Alkoxycarbonyl imidazo[1,2-a]pyridines and medicinal products based on them

 

(57) Abstract:

Alkoxycarbonyl imidazo [1, 2-a]pyridines of formula 1

< / BR>
where R1, R2- C1-4alkyl; R3- C1-4alkoxy-C1-4alkoxy; R4-C1-4alkyl or hydroxymethyl and a is oxygen or NH, or their salts, can be used for the treatment and/or prevention of diseases of the stomach and intestines. 2 s and 5 C. p. F.-ly, 1 table.

The invention relates to new compounds, designed for applications in the pharmaceutical industry as active ingredients in the manufacture of medicines.

In European patent application EP-A-0033094 describes imidazo[1,2-a] pyridine containing in position 8 aryl Deputy representing phenyl, thienyl or pyridyl, or phenyl substituted by chlorine, fluorine, methyl, tert.-butyl, trifluoromethyl, methoxy or cyano. As aryl radicals, of particular interest, in the above-mentioned European patent application EP-A-0033094 named phenyl, o - or p-forfinal, p-chlorophenyl and 2,4,6-trimetilfenil, and most preferred are phenyl, o - or p-forfinal and 2,4,6-trimetilfenil.

In European patent applications EP-A-0204285, EP-A-0228006, EP-AAL, first of all, (substituted) alkynylaryl radical.

In European patent application EP-A-0266890 describes imidazo[1,2-a] pyridine, substituted in position 8 on alkanniny, alkyl or cycloalkyl radical.

The present invention is to develop new compounds with antiulcer and antisecretory properties, method of their production and medicinal products based on them.

It was found that described in detail below compounds, which differ from the known compounds of the prior art primarily by the substitution in position 3 or 8, have surprising and particularly positive properties.

Thus, an object of the present invention are alkoxycarbonyl imidazo[1,2-a]pyridines of formula I

< / BR>
where R1represents C1-C4alkyl,

R2represents C1-C4alkyl,

R3represents C1-C4alkoxy-C2-C4alkoxy,

R4represents C1-C4alkyl or hydroxymethyl, and

A represents O (oxygen) or NH, and their salts.

C1-C4alkyl represents a linear or branched alkyl radicals with the number of atoms uglerodnoi all methyl.

C1-C4alkoxy represents an oxygen atom bound to one of the above C1-C4alkyl radicals. Preferred of them metaxylene radical. C2-C4alkoxy represents an oxygen atom bound to one of the C2-C4alkyl radicals selected from the group of the above C1-C4alkyl radicals. C1-C4alkoxy-C2-C4alkoxy represents a C2-C4CNS moiety linked to C1-C4CNS radical. Preferred among them are 2-methoxyethoxy radical.

As salts of the compounds of formula I can be treated preferably all of the acid additive salt. It should be called the pharmacologically acceptable salts of inorganic and organic acids, usually used in the manufacture of tools in galenical form. Pharmacologically unacceptable salts, which can be primary products of the method carried out upon receipt of the compounds according to the invention on an industrial scale, are converted then using well-known specialist methods in pharmacologically acceptable salt. As such suitable water-soluble, Isleta, Hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, albanova acid, stearic acid, toluensulfonate acid, methanesulfonate acid or 3-hydroxy-2-naphthoic acid, and to obtain the corresponding salt - depending on what kind of acid is used: monobasic or polybasic, and depending on how much salt you want to get the acid is used in an equimolar quantitative ratio or approximately this value.

As examples of compounds include the following: 8-{2-[(2- methoxyethoxy)carbylamine] -6-methylbenzylamine}-2 - methylimidazo[1,2-a]pyridine-3-methanol, 8-{2-[(2-methoxyethoxy)carbylamine]-6-methylbenzylamino}-2 - methylimidazo[1,2-a] pyridine-3-methanol and 8-{2-[(2-methoxyethoxy)carbylamine] -6-methylbenzylamino}-2,3 - dimethylimidazo[1,2-a]pyridine and its salts.

Among the compounds of formula I should provide the following to the T. the above values, as well as salts of these compounds.

