Heterocyclic compounds with substituted phenyl group, the retrieval method (variants), pharmaceutical preparations on their basis and method of inhibiting secretion of gastric acid

 

(57) Abstract:

The invention relates to heterocyclic compounds with substituted phenyl group of formula I or its pharmaceutically acceptable salt, in which R1represents a C1-C6alkyl; R2represents a C1-C6alkyl; R3represents H or halogen and a is a substituted heterocycle, as defined in paragraph 1 of the claims; and X represents NH or O. the Invention also relates to a method for producing compounds of formula I and pharmaceutical preparations for use in the inhibition of the secretion of gastric acid on the basis of these compounds. The technical result is to provide new compounds and pharmaceutical preparations based on them, have anti-inflammatory activity against gastrointestinal diseases. 6 C. and 10 C.p. f-crystals.

The technical field

The present invention relates to new compounds and their therapeutically acceptable salts, which inhibit exogenous or endogenous secretion of gastric acid and therefore can be used in the prevention and treatment of gastrointestinal inflammatory diseases. The following is the event of receiving such new compounds, to pharmaceutical compositions containing as active ingredient at least one compound according to the invention or a therapeutically acceptable salt, and to the use of these active compounds in the manufacture of drugs for the above mentioned medical applications.

Background of the invention

Replaced imidazo[1,2-a]pyrazine disclosed in EP-A-0068378, US 4507294 and EP-A-0204285. Pyrrolo[2,3-d]pyridazine disclosed in WO 91/17164, WO 92/06979, WO 93/08190 and WO 95/19980. Pyrrolo[1,2-a]pyrazine disclosed in US 5041442.

Derivatives of benzimidazole and imidazopyridine, in which the phenyl group is substituted by lower alkyl in position 2 and 6 and which are effective as inhibitors of gastrointestinal N+TO+-ATPase, are disclosed in international patent application PCT/SE 97/00991 (filing date: June 5, 1997) and in Swedish patent application No. 9700661-3 (date of submission: February 25, 1997), respectively.

Review of the pharmacology of the gastric acid pump (H+TO+-ATP-ASE) published in Sachs et al. (1995) Annu. Rev. Pharmacol. Toxicol. 35: 277-305.

Description of the invention

It has been unexpectedly found that the compounds of formula I, represents a substituted heterocyclic compounds in which the phenyl group Zam is about-intestinal H+TO+-ATP-ases and, therefore, as inhibitors of gastric secretion of acid.

Thus, the present invention relates to heterocyclic compounds with substituted phenyl group of the General formula I:

or their pharmaceutically acceptable salts, in which

R1represents a C1-C6alkyl;

R2represents a C1-C6alkyl;

R3represents H or halogen;

represents a substituted heterocycle selected from the

where R4represents N, CH3CH3OH or CH2CN;

R5represents N or C1-C6alkyl;

R6represents N or C1-C6alkyl;

R7represents N or C1-C6alkyl;

n is 0 or 1;

X represents NH or O.

Preferred is a compound according to the invention or its pharmaceutically acceptable salt, in which

represents a

where R4

represents a

where R4, R6and X are such as defined above.

Preferred is a compound according to the invention or its pharmaceutically acceptable salt, in which

represents a

where R4, R5, R6and X are such as defined above.

Preferred is a compound according to the invention or its pharmaceutically acceptable salt, in which

represents a

where R4, R5, R7and X are such as defined above.

Preferred is a connection on p. 1 or its pharmaceutically acceptable salt, in which

represents a

where R4, R5and X are such as defined above.

Preferred is a compound according to the invention or its pharmaceutically acceptable salt, in which

represents a

where R4and X are such as defined above.

Preferred is also a compound of the invention or its pharmaceutically acceptable salt, in which R

or its pharmaceutically acceptable salt.

Also preferred is a compound according to the invention, which represents a 2,3-dimethyl-8-(2,6-dimethylbenzylamine)imidazo[1,2-a]pyrazin

or its pharmaceutically acceptable salt.

