MXPA00005111A - Heterocyclic compounds for inhibition of gastric acid secretion, processes for their preparation and pharmaceutical compositions thereof - Google Patents

Abstract

The present invention relates to heterocyclic compounds of formula (I), in which the phenyl moiety is substituted with lower alkyl in 2- and 6-position, which inhibit exogenously or endogenously stimulated gastric acid secretion and thus can be used in the prevention and treatment of gastrointestinal inflammatory diseases.

Description

HETEROCICLIC COMPOUNDS FOR THE INHIBITION OF THE SECTION OF GASTRIC ACID, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS OF THEM.

TECHNICAL FIELD The present invention concerns new compounds, and therapeutically acceptable salts thereof, which exogenously or endogenously inhibit the stimulated secretion of gastric acid and consequently that can be used in the prevention and treatment of gastrointestinal inflammatory diseases. In additional aspects, the invention concerns compounds of the invention for use in therapy; to processes for preparing such novel compounds; to pharmaceutical compositions containing at least one compound of the invention, or a therapeutically acceptable salt thereof, as the active ingredient; and to the use of the active compounds in the manufacture of medicaments for the aforementioned medical use.

BACKGROUND IN THE SUBJECT The substituted imidazo [1, 2- a] pyrazines are set forth in EP-A-0068378, US 4,507,294 and EP-A-0204285. REF. 120062 Pyrrolo [2, 3-d] pyridazines are disclosed in WO 91/17164, WO 92/06979, O 93/08190 and WO 95/19980. The pyrrolo [1, 2- a] pyrazines are exposed in the USA 5,041,442.

Benzimidazole and imidazo pyridine derivatives, in which the phenyl portion is substituted with lower alkyls at positions 2- and 6, and which are effective as inhibitors of gastrointestinal H +, K + -ATPase, are set forth in the patent application International PCT / SE 97/00991 (registration date: June 5, 1997) and Swedish Patent Application No.: 9700661-3 (record date: February 25, 1997), respectively.

For a review of the pharmacology of gastric acid pumping (H +, K + -ATPase), see Sachs et al. (1995) Annu. Rev. Pharmacol. Toxicol 35: 277-305.

DESCRIPTION OF THE INVENTION Surprisingly, it has been found that the compounds of formula I, which are substituted heterocyclic compounds in which the phenyl portion is substituted with lower C-Ce) alkyl at positions 2- and 6-, are particularly effective as inhibitors of H +, ATPase gastrointestinal and therefore as inhibitors of gastric acid secretion.

In one aspect, the invention thus concerns compounds of general Formula I: where R is C -C, alkyl; R is C-C alkyl; R is H or halogen; Y s a substituted heterocycle selected from? imidazo [1, 2- a] pyrazine) (pyrrolo [2, 3-d] pyridazine) (pyrrolo [2, 3-b] pyridine) (pyrrolo [1, 2- a] pyrazine) imidazo [1, 2- b] pyridazine; imidazo [1, 2- c] pyrimidine- where R4 is H, CH3, CHjOH or CHCN; R5 is H or C; - Ce alkyl; R6 is H, C? -C6 alkyl, aryl, arylalkyl containing 1-2 carbon atoms in the alkyl, C2-C6 alkenyl, halo (C2- Ce alkenyl), C2- C6 alkynyl, C3- C- cycloalkyl or halo (C? ~ alkyl); R is H, halogen, Ci- Ce alkyl, C? ~ Ce alkylthio or thiocyano; n is 0 or l; and X is NH or O.

Preferred compounds according to the invention are those in which: R is CH. or CH.CH ,; R is CH or CH CH. and it is H, Br, Cl or F.

Other preferred compounds according to the invention wherein R 4 is CH 3 or CH 2 OH; Y X, n, R1, R :, RJ, R5, Rd and R7 are as defined for formula I. Particularly preferred are compounds wherein R1, R ~ and R3 are the preferred substituents defined above.

As used herein, the term "C? -Calkyl" denotes a straight or branched alkyl group having from 1 to 6 carbon atoms. Examples of said lower alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, t-butyl and right-side pentyl and hexyl.

The term "halogen" includes fluoro, chloro, bromo and iodo.

Both, pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers are within the scope of the invention. If it were understood that all possible diastereomeric forms (pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers) are within the scope of the invention. Also included in the invention are derivatives of the compounds of Formula I that have the biological function of the compounds of Formula I.