Another object of the invention is a method of obtaining compounds of formula I and their salts. How is that

a) the compounds of formula II,

< / BR>
where R1, R4and A have the above values, or their salts is subjected to interaction with compounds of formula III,

< / BR>
where R2and R3have the values indicated above, and X represents an appropriate reactive tsepliaeva group, or their salts, or

b) for preparing compounds of formula 1 in which R4represents hydroxymethyl, restore the compounds of formula IV,

< / BR>
where R1, R2, R3and A have the above values and then, if necessary, the compound I obtained according to a) or b), translate into their salts, or then, if necessary, from the obtained salts of the compounds of the first release of the compounds I.

The interaction of compounds II with compounds III is carried out according to methods known in the art. The corresponding reactive tsepliaeva group is, for example, halogen atom (preferably chlorine or bromine) or methysulfonylmethane. The exchange reaction is carried out preferably in the presence of based the on, as potassium carbonate, or organic bases such as triethylamine, pyridine, kallidin or 4-dimethylaminopyridine), with the addition of catalysts, such as alkali metal iodide or tetrabutylammonium bromide, can effectively influence the course of the reaction.

The recovery of the compounds IV are carried out by conventional methods, well known to specialists. The reaction is carried out in inert solvents, for example, lower aliphatic alcohols, for example, using the corresponding hydrides, such as borohydride sodium, optionally with the addition of water.

The choice of reaction parameters required for implementing the method, will not deliver qualified difficulties.

Isolation and purification of the substances according to the invention is carried out using known methods, using for this purpose, for example, distillation of the solvent under vacuum and recrystallization of the resulting residue from a suitable solvent or using one of the usual methods of treatment, as, for example, column chromatography on appropriate media.

An acid additive salt is obtained by dissolving the free base in a suitable lannom aliphatic alcohol (ethanol, isopropanol), a ketone such as acetone, or in a simple ether, such as THF or diisopropyl ether, which contains the desired acid or in which then enter the desired acid.

Secretion of salts is carried out by filtration, the resultant deposition rates, planting with a solvent, nerastvorim additive salt or by evaporating the solvent. The salts can be translated by alkalization, for example, an aqueous solution of ammonia, in free base, which in turn can again be converted into an acid additive salt. In this way pharmaceutically unacceptable acid additive salts can be converted into pharmacologically acceptable acid additive salt.

The initial compounds of formula II are known in particular from European patent applications EP-A-0290003 and EP-A-0299470. The initial compounds of formula III are new. They are obtained analogously to methods known from the related publications, namely as follows: in compounds III, where X denotes OH, hydroxyl group interaction with a halogenation agent, such as, for example, thionyl chloride, thienylboronic, phosphoribosyl or oxalicacid transfer in reactive flake is risotti Foundation, it turned into methysulfonylmethane.

The compounds of formula IV are new compounds and are also an object of the present invention. As the compounds of formula I, their get the same interaction of the compounds II, where R4indicates CHO, compounds III, described above.

The following examples explain more way to obtain compounds of formula I. the Reduction of KT denotes room temperature, h means hour(s).

Examples

The final and intermediate products

1. 8-{ 2-[(2-methoxyethoxy)carbylamine]-6-methylbenzylamine}- 2-methylimidazo[1,2-a]pyridine-3-carboxaldehyde

A mixture of 2.0 g (11,35 mmol) of 8-hydroxy-2-methylimidazo[1,2-a]pyridine-3-carboxaldehyde, 1.2 g of anhydrous sodium carbonate, 0.17 g (1,14 mmole) of sodium iodide and 3.3 g (12.8 mmol) of 2-methoxyethanol ether [2-(chloromethyl)-3-were] carbamino acid in 30 ml of acetone is stirred for 24 h at RT and poured into 200 ml of ice water. Then the precipitate is filtered off, dried and recrystallized from toluene/diisopropyl ether. The result of 3.9 g (86,5%) of the compound indicated in the title, with TPL119-120oC.

2. 8-{ 2-[(2-methoxyethoxy)carbylamine] -6-methylbenz-6-methylbenzylamine} -2-methylimidazo[1,2-a] pyridine-3-carboxaldehyde in 40 ml of methanol is mixed at RT with 362 mg (9.3 mmol) of 97% sodium borohydride and stirred for 75 minutes Then poured into ice water, extracted with dichloromethane and concentrated in rotary vacuum evaporator. The remaining oil is crystallized with 5 ml of isopropyl alcohol, 5 ml of toluene and diisopropyl ether. This way obtain 2.7 g (72,7%) of the compound indicated in the title, with TPL121-123oC.

