 to 8 carbon atoms, and preferred is cyclohexyl. "Heteroaryl" includes 5 - and 6-membered monocyclic heteroaryl (preferably furyl, thienyl, imidazolyl, thiazolyl, triazolyl with each other (are preferred imidapril, imidazothiazoles and so on), and bicyclic heteroaryl coupled with a benzene ring (preferably benzimidazolyl, benzothiazolyl and so on).

"Heteroaryl" means the divalent radical in which of the above "heteroaryl removed two arbitrary hydrogen atom, and which preferably means thiazolidin, imidazoline, triazoline, benzimidazolyl, benzothiazolyl, thiadiazolyl, imidazopyridine or imidazothiazole.

As substituents of "optionally substituted aryl", "optionally substituted heteroaryl", "optionally substituted cycloalkyl" and "optionally substituted phenyl" can be used any of the above, and commonly used substituents and can be used many of the same or different substituents. Preferred are substituents selected from halogen atoms (F, Cl, Br, I) lower alkyl, lower alkenyl, lower quinil, -OH, -CN, -NO2, -NH2, -CF3, -O-lower alkyl, -COO-lower alkyl, -COOH, -CO-lower alkyl, -NH-lower alkyl, -N(lower alkyl)2, -CONH2, -CONH-lower alkyl, -CO-N(lower alkyl)2, -SO2-NH2, -SO2-NH-lower alkyl, -SO2-N(lower alkyl)2, -NHCO-lower alkyl is stately as the Deputy of the "optionally substituted lower alkyl" may be used optionally substituted aryl, optionally substituted heteroaryl and optionally substituted cycloalkyl.

"Communication" means the absence of the radical, and the radicals on both ends directly connected to each other.

The compound (I) of the present invention possesses at least one asymmetric carbon atom and, as a result of this, there are optical isomers such as (R) and (S) compounds, racemic compounds, diastereomers, etc. in Addition, depending on the type of Vice can be geometric isomers on double bond, such as (Z) and (E) isomers, and tautomers in the conjugate double bond. The present invention covers all of these isomers or in the form of their separate forms or as mixtures thereof. In addition, the present invention includes a hydrate, a solvate, such as a solvate with ethanol, and crystalline polymorphic substances of the compounds of formula (I).

The compound (I) of the present invention can form salts with acids. Examples of such salts are acid additive salts with mineral acids such as hydrochloric acid, Hydrobromic acid, itestosterone acid, sulfuric acid, nitric acid and phosphoric acid, and organic acid the lot, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonate acid, econsultancy acid and glutamic acid.

Methods of obtaining.

Compounds of the present invention and their salts can be obtained by using different synthetic methods, using traditional methods to build their basic skeleton or type his deputies. Typical methods for their preparation are illustrated in figure 1.

In these formulas, R4a'and R4b'denote hydrogen atoms or together form the fragment is =O or =N~O-lower alkyl; R' represents a protective group for amino group, and this notation is identical throughout the description of the present invention.

At this stage (i) compound (II) interacts with the compound (III) to carry out amidation, followed by the synthesis of the compound (IV). Alternative after carrying out the amidation reaction (i), if necessary, the compound in which R4a'and R4b'together form the fragment =O, is subjected to reduction reaction of (ii), and then synthesize the compound in which R4aAznar, compounds (II) and (III) is injected into the reaction or in a polar solvent, or by themselves in the presence of a condensing reagent at room temperature or when heated or boiled under reflux, with and implemented by the amidation. As the polar solvent is preferred tetrahydrofuran, dimethylformamide and dimethylsulfoxide. As the condensing agent, the preferred N,N'-dicyclohexylcarbodiimide, the hydrochloride of 1-ethyl-3-(N, N-dimethylamino)propylbromide, carbonyldiimidazole and diphenylphosphoryl.

"Protective group for amino group, R' represents a protective group commonly used by experts in the field of technology, and preferred examples of such a group is acyl (acetyl, and so on), -CO-O-lower alkyl (tert-butoxycarbonyl and so on), -benzyloxycarbonyl, -benzyl, and -- Si(lower alkyl)3.