Depending on the process conditions, the final products of Formula I are obtained in either neutral or salt form. Both, the free base and the salts of these final products are within the scope of the invention.

Acid addition salts of the new compounds can in a manner known per se be transformed into the free base using basic agents such as alkali or by ion exchange. The free base obtained can also form salts with organic or inorganic acids.

In the preparation of the acid addition salts, acids such as those forming suitable therapeutically acceptable salts are preferably used. Examples of such acids are hydrohalogenic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, aliphatic acids, alicyclics, heterocyclic or aromatic or sulfonic carboxyls, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, p-hydroxybenzoic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethane sulfonic acid, halogenbenzenesulfonic acid, toluenesulfonic acid or acid Naphthalenesulfonic Preparation The present invention also provides the following processes A and B for the manufacture of compounds with general Formula I.

Process A Process A for manufacturing compounds with general Formula I comprises the following steps: Compounds of General Formula II wherein X1 is OH or NH2, it can be reacted with compounds of the general Formula III where R !, R 'and R "are as defined for the Formula I and Y is a displaceable group, such as a halide, tosyloxy or mesyloxy, for the compounds of Formula I It is convenient to conduct this reaction in an inert solvent, for example acetone, acetonitrile, dimethoxyethane, methanol, ethanol, xylene or dimethylformamide with or without a base.

The base is for example an alkali metal hydroxide, such as sodium hydroxide and potassium hydroxide; a sodium alcoholate, such as sodium methoxide and sodium ethoxide; an alkali metal hydride such as sodium hydride and potassium hydride; an alkali metal carbonate, such as potassium carbonate and sodium carbonate; or an organic amine, such as triethylamine.

Process B Process B for manufacturing compounds with general formula I comprises the following steps: Compounds of General Formula IV Where X is a displaceable group, for example halide, it can be reacted with compounds of the general Formula V Where R1, RJ and R4 are as defined for Formula I and Y2 is NH2 or OH for compounds of general Formula I.

It is convenient to conduct this reaction in an inert solvent, for example acetone, acetonitrile, dimethoxyethane, methanol, ethanol, xylene or dimethylformamide with or without a base. The base is for example an alkali metal hydroxide, such as sodium hydroxide and potassium hydroxide; a sodium alcoholate, such as sodium methoxide and sodium ethoxide; and an alkali metal hydride such as sodium hydride and potassium hydride; an alkali metal carbonate such as potassium carbonate and sodium carbonate; or an organic amine, such as triethylamine.

Pharmaceutical formulations In still another aspect, the invention concerns pharmaceutical compositions containing at least one compound of the invention, or a therapeutically acceptable salt thereof, as the active ingredient.

The compounds of the invention can also be used in formulations together with other active ingredients, for example antibiotics such as amoxicillin.

For clinical use, the compounds of the invention are formulated in pharmaceutical formulations for oral, rectal, parenteral or other administration. The pharmaceutical formulation contains a compound of the invention in combination with one or more pharmaceutically acceptable ingredients. The vehicle can be in the form of diluent a solid, semi-solid or liquid, or a capsule. These pharmaceutical preparations are a further objective of the invention. Usually the amount of active compounds is between 0.1-95% by weight of the preparation, preferably between 0.1-20% by weight, of the preparation for parenteral use and preferably between 0.1 and 50% by weight of the preparations for oral administration.

In the preparation of pharmaceutical formulations containing a compound of the present invention in the form of unit doses for oral administration the selected compound can be mixed with solid or powdered ingredients, such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, derivatives of cellulose, gelatin and other suitable ingredients, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, stearyl sodium fumarate and polyethylene glycol waxes. The mixture is then processed into pellets or compressed into tablets.

Soft gelatin capsules can be prepared with capsules containing a mixture of the active compound or compounds of the invention, vegetable oil, fat, or other suitable vehicles for soft gelatin capsules. Hard gelatin capsules may contain granules of the active component. Hard gelatine capsules may also contain the active compound in combination with powdered solid ingredients such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.

The unit doses for rectal administration can be prepared (i) in the form of suppositories containing the active substance mixed with a neutral fat base; (ii) in the form of a rectal gelatin capsule containing the active substance in a mixture with a vegetable oil, mineral oil or other vehicle available for rectal gelatin capsules; (iii) in the form of a micro-enema ready to be used; or (iv) in the form of a dry formulation for micro enema to be reconstituted in a suitable solvent just prior to administration.