3. 8-{ 2-[(2-methoxyethoxy)carbylamine] -6-methylbenzylamino} -2-methylimidazo[1,2-a]pyridine-3-carboxaldehyde

A mixture of 2.0 g (11,41 mmol) of 8-amino-2-methylimidazo[1,2-a]pyridine-3-carboxaldehyde, 1,21 g (11,41 mmol) of anhydrous sodium carbonate, 0.17 g (1,14 mmole) of sodium iodide and 3.5 g (13.6 mmol) of 2-methoxyethanol ether [2-(chloromethyl)-3-were]carbamino acid in 30 ml of acetone is stirred for 24 h at RT and concentrated in rotary vacuum evaporator. The residue is mixed with 100 ml water, then extracted with ethyl acetate, the organic phase is dried with magnesium sulfate and concentrated in vacuo. The residue is recrystallized from toluene. The result of 3.31 g (73%) of the compound indicated in the title, with TPL153 to 155oC.

4. 8-{2-[(2-methoxyethoxy)carbylamine]-6-methylbenzylamino} -2-methylimidazo[1,2-a]pyridine-3-methanol

2.8 g (7,06 moles) 8-{2-[(2-methoxyethoxy)carbonylation is the atrium analogously to example 2, the methanol is distilled off in a vacuum, mixed with water and ethyl acetate and a solution of potassium hydrogen phosphate establish a pH of 9. Then extracted several times with ethyl acetate, dried, concentrated in vacuo and recrystallized from toluene/diisopropyl ether. In this way receive 2.28 g (81%) of the compound indicated in the title, with TPL138-140oC.

5. 8-{2-[(2-methoxyethoxy)carbylamine]-6-methylbenzylamino} -2,3-dimethylimidazo[1,2-a]pyridine-isopropyl alcohol (1/1)

A mixture of 3.0 g (18.6 mmol) of 8-amino-2,3-dimethylimidazo[1,2-a]pyridine, 4.9 g (46.2 mmol) of anhydrous sodium carbonate, 0.28 g (of 1.86 mmole) of sodium iodide and 5.8 g (22.5 mmole) 2-methoxyethanol ether [2-(chloromethyl)-3-were] carbamino acid in 30 ml of acetone is stirred for 20 h at RT. Then filtered, concentrated in vacuo, mixed with water and ethyl acetate, diluted hydrochloric acid to establish a pH 6 and extracted with ethyl acetate. The organic solution is dried and concentrated in vacuo. The residue is dissolved in 40 ml of acetone and mixed with a solution of 1.2 g (10.3 mmol) of fumaric acid in 80 ml of acetone. The precipitation of crystals does not occur. Then re-concentrated solution is mixed with toluene and isopropyl alcohol at a temperature of 0o< and 10 ml of water, caustic soda establish pH 9 and the free base extracted with ethyl acetate. After concentration in vacuo was dissolved in toluene/isopropyl alcohol and at a temperature of 0oC precipitated with petroleum ether (TKip40oC). The result is 2.2 g (26.7 percent) of the connection specified in the header, with TPL85-86oC.

6. 8-{2-[(2-methoxyethoxy)carbylamine]-6-methylbenzylamine} -2-methylimidazo[1,2-a]pyridine-3-methanol.

A mixture of 178 mg (1.0 mmol) of 8-hydroxy-2-methylimidazo[1,2-a]pyridine-3-methanol, 117 mg (1.1 mmole) of anhydrous potassium carbonate, 15 mg (0.1 mmole) of sodium iodide and 283 mg (1.1 mmole) 2-methoxyethanol ether [2-(chloromethyl)- 3-were]carbamino acid in 5 ml of acetone is stirred for 48 h at RT, then processed as in example 2 and chromatographic using ethyl acetate/isopropyl alcohol (ratio 9:1). This way obtain 247 mg (62%) of the connection specified in the header.