"Lower alkylene" means the divalent radical in which of the above "lower alkyl" removed two arbitrary hydrogen atom, and which preferably means alkylene having from 1 to 4 carbon atoms, especially methylene or ethylene.

In the case of compounds in which R4a'and R4b'together form the fragment =O connectivity. The reduction can be carried out with stirring in the above-mentioned inert solvent in the presence of a reducing agent. Alternative catalytic hydrogenation can be carried out in the presence of palladium-on-coal (Pd/C) or similar catalysts under atmospheric or increased pressure.

As a reducing reagent preferred natrojarosite, cyanoborohydride, etc. In an inert solvent is preferred examples are methanol, ethanol, dimethylimidazolidine, acetic acid, etc. or their mixture; the solvent can be selected accordingly depending on the conditions of various reactions.

The compound (II), where R3means N can also be obtained by well-known reactions of N-alkylation to introduce the lower alkyl in the fragment R3. In particular, the compound in which R3means N, reacts with aldehydes (formaldehyde, acetaldehyde, and so on) in an inert solvent in the presence of a reducing reagent with stirring and cooling or under heating (boiling under reflux). An alternative may be conducted by catalytic hydrogenation in prisutstvie is. scheme 2).

This stage of removing the protective group in the compound (IV) is carried out for the synthesis of compound (I) of the present invention. Removing the protective group may be carried out in the usual ways. In relation to removing the protective group for amino group, it can be easily carried out (i) by treatment with an acid, such as triperoxonane acid, or a mixture of hydrochloric acid and dioxane for such protective groups as tert-butoxycarbonyl or formyl; (ii) by way catalytic reduction using palladium-on-coal (Pd/C) or similar catalyst for such protective groups as benzyl or benzyloxycarbonyl, and (iii) when treated with water or a fluoride anion (Tetra-n-butylammonium) or similar reagents for such protective groups, such as Si-(lower alkyl)3(see diagram 3).

This method is a method in which the amine (V) is introduced into the reaction with the epoxide (VI) to synthesize compound (I) of the present invention. This reaction is a process in which the amine (V) and the epoxide (VI), either by itself or in an inert solvent, as described above, are connected to each other for a time from 1 to 24 hours when heating or boiling under reflux, preeda (VI), and salts of amine (V) (for example, triptoreline, hydrochloride). In this case, the reaction mixture may be added to the base, for example sodium bicarbonate or diisopropylethylamine.

In the above easy methods to get, among other things, for the purification of the obtained substance is possible destruction of unwanted side products using recrystallization, grinding, preparative thin-layer chromatography, flash chromatography on silica gel, as described in the work of Steele (W. C. Still) with co-workers, J. Org. Chem., 43, 2923 (1978), liquid medium pressure chromatography or HPLC. The product, purified HPLC, can be allocated in the form of its corresponding salt.

Starting compound used in the above synthesis methods, can be easily obtained by methods known to experts in this field of technology. Appropriate means of obtaining the source of the compounds described in this invention (see scheme 4).

(In these formulas, R" means a hydrogen atom or aracelio protective group (e.g. aryl group, optionally substituted lower alkalinous group), in the future, these designations are the same).

This method is a method in which (i) compound (V, and (iii) conduct additional reduction of compound (VIII), as a result of this exercise the synthesis of compound (II).

Stage (i) can be carried out in the same manner as in the second method of obtaining, and under the same reaction conditions such as reaction temperature and solvent. Protection (ii) are carried out by the known method of protecting an amino group, and preferred is the use of di-tert-BUTYLCARBAMATE or similar reagents. Response recovery (iii) can be carried out by reduction with metals, catalyst recovery, and so on (see schemes 5 and 6).

(In these formulas V means a halogen atom and R"' is lower alkyl or aracelio protective group, in the future, these designations are the same).

Substituted derivatives of thiazolinediones acids, some of the compounds (III) can be obtained as described below.

The method of obtaining (A).

The compound (IX) and the compound (X) are introduced into the reaction in the above-mentioned inert solvent at room temperature or at boiling under reflux, this may be the compound obtained (Chi). Upon further hydrolysis of the compound (Chi) can be poety, and the way to make this easily understood by a person skilled in the art.