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% by weight of the active ingredient and the remainder consisting of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain coloring agents, flavoring agents, saccharin and carboxymethylcellulose or other thickening agents. Liquid preparations for oral administration can be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.

Solutions for parenteral administration can be prepared as a solution of a compound of the invention in a pharmaceutically acceptable solvent, preferably in a concentration from 0.1% to 10- by weight. These solutions may also contain stabilizing ingredients and / or regulatory ingredients • and are administered in unit doses in the form of ampoules or in vials.

Solutions for parenteral administration can also be prepared as a dry preparation to be reconstituted with a suitable extemporaneously solvent before use.

The typical daily dose of the active substance varies over a wide range and will depend on several factors such as for example the individual requirements of each patient, the route of administration and the disease. In general, oral and parenteral doses will be in the range of 5 to 1000 mg per day of active substance.

The compounds according to the invention can be used in formulations together with other active ingredients, for example for the treatment or prophylaxis of conditions involving infection by Heli cobacter pyl ori of the human gastric mucosa. Other active ingredients can be antimicrobial agents, in particular. - b-lactam antibiotics, such as amoxicillin, ampicillin, cephalosporins, cefaclor or cefixime; macrolides such as erythromycin or clarithromycin; tetracyclines such as tetracycline or doxycycline; - aminoglycosides such as gentamicin, kanamycin or amikacin; - quinolones such as norfloxacin, ciprofloxacin or enoxacin; - others such as metronidazole, nitrofurantoin or chloramphenicol; or preparations containing bismuth salts such as bismuth subcitrate, bismuth subsalicylate, bismuth subcarbonate, bismuth subnitrate or bismuth subgalate.

EXAMPLES Example 1 . 1 Synthesis of 2, 3-dimethyl-8- (2,6-dimethylbenzylamino) imidazo fl, 2- a] pyrazine A stirred mixture of 8-chloro-2,3-dimethylimidazole [1, 2-a] pyrazine (0.5 g, 2.8 mmol) and 2,6-dimethylbenzylamine (0.41 g, 3.0 mmol) in xylene (10 ml) was refluxed by 24 hours. The mixture was evaporated under reduced pressure, dissolved in methylene chloride (20 ml) and washed with a 5% sodium carbonate solution in water (20 ml). The organic layer was separated and evaporated under reduced pressure and the residue was purified by column chromatography on silica gel. Crystallization of pentane gave 90 mg (23 i) of the title compound.

-NMR (300 MHz, CDC13): d 2.35 (s, 6H), 2.45 (s, 6H), 4.70 (d, 2H), 5.60 (bs, 1H), 7.05- 7.20 (, 3H), 7.25 (dd, 1H), 7.40 (d, 1H).

Example 1.2 Synthesis of 2, 3-dimethyl-8- (2,6-dimethylbenzyloxy) imidazo [1, 2-a] pyrazine Sodium hydride (0.15 g, 3 mmol) (50 ml in oil) was added to a stirred solution of 2,6-dimethylbenzylalcohol in acetonitrile (10 ml). 8-chloro-2, 3-dimethylimidazo [1, 2-a] pyrazine (0.4 g, 3 mmol) were added and the reaction mixture was refluxed for 20 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in methylene chloride and washed with water. The organic layer was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using ethyl acetate: petroleum ether (40-60) 1: 1 as eluent. Crystallization of the petroleum ether gave 0.42 g (50% 9 of the title compound.

? 'E- NMR (300 MHz, CDC13): d 2.35 (s, 3H), 2.40 (s, 3H), 2.45 (s, 6H), 5.6 (s, 2H) 6.95- 7.15 (, 3H), 7.35-7.45 (m, 2H).

BIOLOGICAL TESTS 1. Experiments in vi tro Inhibition of acid secretion in rabbit gastric glands The inhibitory effect on the secretion of in vi tro acid in isolated rabbit gastric glands was measured as described by Berglindh et al. (1976) Acta Physiol. Scand. 97, 401-414.

Determination of the activity HX X -ATPasa The membrane vesicles (2.5 to 5 μg) were incubated for 15 minutes at + 37 ° C in 18 mM Pipes / Tris buffer at pH 7.4 containing 2 mM MgCl, 10 mM KCl and 2 mM ATP. The ATPase activity was estimated as to release the inorganic phosphatase of ATP, as described by LeBel et al., (1978) anal. Biochem. 85, 86-89.