According to the invention a method for obtaining compounds according to the invention, in which the compounds of General formula II

where X1is a HE or NH2,

subjected to interaction with the compound of General formula III

where R1, R3and R4such as defined for formula I, a Y1represents tsepliaeva group, such as halide, tosylate or mesilate.

According to the invention a method for obtaining compounds according to the invention, in which the compounds of General formula IV

where X2represents tsepliaeva group, is subjected to the interaction with the compound of General formula V

where R1, R3and R4such as defined for formula I, a Y

In this invention a method of inhibiting secretion of gastric acid, in which the mammal, including man, in need of such inhibition, introducing an effective amount of the compounds according to the invention.

The present invention additionally relates to a pharmaceutical preparation for use in the inhibition of the secretion of gastric acid, in which the active ingredient is a compound according to the invention.

The invention also relates to pharmaceutical drug having anti-inflammatory activity against gastrointestinal diseases, in which the active ingredient is a compound according to the invention.

Used herein, the term "C1-C6alkyl" means normal or branched alkyl group having from 1 to 6 carbon atoms. The examples of the mentioned lower alkyl include methyl, ethyl, n-propyl, ISO-propyl, n-butyl, ISO-butyl, sec-butyl, tert-butyl, and pentyl and hexyl normal and branched chain.

The term "halogen" includes fluorine, chlorine, bromine and iodine.

Both the pure enantiomers, racemic mixtures and unequal mixtures of the two EN (pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers) are included in the scope of this invention. The invention also includes derivatives of compounds of formula I which possess biological function of compounds of formula I.

Depending on the conditions of the final products of formula I are produced either in a neutral form or in salt form. As free base and salts of these end-products are included in the scope of this invention.

Salt accession acids of these new compounds by a method known per se, can be converted into the free base using basic agents such as alkali, or by ion exchange. The obtained free base may form salts with organic or inorganic acids.

Upon receipt of salts accession acid is preferably used such acids, which respectively form a therapeutically acceptable salt. Examples of such acids are halogenation acid, such as chloromethane acid, sulfuric acid, phosphoric acid, nitric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as Mura, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, ximalayasha acid, pyruvic acid, p-oxybenzone acid, albanova acid, methanesulfonate acid, econsultancy acid, oxetanemethanol acid, halogeenvalgusega acid, toluensulfonate acid or naphthalenesulfonate acid.

When carrying out the claimed methods for producing compounds according to the invention the reaction of interaction of the compounds of General formula II with a compound of General formula III is conveniently carried out in an inert solvent, for example acetone, acetonitrile, dimethoxyethane, methanol, ethanol, xylene or dimethylformamide, with reason or without it.

This Foundation represents, for example, alkali metal hydroxide, such as sodium hydroxide and potassium hydroxide; sodium alcoholate such as sodium methylate and sodium ethylate; alkali metal hydride such as sodium hydride and potassium hydride; carbonates of alkali metal such as potassium carbonate and sodium carbonate; or an organic amine, such as triethylamine.

The reaction of interaction of the compounds of General formula IV with a compound of General formula V is conveniently carried out in an inert De, with or without him. The base is a hydroxide of an alkali metal such as sodium hydroxide and potassium hydroxide; sodium alcoholate such as sodium methylate and sodium ethylate; alkali metal hydride such as sodium hydride and potassium hydride; carbonates of alkali metal such as potassium carbonate and sodium carbonate; or an organic amine, such as triethylamine.

Pharmaceutical

In another aspect this invention relates to pharmaceutical compositions containing as active ingredient at least one compound according to the invention or a therapeutically acceptable salt.

Compounds according to the invention can also be used in preparations together with other active ingredients, such as antibiotics, such as amoxicillin.

For clinical use of the compounds according to the invention is prepared in the form of pharmaceutical preparations for oral, rectal, parenteral or other way of introduction. The pharmaceutical preparation contains the compound according to the invention in combination with one or more pharmaceutically acceptable ingredient. The carrier may be in the form of solid, polut is retene. Usually the number of active connections is in the range from 0.1 to 95% by weight of the preparation, preferably from 0.1 to 20 wt.% in preparations for parenteral use and preferably from 0.1 to 50 wt.% in preparations for oral administration.