Method get ().

It is possible to obtain the compound (IIIb) from compound (XIb), which are synthesized from the known ester 2-aminothiazolyl-4-icarbonell acid generally accepted method for N-alkylation or acylation (see diagram 7).

(In these formulas, Z means-CN or-CH2-Other" in the future, these designations remain the same).

This method is a method in which the compound (XIV) and the compound (III) are entered in the amidation reaction for obtaining the compound (XV), which is then introduced into the reaction and recovery (if Z means-CN) or (b) in response unprotect (if Z denotes-CH2-Other") to obtain the compound (Va).

The amidation between the compound (XIV) and compound (III) can be carried out as the first stage of the first method as described above. The amidation can be carried out alternative well-known method using the lowest Olkiluoto ether or Arakelova ether as a reactive derivative of compound (III) instead of the compound (III). In reaction conversion of compound (XV) to compound (Va) rehabilitation and orida cobalt, of sodium borohydride or similar reagents. In addition, during this reaction, the connection with groups of R4a'and R4b'forming together fragment =O, is restored in the connection in which R4ais H and R4bis IT group. Unprotect b) can be carried out as the second stage of the first method as described above.

The compound (I) of the present invention obtained as such, can be isolated and purified in the form of free connection, in the form of its salt obtained by a commonly known procedure of formation of the salt, hydrate, MES with different solvents such as ethanol, or in the form of a crystalline polymorphic modifications. Selection or purification can be carried out using conventional chemical operations such as extraction, concentration, evaporation, crystallization, filtration, recrystallization and various chromatographic methods.

Can be allocated to different isomers through the use of physico-chemical differences between the isomers. For example, a racemic compound can be separated into pure stereochemical isomers well-known method of separation of racemates (naprimel acid (tartaric acid, etc. with the subsequent implementation of the optical separation). In the case of formation of a mixture of diastereoisomeric separation can be conducted by a conventional method such as fractional crystallization or chromatography. Optically active compounds can also be obtained using the appropriate optically active starting materials.

Industrial applicability.

Amide derivatives of the present invention represented by the General formula (I) or their salts have the effect of promoting insulin secretion and action, increasing sensitivity to insulin, and therefore can be used as therapeutic agents for the treatment of diabetes.

As confirmed by the test tolerance to glucose and hypoglycemic test models of insulin-resistant animals, which will be described below, the compounds of the present invention have as good effect, promoting insulin secretion and action, increasing sensitivity to insulin, and are useful for the treatment of diabetes.

The effect of the compounds of the present invention is confirmed by the following tests.

1. Hypoglycemic shall epostl to insulin] .

In male mice kk-lines were determined blood sugar levels when feeding (blood sugar level was 200 mg/DL or more) and they were randomly divided into several groups. The test drug was administered necessarily by mouth once a day for four days and compared the level of sugar in the blood after a period of from 15 to 18 hours from the last injection with glucose levels before injection (n=6), and then calculated the rate of hypoglycemia (%). Blood was sampled from the tail vein of the mouse using a glass capillary tube (pretreated with heparin), it was removed protein and to establish the level of blood sugar is the amount of glucose (mg/DL) in the supernatant was determined by calorimetric method oxidase oxidation of glucose.

As a result, found that the compounds of the present invention significantly lowers the blood sugar level compared to the blood sugar level prior to the introduction of the test drug in both cases and oral, and subcutaneous injections and speed (coefficients) of hypoglycemia with the introduction of 10 mg/kg was 47% (p<0,01) for compounds of example 1, 52% (p<0,01) for compounds of example 2-b, 50% (p<0,01) for connection etenia have excellent action, increasing sensitivity to insulin.