The compound of Example 1 had an IC5o value of 0.16 μM and the compound of Example 2 had a value of 2. In vivo experiments Inhibitory effect on acid secretion in female rats Female rats of the race Sprague-Da and were used. They were equipped with cannulated fistulae in the stomach (lumen) and the upper part of the duodenum, for collection of gastric secretions and administration of the test substances, respectively. A recovery period of 14 days after surgery was maintained before the start of the test.

Before the secretory tests, the animals were deprived of food but not water for 20 hours. The stomach was repeatedly washed through the gastric cannula with squirts of water (+ 37 ° C), and 6 ml of the Ringer-Glucose given subcutaneously. Acid secretion is stimulated with infusion for 2.5-4 hours (1.2 ml / h, subcutaneously) of pentagastrin and carbacol (20 and 110 nmol / Kg-h, respectively), during which time the gastric secretion was collected in fractions each 30 minutes. The test substances or vehicle were given either 60 minutes after the start of the stimulation (intravenous or intraduodenal dosing, 1 ml / kg), or 2 h before the start of the stimulation (oral dosage, 5 ml / kg, gastric cannula closed) . The time interval between dosing and stimulation can be increased in order to study the duration of the action. Samples of gastric juice are titrated until pH 8.0 with NaOH, 0.1 M, and the removed acid calculated as the product of the titrated volume and concentration.

Additional calculations are based on average group responses of 4-6 rats. In the case of administration during stimulation; the acid removed during the periods after the administration of the test substance or vehicle are expressed as partial responses, placing the acid removed within the 30 minute period preceding the administration of 1.0. The percentage of inhibition is calculated from the partial responses taken by the test compounds and the vehicle. In the case of administration before stimulation; the percentage of inhibition is calculated directly from the removed acid recorded after the test compound and the vehicle.

Bioavailability in rat Adult rats of the race Sprague-Dawl and were used. One to three days prior to the experiments all the rats were prepared by cannulation of the left carotid artery under anesthesia. The rats used for intravenous experiments were also cannulated in the jugular vein (Popovic (1960) J. Appl. Physiol. 15, 727-728). The cannulas were exteriorized to the nape of the neck.

Blood samples (0.1-0.4 g) are drained repeatedly from the carotid artery at intervals up to 5.5 hours after the dose administered. The samples were frozen until analysis of the test compounds.

Bioavailability is evaluated by calculating the quotient between the area under the blood / plasma concentration curve (AUC) that followed administration (i) intraduodenal (id) or oral (po) and intravenous (iv) administration of the rat or of the dog respectively.

The area under the curve of blood concentrations Vs. The time, AUC, is determined by trapezoidal log / linear rule and extrapolated in affinity by dividing the last determination of blood concentration between the constant of the elimination rate in the terminal phase. The systemic bioavailability (F 2) following the mtraduodenal or oral administration is calculated as F (.) = (AUC (p.o. or i.d.) / AUC (i.v.) X 100.

Inhibition of gastric acid secretion and bioavailability in the concise dog.

Labrador Retriever or Harrier dogs of either sex were used. They were equipped with a duodenal fistula for the administration of the test compounds or vehicle and a cannulated gastric fistula or a bag-Heidenhaim for the collection of gastric secretion.

Before the secretory tests the animals were fasted for approximately 18 hours but the water was allowed freely. The secretion of gastric acid is stimulated by up to 6.5 hours of infusion of histamine dihydrochloride (12 ml / hour) at a dose to produce approximately 80% of the individual maximum secretory response, and gastric juice collected in consecutive fractions of 30 minutes. The test substance or vehicle is given orally, i.d. or i.v. or 1.5 hours before initiating the histamine infusion, in a volume of 0.5 ml / Kg of body weight. In the case of oral administration, it would be indicated that the test compound be administered in the main stomach secreting the acid from the dog's Heidenham bag.

The acidity of the gastric juice samples is determined by titrations up to pH 7.0, and the acid removed calculated. The acid removed is the collection periods after administration of the test substance or vehicle is expressed as fractionated responses, placing the acid removed in the fraction that precedes the administration of 1.0. the percentage of inhibition is calculated from the fractional responses drawn by the test compounds and the vehicle.

Blood samples for analysis of the concentration of the test compounds in plasma are taken at intervals up to 4 hours after dosing. The plasma is separated and frozen in the 30 minutes after the collection and analyzed later. Systemic bioavailability (F%) after oral administration i.d. is calculated as described above in the rat model.