7. 8-{ 2-[(2-methoxyethoxy)carbylamine]-6-methylbenzylamine} -2,3-dimethylimidazo[1,2-a]pyridine.

Analogously to example 5 is subjected to interaction 2.0 g (12.4 mmol) of 8-hydroxy-2,3-dimethylimidazo[1,2-a] pyridine, 3.6 g (13.9 mmol) of 2-methoxyethanol ether [2-(chloromethyl)-3-methylphen is 5%) compound specified in the header, with TPL107-108oC.

Original products

AA. 2-Methoxyethylamine ether [2-(hydroxymethyl)-3-were] carbamino acid

To a solution of 33 g (0,24 mol) 2-amino-6-methylbenzylamino alcohol and to 19.4 ml (0,24 mol) of pyridine in 600 ml of isopropyl alcohol at a temperature of 10oC is added dropwise with stirring and cooling a 33.2 g (0,24 mol) 2-methoxyethanol ether Harborview acid. Stirring is continued for another 2 h at 0oC, then mixed with water and isopropylacetate and several times extracted with isopropylacetate. The organic phase is dried with magnesium sulfate and concentrate under 50oC in a rotary vacuum evaporator. The remainder chromatographic on silicagel column using ethyl acetate. After concentration in vacuo receive 36 g (68%) of the compound indicated in the title, in the form of butter.

AB. 2-Methoxyethylamine ether [2-(chloromethyl)-3-were] carbamino acid

To a solution of 18.0 g (0,075 mol) of the above compound in 80 ml of toluene at a temperature of 17-20oC added dropwise with stirring and cooling, 9.4 g (0,079 mole) of thionyl chloride and left overnight at RT. Then cooled in an ice bath, rubbing and consequently the exact solution and crystallization from toluene/petroleum ether (TKip40oC) receive an additional 4.8 g (24.7 per cent) of sediment with similar melting temperature.

B. 8-hydroxy-2-methylimidazo[1,2-a]pyridine-3-carboxaldehyde

4.77 g (0,02 mol) of 8-benzyloxy-2-methylimidazo[1,2-a]pyridine is stirred mixture of Vilsmeier containing 20 ml of dimethylformamide and 2.3 ml of phosphorus oxychloride, for 2.5 hours at a temperature of 60oC and the mixture is separated in the usual manner with ice water and potassium bicarbonate. In this way receive 8-benzyloxy-2-methylimidazo[1,2-a] pyridine-3-carboxaldehyde with TPL105-106oC (from diisopropyl ether). This connection, similarly to that described by Kaminski and others, in Journ. Med. Chem. 28, 876 (1985), Methode N. , dibenzyline to the connection specified in the header, with TPL251-252oC.

Industrial applicability

The compounds of formula I and their salts have valuable pharmacological properties, ensuring their industrial applicability. First of all, they have a pronounced ability to inhibit the secretion of gastric acid and is excellent protective effect against stomach and intestines of warm-blooded. This, along with good solubility in water of the compounds according to the invention are distinguished by high isberto, the absence of significant side effects and a wide therapeutic range.

Under the concept of "protection of the stomach and intestines, in the context of the invention refers to the prevention and treatment of diseases of the gastrointestinal tract, primarily gastrointestinal inflammatory diseases and lesions (such as, for example, gastric ulcer, duodenal ulcer, gastritis, gastric irritation caused by high acidity or certain drugs), which may be caused, for example, by microorganisms (e.g. Helicobacter pylori), bacterial toxins, medicaments (for example, some anti-inflammatory drugs and Antirheumatic drugs), chemicals (e.g. ethanol), acid gastric juice or stressful situations. Compounds according to the invention have, in addition, a private action against germ Helicobacter pylori.

Its excellent antiulcer and indiscrezioni properties held pilot-tested on various models, the compounds according to the invention in an unexpected way noticeably superior to the compounds known from the prior art. Due to these properties, the compounds of formula I and their FM their application they can find primarily for the treatment and/or prevention of diseases of the stomach and intestines, as well as for the treatment of osteoporosis.

The object of the invention are therefore compounds of the invention possessing the ability to inhibit the secretion of acid gastric juice.