2. Test for glucose tolerance on standard mice [action, promoting insulin secretion].

Male rats of the SD line (at the age of six weeks) were subjected to fasting during the day, randomly divided into several groups and tested on oral glucose tolerance (OGTT) (n=4). The test compound was administered orally 30 min before the injection of glucose (2 g/kg by mouth). The blood was collected by a glass syringe treated with heparin, from abdominal artery in rats during anesthesia pentobarbital, it was removed protein and to establish the level of blood sugar is the amount of glucose (mg/DL) in the supernatant was determined by calorimetric method oxidase oxidation of glucose. The level of insulin was determined by establishing the number of insulin (ng/ml) in plasma radioimmune assay (RIA). As a result, when the introduction of 10 mg/kg compound of example 4, the secretion of insulin was increased threefold from the point of view of the AUC-ratio and blood glucose levels were reduced by 90% compared to a sugar level prior to the introduction. Based on this result, it was established that the compounds of the present invention have excellent activity, promoting Auda useful as an anti-obesity or means, lowering lipid levels.

Pharmaceutical composition comprising one or more compounds of the present invention or their salts as effective(data) ingredient(s) may be obtained using a conventional pharmaceutically acceptable carrier. Introduction the pharmaceutical compositions may be implemented in any form of oral and parenteral administration using injections, suppositories, percutaneous means, medicines for inhalation or subcutaneous injections.

Question about the dose may reasonably be resolved in each case when considering symptoms, age, sex, etc. of the patient, but usually it is for adults from about 0.01 to 100 mg/kg daily in the case of oral administration, and this introduction is carried out as a lump sum or divided into two or four portions. If the symptomatology is an intravenous infusion, the injection is carried out once or several times a day ranging from 0.001 to 10 mg/kg per injection for an adult.

As for the media for the pharmaceutical form, the examples can serve as a solid or liquid non-toxic substances used in the pharmaceutical industry.

As for solid compositionality, granules, etc., In such a solid composition is mixed with one or more active connection with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, agar, pectin, metasilicate-magnesium aluminate and magnesium aluminate. In addition, the composition may be incorporated with the conventional method of incremental components other than the inert diluent, such as masively, for example magnesium stearate, shredders, for example, the glycolate, calcicolous, stabilizers such as lactose, and an auxiliary dispersant, such as glutamic acid and aspartic acid. If necessary, tablets and capsules can be enclosed in a shell made of sugar or film of a substance soluble in the stomach or intestines, such as sucrose, gelatin, hydroxypropylcellulose and phthalate of hydroxypropylmethylcellulose.

Liquid compositions for oral administration comprise pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and contain a generally used inert diluent such as purified water and ethanol. In addition, such compositions can contain, in addition estately, oblagorazhivanii, taste enhancers, aromatic agents, antiseptics, etc.

Injections for parenteral administration comprise sterile aqueous and non-aqueous solutions, suspensions and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Non-aqueous solutions and suspensions include, for example, propylene glycol, polyethylene glycol, vegetable oils such as cocoa butter, olive oil and sesame oil, alcohols such as ethanol, gum Arabic (of the Arabian gum, Polysorbate 80 (trade mark) etc., in Addition, such compositions can contain auxiliary agents such as isotherwise tools, antiseptics, moisturizers, emulsifiers, stabilizers (e.g., lactose), and auxiliary dispersing agents (for example, glutamic acid and aspartic acid). They can be sterilized, for example, by filtration through a filter that protects against bacteria, connection with a bactericidal substance or radiation. They can also be used by preparation of sterile solid compositions prior to use, this composition is then dissolved in sterile water or in storiesleggy examples. Compounds of the present invention is not limited to those mentioned in the following examples compounds and, in addition, they cover all of the connections already described General formula (I), their salts, their hydrates, their geometric and optical isomers and crystalline polymorphs. The way to obtain the starting compounds used in the present invention, also shown below as reference examples.

Referential example 1.

In the cyclization reaction was introduced to 1.87 g of N-benzylethanolamine and 1,82 g methyl-4-chloroacetoacetate, they were subjected to a cyclization reaction to obtain 3,10 g of methyl-(2-benzylimidazole-4-yl)acetate.

Referential example 2.

In the hydrolysis reaction was introduced 3,05 g of methyl-(2-benzylimidazole-4-yl)acetate to obtain 1.12 g (2-benzylimidazole-4-yl)acetic acid.