It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Having described the invention as above, it is claimed as property in the following:

Claims (23)

1. A compound of the formula I or a pharmaceutically acceptable salt thereof, which is characterized in that R "is C -C, alkyl; R is C: -C, alkyl; R is H or halogen; and is a substituted heterocycle selected from fifteen 25 where R- is H, CHJf CH_OH or CH_CN; R ~ 'is H or C: -Ce alkyl; R ° is H, C, -C, alkyl, aryl, arylalkyl containing 1 to 2 carbon atoms in the alkyl part, CC alkenyl, halo (Cj-C, alkenyl), C- C6 alkynyl, Cj- C cycloalkyl or halo (C-C, alkyl); R is H, halogen, C -.- C, alkyl, Ci- C 0 alkylthio or thiocyano; n is 0 or 1; Y X is NH or O.

2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is characterized in that is wherein R ', R and X are as defined in claim 1.

3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof which is characterized in that is wherein R4, Rc and X are as defined in claim 1.

4. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is characterized in that XX is wherein R4, R, R and X are as defined in claim 1.

5. A compound according to claim q, or a pharmaceutically acceptable salt thereof, which is characterized in that is wherein R4, R5, R7 and X are as defined in claim 1.

6. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is characterized in that is wherein R ", R and X are as defined in claim 1.

7. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is characterized in that is wherein R "and X are as defined in claim 1.

8. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein RJ and R are independently CH or CH ^ CH ..

9. A compound according to claim 2 which is characterized in that it is the compound 2, 3-dimethyl-8- (2,6-dimethylbenzylamino) imidazo [1, 2-a] pyrazine or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 2 which is characterized in that it is the compound 2, 3-dimethyl-8- (2,6-dimethylbenzyloxy) imidazo [1, 2-a] pyrazine or a pharmaceutically acceptable salt thereof.

11. A process for the preparation of a compound according to any one of claims 1 to 10, characterized in that it comprises reacting a compound of the general Formula II wherein X * is OH or NH_, with a compound of the general Formula III wherein R, R and R are as defined for Formula I and Y is a displaceable group.

12. A process for the preparation of a compound according to any of claims 1 to 10, which is characterized in that it comprises reacting a compound of general Formula IV wherein X "is a displaceable group, with a compound of general Formula V where R ", R and R ~ are as defined for Formula 1, and Y is NH or OH.

13. A compound according to any one of claims 1 to 10 for use in therapy.

14. A pharmaceutical formulation which is characterized in that it contains a compound according to any one of claims 1 to 10 as an active ingredient in combination with a pharmaceutically acceptable carrier-o-diluent.

15. Use of a compound according to any one of claims 1 to 10 for the manufacture of a medicament for the inhibition of gastric juice secretion.

16. Use of a compound according to any one of claims 1 to 10 for the manufacture of a medicament for the treatment of gastrointestinal inflammatory diseases.

17. Use of a compound according to any one of claims 1 to 10 for the manufacture of a medicament for the treatment or prophylaxis of conditions that involve infection by -philic character pyl ori of the human gastric mucosa, which is characterized in that said salt is adapted to be administered in combination with at least one antimicrobial agent.

18. A method for inhibiting gastric acid secretion which is characterized in that it comprises administering to a mammal, including man, in need of such inhibition an effective amount of a compound according to any one of claims 1 to 10.

19. A method for the treatment of gastrointestinal inflammatory diseases which is characterized in that it comprises administering to a mammal, including man, in need of such treatment an effective amount of a compound according to any one of claims 1 to 10.

20. A method for the treatment or prophylaxis of conditions involving infection by Heli cobacter pyl ori of the human gastric mucosa, which is characterized in that it comprises administering to a mammal, including man, in need of such treatment an effective amount of a compound such as claimed in any one of claims 1 to 10, wherein said salt is administered in combination with at least one antimicrobial agent.

21. A pharmaceutical formulation for use in the inhibition of gastric acid secretion which is characterized in that the active ingredient is a compound according to any one of claims 1 to 10.

22. A pharmaceutical formulation for use in the treatment of gastrointestinal inflammatory diseases which is characterized in that the active ingredient is a compound according to any one of claims 1 to 10.

23. A pharmaceutical formulation for use in the treatment or prophylaxis of conditions involving infection by Heli cobacter pyl ori of the human gastric mucosa, which is characterized in that the active ingredient is a compound according to any one of claims 1 to 10 in combination with the minus an antimicrobial agent.