The invention further includes the use of compounds according to the invention for the manufacture of medicines, which are able to inhibit the secretion of gastric acid, which are intended for the treatment and/or prophylaxis of the aforementioned diseases.

The invention further includes the use of compounds according to the invention for the treatment and/or prophylaxis of the aforementioned diseases.

Another object of the present invention are drugs, containing one or more compounds of the formula I and/or their pharmacologically acceptable salts.

Medications manufactured using well-known and available to the specialist methods. As drug compounds according to the invention possess pharmacological activity (i.e. active ingredients), used either as such or preferably in combination with appropriate pharmaceutical excipients and/or fillers, and they can Isrotel eticheskoi system), emulsions, suspensions or solutions, the content of active substances which thus is preferably from 0.1 to 95 %, and due to the choice of auxiliary substances and fillers, you can receive funds in galenical form exactly corresponding to the current matter and/or to the desired onset of action (for example, in the form of prolonged action or in a form resistant to gastric juice).

The choice of excipients, carriers respectively for producing the required preparative forms for professionals with experience in this field, the difficulty is not. Along with solvents, thickeners, basic substances for suppositories, excipients for tablets and other carriers of active substances can be applied, for example, coatings for tablets, antioxidants, dispersants, emulsifiers, antispyware, flavorings, preservatives, substances that promote the solubility of the dyes or primarily promoters for permeability and complexing agents (e.g. cyclodextrins).

Active ingredients may be administered for oral, parenteral or percutaneous injection.

It was the mouth of the oral introduction, if necessary, assigned in the form of several, preferably from 1 to 4 single doses should contain the active ingredient, respectively, the active ingredients in amounts of from about 0.01 to about 20, preferably 0.05 to 5, especially 0.1 to 1.5 mg/kg of body weight. For parenteral administration can be assigned drugs at roughly the same dosage of active substances or (particularly when administered intravenously), usually with a lower dosage. Select the required optimal dosage, as well as the form of the introduction of active substances in each case by a competent expert in the field defines itself.

When using compounds according to the invention and/or their salts for the treatment of the above diseases, the pharmaceutical compositions can contain one or more pharmaceutically active ingredients belonging to other groups of drugs, such as antacids, for example aluminum hydroxide, magnesium aluminate; tranquilizers, such as benzodiazepines, for example diazepam; antispasmodic, as, for example, becamevery, camylofin; antiholinergicescoe means, as, for example, oxyphencyclimine the coefficients, vitamins or amino acids.

In this connection it should be emphasized the special importance of the compounds according to the invention when applied in combination with other drugs, any abscopal the secretion of acid, to which belong, for example, H2-blockers (e.g. cimetidine, ranitidine), inhibitors of H+/K+- adenosinetriphosphatase (for example, omeprazole, pantoprazole), or, further, to so-called peripheral antiholinergicheskimi means (as, for example, pirenzepine, telenzepine), as well as with gastrinoma antagonists with additional and even sverhpopulyarnogo reinforcement of the main steps and/or the elimination or reduction of side effects, or, further, in combination with substances that have antibacterial properties (as, for example, cephalosporins, tetracyclines, Kalinicheva acid, penicillins, or bismuth salt), to fight against Helicobacter pylori.

Pharmacology

Excellent protective effect of the compounds according to the invention in relation to the stomach and their ability to inhibit the secretion of acid gastric juice is confirmed by the results of experimental studies conducted on animal models. Compounds according to the invention, the last pilot phase of the compounds in the examples.

The test of inhibiting the secretion of action on perponderance the stomach of rats

The table below presents the effect of the compounds according to the invention after intravenous injection on-stimulated pentagastrin the secretion of acid perponderance stomach of rats in vivo.

Technique

In anesthetized rats (rat lines CD, female, 200-250 g; 1.5 g/kg, i. m. urethane) after tracheotomy incision on the Central line epistyles region dissected the stomach and entered transoral one PVC-catheter was fixed in the esophagus, and the other in the gatekeeper so that the ends of the soft tubes included in the lumen of the stomach. A catheter extending from the pylorus, through the side hole on the right side of the abdomen came out.