Reference example 3.

In the alkylation reaction was introduced 0.8 g of methyl 2-(3-effect-free remedy 1H-1,2,4-triazole-5-yl)acetate and 0.79 g of benzylbromide to get 0,79 g ethyl-2-(3-benzylmorphine-1H-1,2,4-triazole-5-yl)acetate.

Reference example 4.

In response dibenzylamine entered 8,72 g of the hydrochloride of ethyl-(1-benzylimidazole-2-yl)acetate to obtain 4,74 g GI who were 1.07 g of the hydrochloride of ethyl-(imidazol-2-yl)acetate and 1.69 g of 4-chlorobenzylamino to obtain 0.75 g of ethyl-[1-(4-chlorbenzyl)imidazol-2-yl)]acetate.

Reference example 6.

In the reaction of alkylation entered 15.2 g of 2-methylimidazole and 40.7 g of 4-nitrobenzimidazole to obtain 24.8 g of 2-methyl-1-(4-nitrobenzyl)imidazole.

Reference example 7.

To obtain a 13.9 g of ethyl-[1-(4-nitrobenzyl)imidazol-2-yl] acetate in the reaction entered 24.8 g of 2-methyl-1-(4-nitrobenzyl)imidazole with 22 ml of ethylchloride in the presence of 32 ml of triethylamine.

Reference example 8.

In reaction to the disclosure of the cycle entered 7,71 g (S)-2-phenoxyethylamine and 10,34 g of the hydrochloride of 2-(4-nitrophenyl)ethylamine in the presence of 5.20 g of triethylamine to obtain 6,35 g (S)-1-phenoxy-3-{[2-(4-nitrophenyl)ethyl]amino}-2-propanol.

Reference example 9.

In the reaction of acylation entered 6,35 g (S)-1-phenoxy-3-{[2-(4-nitrophenyl)ethyl]amino}-2-propanol and 4 g of di-tert-BUTYLCARBAMATE to get 7,94 g of tert-butyl(S)-N-(2-hydroxy-3-phenoxypropan)-N-[2-(4-nitrophenyl)ethyl] carbamate.

Reference example 10.

In response recovery entered 7,94 g of tert-butyl(S)-N-(2-hydroxy-3-phenoxypropan)-N-[2-(4-nitrophenyl)ethyl] carbamate for receipt of 5.15 g of tert-butyl(S)-N-(2-hydroxy-3-phenoxypropan)-N-[2-(4-AMINOPHENYL)ethyl]carbamate.

Reference example 11.

In response dehydr is etona to get 8,63 g (S)-1-{2-[3-(4-nitrophenyl)propyl]amino}-3-phenoxy-2-propanol.

Referential example 12.

In the amidation reaction is introduced 621 mg of tert-butyl(S)-N-(2-hydroxy-3-phenoxypropan)-N-[2-(4-AMINOPHENYL)ethyl] carbamate and 403 mg of 2-(2-methylthiazole-4-yl)acetic acid to obtain 765 mg of tert-butyl(S)-N-(2-hydroxy-3-phenoxypropan)-N-{2-[4-[[2-(2-methylthiazole-4-yl)acetyl]amino]phenyl]ethyl} carbamate.

Reference example 13.

In response recovery entered 2.15 g of tert-butyl(S)-N-[(2-hydroxy-3-phenoxy)ethyl] -N-{2-[4-[2-[1-(4-nitrobenzyl)imidazol-2-yl]atsetamino]phenyl] ethyl} carbamate in the presence of 4 ml of 4 n solution of hydrogen chloride in ethyl acetate to obtain 960 mg of tert-butyl(S)-N-[(2-hydroxy-3-phenoxy)ethyl]-N-{2-[4-[2-(imidazol-2-yl)atsetamino]phenyl]ethyl}carbamate.

Reference example 14.

In the reaction of alkylation introduced 340 mg of tert-butyl(S)-N-[(2-hydroxy-3-phenoxy)ethyl] -N-[2-[4-[2-(imidazol-2-yl)atsetamino] phenyl]ethyl]carbamate and 110 mg of 4-methoxybenzylamine to obtain 160 mg of tert-butyl(S)-N-[(2-hydroxy-3-phenoxy)ethyl]-N-[2-[4-[2-[1-(4-methoxybenzyl)imidazol-2-yl]atsetamino]phenyl]ethyl]carbamate.