In the preparation of pharmaceutical preparations containing the compound of the present invention, in the form of dosage units for oral administration selected compound may be mixed with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium fumarate and polietilenglikolya waxes. Then this mixture is processed into granules or pressed into tablets.

Soft gelatin capsules may be prepared with capsules containing a mixture of active compound or compounds according to the invention, vegetable oil, fat or other suitable environment for soft gelatin capsules. Hard gelatin capsules may contain granules of the active compound. Hard gelatin capsules may contain, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine.

Dosage units for rectal injection can be prepared (1) in the form of suppositories which contain the active substance is mixed with a neutral fat base; (2) in the form of gelatin capsules for rectal administration, which contain the active substance in a mixture with a vegetable oil, paraffin oil or other suitable medium for gelatin capsules for rectal administration; (3) in the form of ready microenemas or (4) in the form of a dry preparation for cooking microenemas, which is subject to dilution with a suitable solvent just before the introduction.

Liquid preparations for oral administration can be prepared in the form of syrups or suspensions, for example solutions or suspensions containing from 0.1 to 20 wt.% the active ingredient, and the rest is sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, corrigentov, saccharin and carboxymethyl cellulose or other thickener. Liquid preparations for oral administration can be prepared

Solutions for parenteral administration can be prepared in the form of a solution of the compounds according to the invention in a pharmaceutically acceptable solvent, preferably in a concentration of from 0.1 to 10 wt.%. These solutions may also contain stabilizers and/or buffers, and their release in standard doses in the form of ampoules or vials.

Solutions for parenteral administration can also be prepared in the form of a dry preparation which is subject to dilution with a suitable solvent prior to use.

A typical daily dose of the active substance varies widely and depends on various factors, such as, for example, an individual need of the patient, route of administration and the disease. In General oral and parenteral dosage should be in the range of 5 to 1000 mg of active ingredient per day.

Compounds according to the invention can also be used in preparations together with other active ingredients, for example for the treatment or prophylaxis of conditions involving infection by Helicobacter pylori infection of the gastric mucosa of man. Such other active ingredients can be antimicrobial agent, in particular:

macrolides, such as erythromycin or clarithromycin;

the tetracyclines, such as tetracycline or doxycycline;

- aminoglycosides, such as gentamicin, kanamycin or amikacin;

- quinolones such as norfloxacin, ciprofloxacin or enoxacin;

- other tools, such as metronidazole, nitrofurantoin, or chloramphenicol; or

- preparations containing bismuth salt such as basic bismuth citrate, basic bismuth salicylate, basic bismuth carbonate, basic bismuth nitrate or basic gallate of bismuth.

EXAMPLES

Example 1.1

Synthesis of 2,3-dimethyl-8-(2,6-dimethylbenzylamine)imidazo[1,2-a]pyrazine

Stir a mixture of 8-chloro-2,3-dimethylimidazo[1,2-a]pyrazine (0.5 g, 2.8 mmol) and 2,6-dimethylbenzylamine (0,41 g, 3.0 mmol) in xylene (10 ml) is heated under reflux for 24 hours. This mixture is evaporated under reduced pressure, dissolved in methylene chloride (20 ml) and washed with 5% sodium carbonate solution in water (20 ml). The organic layer is separated and evaporated under reduced pressure and the residue is purified column chromatography on silica gel. By recrystallization from pentane receive 90 mg (23%) specified in the header SOER>

Example 1.2

Synthesis of 2,3-dimethyl-8-(2,6-dimethylbenzylamine)imidazo[1,2-a]pyrazine

Sodium hydride (0.15 g, 3 mmol) (50% in oil) is added to a stirred solution of 2,6-dimethylbenzyl alcohol in acetonitrile (10 ml). Then add 8-chloro-2,3-dimethylimidazo[1,2-a]pyrazine (0.4 g, 2.8 mmol) and this reaction mixture is heated under reflux for 20 hours. The solvent is evaporated under reduced pressure, the residue is dissolved in methylene chloride and washed with water. The organic layer is evaporated under reduced pressure and the residue purified column chromatography on silica gel, using as eluent a mixture of ethyl acetate:petroleum ether (40-60) 1:1. By recrystallization from petroleum ether get 0,42 g (50%) specified in the connection header.