After thorough rinsing (about 50-100 ml) of the stomach at a temperature of 37oC continuously prinzivalli warm physiological NaCl solution (0.5 ml/min, pH 6.8 or 6.9; device type Braun-Unita (I). In the assembled (using a measuring cylinder) every 15 min affliate determined pH (meter pH-Meter 632, glass electrode EA 147; = 5 mm , Metrohm) and by titration with a freshly prepared 0,01 H NaOH to pH 7 (device Dosimat 655 Metrohm) was determined by the selected HCl.

The body temperature of experimental animals using infrared radiation and heating pad (automatic, stepless regulation through the rectal temperature sensor) maintained at the constant level of 37.8-38oC.

The compounds of formula I are of low toxicity. For example, for compounds of example 2, the values of LD50be:

Mouse.R. about. - > mg/kg

Rats R. O. - > mg/kg

Mouse/ - about 80 mg/kg

Rats in the/in to about 20 mg/kg

Obtaining compositions medicines can be illustrated by the following examples:

a) Tablets containing 40 mg of active ingredient

20 kg 8-{2-[(2-methoxyethoxy)carbylamine]-6-methylbenzylamine}-2 - methylimidazo[1,2-a] pyridine-3-methanol, 40 kg of milk sugar, 26 kg of maize starch and 3 kg of polyvinylpyrrolidone was soaked in 20 liters of water and then granularit passing through sieves with mesh size of 1.25. The granulate is dried in the fluidized bed to obtain a product with a moisture content of 50 - 60% and then see what the 200 mg tablets with a diameter of 8 mm

b) Capsules with a content of 30 mg of active ingredient

300 g of 8-{2-[(2-methoxyethoxy)carbylamine]-6-methylbenzylamine}-2 - methylimidazo[1,2-a] pyridine-3-methanol, 695 g of microcrystalline cellulose and 5 g of amorphous silicic acid is subjected to fine grinding, thorough mixing and encapsulating the formation of hard gelatin capsules 4 size.

) Capsules with a content of 10 mg of active ingredient

100 g of 8-{2-[(2-methoxyethoxy)carbylamine]-6-methylbenzylamino}-2 - methylimidazo[1,2-a] pyridine-3-methanol, 895 g of microcrystalline cellulose and 5 g of amorphous silicic acid is subjected to fine grinding, thorough mixing and encapsulating the formation of hard gelatin capsules 4 size.

g) Capsules with a content of 10 mg of active ingredient

Dissolve and 3.16 g of 8-{2-[(2-methoxyethoxy)carbylamine]-6 - methylbenzylamine} -2,3-dimethylimidazo[1,2-a]pyridine in solution, 165.5 g of mannitol and 0.5 g of sodium carbonate in 1300 ml of distilled water and sterile filtered. The resulting solution was poured into 5 ml in 15 ml ampoules and lyophilized. The lyophilisate can be again transferred to an aqueous solution with 10 ml of water.

1. Alkoxycarbonyl imidazo [1,2-a] pyridines of formula I

1-4alkoxy-C2-4alkoxy;

R4represents C1-4alkyl or hydroxymethyl;

And means O (oxygen) or NH,

and their salts.

2. The compounds of formula I under item 1, in which R4represents a hydroxymethyl and a represents O (oxygen), a R1, R2and R3have the designations indicated in paragraph 1, and their salts.

3. Replaced imidazo [1,2-a] pyridine of formula I on p. 1, representing 8-{2-[(2-methoxyethoxy)carbylamine]-6-methylbenzylamine}-2-methylimidazo [1,2-a] pyridine-3-methanol and its salts.

4. Replaced imidazo [1,2-a] pyridine of formula I on p. 1, representing 8-{ 2-[(2-methoxyethoxy)carbylamine]-6-methylbenzyl-amino}-2-methylimidazo [1,2-a] pyridine-3-methanol and its salts.

5. Replaced imidazo [1,2-a] pyridine of formula I on p. 1, representing 8-{ 2-[(2-methoxyethoxy)carbylamine]-6-methylbenzyl-amino}-2,3-dimethylimidazo [1,2-a] pyridine and its salts.

6. Drug antacid drug intended for the treatment and prevention of gastrointestinal diseases, including peptic ulcer disease, including an active ingredient and pharmaceutically acceptable additives, wherein the active ingredient is used as a compound of formula I deistvie.

 

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