Reference example 15.

In response recovery entered 370 mg of tert-butyl(S)-N-(2-hydroxy-3-phenoxypropan)-N-[2-[4-[[2-(2-aminothiazol-4-yl)-2-oxoacyl] amino]phenyl] ethyl] carbamate for palatal]carbamate.

Reference example 16.

In the amidation reaction is introduced 960 mg of tert-butyl 2-(4-AMINOPHENYL)ethylcarbamate and (2-benzylimidazole-4-yl)acetic acid to obtain 500 mg of tert-butyl-[2-[4-[2-(2-benzylimidazole-4-yl)acetylamino]phenyl]ethyl] carbamate.

Reference example 17.

In the reaction of removing the protective group introduced 1.0 g of tert-butyl-[2-[4-[2-(2-benzylimidazole-4-yl)acetylamino]phenyl]ethyl]carbamate to obtain 690 mg of N-[4-(2-amino-ethyl)phenyl]-2-(2-benzylimidazole-4-yl)ndimethylacetamide.

Reference example 18.

In response recovery entered 6,40 g of N-methyl-4-cyanomethylene to obtain 4.61 in g of 2-(4-methylaminophenol)ethylamine.

Reference example 19.

In the reaction of acylation entered 2,03 g of 2-(4-methylaminophenol)ethylamine and 3,20 g of di-tert-BUTYLCARBAMATE to get 3,20 g of tert-butyl 2-(4-methylaminophenol)ethylcarbamate.

Reference example 20.

In the reaction of condensation introduced to 1.14 g of ethyl-2-(1-methylbenzimidazole-2-yl)acetate and 970 mg of 4-aminobenzaldehyde to obtain 1.19 g of 4'-cyanomethyl-2-(1-methylbenzimidazole-2-yl)acetanilide.

Reference example 21.

In response recovery introduced to 1.15 g of 4'-cyanomethyl-2-(1-methylbenzimidazole-2-yl)acetanilide is 2">

In the reaction of reductive amination entered 1.52 g of tert-butyl(S)-N-[2-(4-AMINOPHENYL)ethyl] -N-(2-hydroxy-3-phenoxypropan)carbamate and 0.23 g of propionic aldehyde to obtain 1,69 g of tert-butyl(S)-N-(2-hydroxy-3-phenoxypropan)-N-[2-(4-propylaminoethyl)ethyl]carbamate.

Compounds of reference examples 1-a to 21-as shown in the following tables 1-20, were obtained in the same manner as the connection in the above reference examples 1-21. Presented in these tables, the compounds of reference examples 1-a to 1-n, reference examples 2A to 2-y reference examples 5-a to 5-f, reference example 7 and reference examples 9-a (compound of low polarity) and 9-b (compound of high polarity), reference examples 10 and (compound of low polarity) and 10 b (compound of high polarity), reference examples 12-a to 12-ml, reference examples 16-a and 16-b, reference examples 17-a and 17-b of reference example 20 and reference example 21-a were obtained in the same manner as described in reference examples 1, 2, 5, 7, 9, 10, 12, 16, 17, 20 and 21, respectively.

Example 1.

A solution of 670 mg of N-[4-(2-amino-ethyl)phenyl] -2-(2-benzylimidazole-4-yl)ndimethylacetamide and 300 mg of (S)-2-[(phenoxy)methyl]oxirane in 20 ml of 2-propanol was heated with reverse is matography on silica gel (eluent: chloroform/methanol = 10/1). The obtained solid residue was recrystallized from methanol to obtain 250 mg (S)-2-(2-benzylimidazole-4-yl)-4'-[2-[(2-hydroxy-3-phenoxypropan)amino]ethyl]acetanilide.

Example 2.