1H-NMR (300 MHz, DCl3): 2,35 (s, 3H), 2.40 a (s, 3H), of 2.45 (s, 6H), 5,6 (s, 2H) 6,95-to 7.15 (m, 3H), 7,35-7,45 (m, 2H).

BIOLOGICAL TESTS

1. Experiments in vitro

Inhibition of acid secretion in isolated gastric glands of the rabbit

Inhibitory effect on the secretion of acid in vitro in isolated gastric glands of the rabbit was measured as described in Berglindh et al. (1976) Acta Physiol. Scand. 97, 401-414.

Definition 15 minutes at +37°With 18 mm Pipes buffer/Tris, a pH of 7.4, containing 2 mm MgCl2, 10 mm KCl and 2 mm ATP. ATP-asnow activity was assessed by the release of inorganic phosphate from ATP, as described in LcBel et al. (1978) Anal. Biochem. 85, 86-89.

The compound of Example 1 had the value of the IC50equal to 0.16 μm, and the compound of Example 2 had a value IC50equal 2,78 mm.

2. Experiments in vivo

Inhibitory effect on the secretion of acid in female rats

Use female rats Sprague-Dawly. Collection of gastric secretions and the introduction of the test substances they set kanalirovanie fistula into the stomach (abdomen) and in the upper part of the duodenum, respectively. Before testing the recovery period after surgery assign 14 days.

Before the tests on the production of animals for 20 hours deprived of food but not water. The stomach periodically washed (+37°C) through the gastric cannula tap water and subcutaneously injected with 6 ml of Ringer-Glucose. The secretion of acids stimulate infusion for 2.5-4 hours (1.2 ml/h, subcutaneously) of pentagastrin and carbachol (20 and 110 nmol/kg / hour, respectively) and during this time collect fractions of gastric secrets for periods of time of 30 minutes. Test substance or carrier is administered either Chea before stimulation (oral dosing, 5 ml/kg, gastric cannula is closed). To study the duration of the time interval between dosing and stimulation can be increased. Samples of gastric juice is titrated with 0.1 M NaOH to pH 7.0 and the release of acid calculated as the product of the volume of the titrant concentration.

Further calculations based on the mean response for group of 4-6 rats. In the case of the introduction while stimulating the release of acid during periods of time after administration of the test substance or medium is expressed as the fractional values of the reaction, assuming a 1.0 release of acid for a period of 30 minutes prior to the introduction. The percentage inhibition is calculated from the fractional values of the reaction caused by the test compound and a carrier. In the case of the introduction to incentive the percentage of inhibition is calculated directly from the output of acid recorded after administration of the tested compounds and the media.

Bioavailability in rats

Use of adult rats Sprague-Dawly. For one to three days before the experiments, all rats under anesthesia establish cannula into the left carotid artery. Rats used for intravenous experiments, introducing blood Samples (0.1-0.4 g) repeatedly withdrawn from the carotid artery at intervals of up to 5.5 hours after administration of the dose. To analyze the test compound samples frozen.

Bioavailability is determined by calculating the ratio between the area under the curve concentration in the blood/plasma (AUC) after (1) vnutribolnichnogo (C. D.) or orally (p. O.) introduction and (2) intravenous (centuries) introduction the rat or the dog, respectively.

The area under the curve concentration in blood from time to time, AUC, is determined by the logarithmic/linear trapezoid rule and extrapolate to infinity by dividing the last set concentration in the blood at a constant rate of elimination in the final phase. Systemic bioavailability (F%) after vnutribolnichnogo or oral administration is calculated as

F (%)=AUC (p. O. or C. D.)/AUC (century. century.))×100.

Inhibition of the secretion of gastric acid and bioavailability in dogs, in consciousness

Use dog breed Labrador or Hound of both sexes. They set duodenal fistula for administration of test compounds or vehicle and kanilirovannoy gastric fistula or pocket Heidenheim to collect gastric secretion.

Before the tests on the secretion of animals kept without food for about 18 hours, but the water give bitamina dihydrochloride (12 ml/h) dose, which causes a response of approximately 80% of the individual maximal secretory response, and the gastric juice is collected in the subsequent 30-minute periods of time. The test substance or filler injected oral, century, etc. or centuries after 1 hour or 1.5 hours after the start of infusions of histamine in the amount of 0.5 ml/kg of body weight. In the case of oral administration, it should be noted that the test compound is injected into secreting acid the stomach of dogs with pocket Heidenheim.

The acidity of the samples of gastric juice is determined by titration to pH 7.0 and calculate the yield of acid. The release of acid in the intervals of the collection after the introduction of the test substance or medium is expressed as the fractional values of the reaction, assuming a 1.0 release of acid for a period of time preceding the introduction. The percentage inhibition is calculated from the fractional values of the reaction caused by the test compound and a carrier.

Blood samples for analysis on the concentration of the test compound in the plasma of selected time intervals up to 4 hours after dosing. After selection, the plasma separated and frozen within 30 minutes and later analyze. Systemic bioavailability (F%)licence connection with the substituted phenyl group of formula I

or its pharmaceutically acceptable salt,

where R1represents a C1-C6alkyl;

R2represents a C1-C6alkyl;

R3represents H or halogen;

represents a substituted heterocycle selected from the

or

where R4represents N, CH3CH2HE or CH2CN;

R5represents N or C1-C6alkyl;

R6represents N or C1-C6alkyl;

R7represents N or C1-C6alkyl;

n = 0 or 1;

X represents NH or O.

2. Connection on p. 1 or its pharmaceutically acceptable salt, in which

represents a

where R4, R5and X are such as defined in paragraph 1.

3. Connection on p. 1 or its pharmaceutically acceptable salt, in which

represents a

where R4, R6and X are such as defined in paragraph 1.

4. Connection on p. 1 or SUP>, R6and X are such as defined in paragraph 1.

5. Connection on p. 1 or its pharmaceutically acceptable salt, in which

represents a

where R4, R5, R7and X are such as defined in paragraph 1.

6. Connection on p. 1 or its pharmaceutically acceptable salt, in which

represents a

where R4, R5and X are such as defined in paragraph 1.

7. Connection on p. 1 or its pharmaceutically acceptable salt, in which

represents a

where R4and X are such as defined in paragraph 1.

8. Connection on p. 1 or its pharmaceutically acceptable salt, in which R1and R2independently represent CH3or CH2CH3.

9. Connection on p. 2, which represents a 2,3-dimethyl-8-(2,6-dimethylbenzylamine)imidazo[1,2-a]pyrazin

or its pharmaceutically acceptable salt.

10. Connection on p. 2, which represents a 2,3-dimethyl-8-(2,6-dimethylbenzylamine)imidazo[1,2-a]pyrazin

or its pharmaceutically acceptable salt.

11. A method of obtaining a compound according to any one of paragraphs.1-10SUB>,

subjected to interaction with the compound of General formula III

where R1, R3and R4such as defined for formula I;

Y1represents tsepliaeva group.

12. A method of obtaining a compound according to any one of paragraphs.1-10, in which the compounds of General formula IV

where X2represents tsepliaeva group,

subjected to interaction with the compound of General formula V

where R1, R3and R4such as defined for formula I;

a Y2represents NH2or HE.

13. The compound according to any one of paragraphs. 1-10 for inhibiting secretion of gastric acid.

14. Method of inhibiting secretion of gastric acid, in which the mammal, including man, in need of such inhibition, introducing an effective amount of a compound according to any one of paragraphs.1-10.

15. Pharmaceutical preparation for use in the inhibition of the secretion of gastric acid, in which the active ingredient is a compound according to any one of paragraphs.1-10.

16. Pharmaceutical drug having anti-inflammatory activity in ethnoses PP.1-10.



 

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