To a 10 ml solution in methanol 285 mg of tert-butyl(S)-N-(2-hydroxy-3-phenoxypropan)-N-[2-[4-[[2-(2-aminothiazol-4-yl)-2-hydroxyacetic] amino]phenyl] ethyl] carbamate was added at room temperature, 10 ml of 4 n solution of hydrogen chloride in ethyl acetate. The reaction mixture was stirred at room temperature for four hours. The solvent was evaporated and the residue was purified by the method of column chromatography on silica gel (eluent: chloroform/methanol = 7/1) to give 222 mg of the dihydrochloride (S)-4'-[2-[(2-hydroxy-3-phenoxypropan)amino]ethyl]-2-(2-aminothiazol-4-yl)-2-hydroxyacetanilide.

Example 3.

To 10 ml of solution in ethanol 0.40 g of tert-butyl(S)-N-[2-[4-[2-(3-cyanophenylacetic-4-yl)acetylamino]phenyl]ethyl]-N-(2-hydroxy-3-phenoxypropan] carbamate was added 10 ml of 4 n solution of hydrogen chloride in ethyl acetate. The mixture was stirred over night at room temperature, and the solvent was evaporated in vacuum. To the obtained crystals were added 5 ml of a mixture of methanol-ethanol (4: 1), then the mixture is heated and washed crystals. After keeping the ethyl]-2-[2-(3-cyanovinylene)thiazol-4-yl]acetanilide.

Example 4.

To 470 mg of tert-butyl(S)-N-[(2-hydroxy-3-phenoxy)propyl]-N-[2-[4-[2-(2-phenylimidazol-4-yl)atsetamino] phenyl] ethyl] carbamate was added 20 ml of methanol and 10 ml of 4 n solution of hydrogen chloride in ethyl acetate and the mixture was stirred for 4.5 hours at room temperature. The solvent was evaporated in vacuum and the crude crystals are recrystallized from a mixture of ethanol-ethyl acetate, received 150 mg of the dihydrochloride (S)-2-(2-phenylimidazol-4-yl)-4'-[2-[(2-hydroxy-3-phenoxypropan)amino]ethyl]acetanilide.

The compounds of examples 1 to 4-dl, is given in tables 21-27 received as well as compounds in examples 1-4. In these tables, the compounds of examples 1-a to 1-e, examples 2-a - 2-s, 3-a - 3-i and examples 4-a - 4-dl obtained in the same way as the compounds of examples 1, 2, 3, and 4, respectively.

As it is used here and hereinafter, the chemical structural formulas and physical-chemical properties of the compounds of reference examples 1-22 are shown in tables 1-20 and chemical structural formulas and physical-chemical properties of the compounds of examples 1-4-dl, is given in tables 21-27.

Symbols in the tables have the following meanings:

Ref. : the number of the reference example; Etc. : room example; Salt: salt; Swart was used TMS, as the solvent DMSO-d6if not specified]; s - singlet; d - doublet; Ng - Hertz; m - multiplet; rs broad singlet; t - triplet; q - quadruplet; MC(m/z): mass spectrometric analysis (m/z, mass/charge); Me: methyl; Et: ethyl; n-Rn: n-propyl; iPr: isopropyl: PNEC: n-hexyl; Ph: phenyl: Naph: naphthyl; snekh: cyclohexyl; PY: pyridyl; Th: thienyl; Fu: furyl; BOC: tert-butoxycarbonyl; 1-Me-1H-Bzim-2-yl: 1-methyl-1H-benzimidazole-2-yl; 1-Bn-1H-Bzim-2-yl: 1-benzyl-1H-benzimidazole-2-yl; 1H-Impy-2-yl: 1H-imidazo[4,5-b]pyridyl-2-yl; 3-Su-1H-Traz-5-yl: 3-effect-free remedy 1H-1,2,4-triazole-5-yl; 3-BnSu-1H-Traz-5-yl: 3-benzylmethyl-1H-1,2,4-triazole-5-yl; 2-Me-Thdiaz-5-yl: 2-methyl-1,3,4-thiadiazole-5-yl; 1H-Bzim-2-yl: 1H-benzimidazole-2-yl; 1-Bn-1H-Im-4-yl: 1-benzyl-1H-imidazol-4-yl; Imthz-6-yl: imidazo[2,1-b]thiazol-6-yl; Bzthz-2-yl: benzothiazol-2-yl; 2-(Ph-NH)-Thz-4-yl: 2-phenylimidazol-4-yl and 1-Bn-1H-Im-2-yl: 1-benzyl-1H-imidazol-2-yl.

Compounds other than those described above, are listed in the following tables 28 and 29. These compounds can be synthesized using the above methods or the methods described in the examples, or using modified methods, well known to experts in this field that do not require special experiments.

An example of obtaining the composition for perora the

A portion of the compounds according to the present invention a mass of 7 g mixed with 538,4 g lactose in a plastic bag. This mixture is ground to powder using a mill for samples (manufactured by Hosokawa Micron). A portion of the powdered mixture mass 541,4 g uniformly mixed with 135,1 g corn starch in a machine for granulating and coating in the fluidized bed (production Ogawara Seisakusyo). To the resulting product type spray 210 g 10% solution of hydroxypropylcellulose to perform granulation. After drying, the thus obtained granules were passed through 20 mesh, is mixed with 2.1 g of magnesium stearate and then prepared in the form of tablets at the rate of 100 mg per tablet by placing the obtained granules in a rotary tablet press machine (manufactured by Hata Tekkosyo) using the matrix/the punch with 6.5 mm x 7.8 R. Using the apparatus for coating (production Freud Sangyo), spray 350g forming coating solution containing a 20.3 g hydroxypropylmethylcellulose, 2.8 g of polyethylene glycol 6000, and 11.2 g of titanium oxide and 0.7 g of talc, on the thus prepared tablets thereby obtaining tablets with a film coating, and the coating weight of each tablet is 5 mg

sollen, benzimidazolyl, benzothiazolyl, thiadiazolyl, imidazopyridine or imidazothiazole;

X is a bond, -NR5-, -NR5CO-, -NR5ONH-, -NR5SO2- or-NR5C(=NH)NH-;

R1means H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted pyridyl, thienyl, furyl, thiazolyl, benzimidazolyl, imidazopyridine, triazolyl, thiadiazolyl, imidazolyl, imidazothiazoles, benzothiazolyl or optionally substituted cyclohexyl, the substituents selected from halogen atoms, lower alkyl, -OH, -CN, -NO2, -CF3, -NH2, -O-lower alkyl, and the substituents optionally substituted lower alkyl can be optionally substituted phenyl, naphthyl, furyl, thienyl or pyridyl;

R2a, R2bmean H or lower alkyl, which may be the same or different;

R3means hydrogen or lower alkyl;

R4a, R4bmean N or HE may be the same or different, or R4aand R4btaken together form a group =O or =N-O-lower alkyl; and

R5means H or lower alkyl.

2. Amide derivative or its salt under item 1, where a represents thiazolidin, imidazolidin means bond or-NR5-.

3. Amide derivative or its salt under item 2, where a means thiazolidin or imidazoline, X is-NR5and R1means lower alkyl, which is substituted by optionally substituted phenyl or naphthyl, or optionally substituted phenyl.

4. (S)-2-(2-Benzylimidazole-4-yl)-4'-[2-[(2-hydroxy-3-phenoxypropan)amino]ethyl]acetanilide;

(S)-2-[2-(3-forgenerating)-thiazol-4-yl] -4'-[2-[(2-hydroxy-3-phenoxypropan)amino]ethyl]acetanilide;

(S)-2-(2-phenylimidazol-4-yl)-4'-{ 2-[(2-hydroxy-3-phenoxypropan)amino]propyl}acetanilide and

(S)-2-(2-phenylimidazol-4-yl)-4'-{ 2-[(2-hydroxy-3-phenoxypropan)amino]ethyl}acetanilide or their salts.

5. Pharmaceutical composition, promoting insulin secretion and increases susceptibility to insulin-containing amide derivative of p. 1 and pharmaceutically acceptable carrier.

6. The pharmaceutical composition under item 5 as a therapeutic agent for the treatment of diabetes.

 

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