MXPA01003047A - Tetrahydropyridoethers - Google Patents

Abstract

Compounds of formula (I) in which the substituents have the meanings mentioned in the description, are suitable for the prevention and treatment of gastrointestinal diseases.

Description

TETRAHIDROPIRIDOETERES Field of Invention The present invention relates to new compounds which are used in the pharmaceutical industry as active compounds for the production of medicaments.

Antecedents of the Invention. U.S. Patent 4,468,400 discloses tricyclic imidazo [1,2- a] pyridines having several ring systems fused to the imidazopyridine matrix structure which are mentioned as being suitable for the treatment of peptic ulcer diseases.

Summary of the Invention. The present invention relates to compounds of the formula I (I) wherein R1 is methyl or hydroxymethyl, one of the substituents R2a and R2b is hydrogen and the other is hydroxyl, methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxyl, one of the substituents R3a and R3b is hydrogen and the other is hydroxyl, methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, wherein R2a or R2b on the one hand, and R3a or R3b on the other hand, are not simultaneously hydroxyl, and their salts. Suitable salts of compounds of the formula I are especially all the acid addition salts. Particular mention is made of the pharmacologically tolerable salts of the inorganic and organic acids normally used in the pharmaceutical industry. Said suitable salts are acid addition salts soluble in water and not soluble in water with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-acid. 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, embonic acid, stearic acid, toluenesulfonic acid , methanesulphonic acid or 3-hydroxy-2-naphthoic acid, wherein the acids are used in the preparation of salt -depending on whether the acid is mono- or polybasic and depending on which salt is desired- in an equimolar quantitative proportion or a differentiation of it. Pharmacologically intolerable salts, which can be obtained initially as process products, for example in the Preparation of the compounds according to the present invention on an industrial scale, are converted into pharmacologically tolerable salts through processes known to those skilled in the art. In accordance with the knowledge of the experts, the compounds of the present invention, as well as their salts, may contain, for example, when different amounts of solvents are isolated in crystalline form. Therefore, all the solvates and in particular all the hydrates of the compounds of the formula I, as well as all the solvents and in particular all the hydrates of the salts of the compounds of the formula I, are included within the scope of present invention. The compounds of the formula I have three chiral centers. The present invention relates to the eight conceivable stereoisomers in any desired mixing ratio of one to the other, including the pure enantiomers, which are the preferred material of the present invention. A preferred embodiment of the present invention are the compounds of the formula I * (I *) wherein R1 is methyl or hydroxymethyl, one of the substituents R2a and R2b is hydrogen, and the other is hydroxyl, methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxyl, one of the substituents R3a and R3b is hydrogen and the other is hydroxyl, methoxy , ethoxy, isopropoxy, methoxyethoxy, or methoxypropoxy, wherein R2a or R2b on the one hand, and R3a or R3b on the other hand, are not simultaneously hydroxyl, and their salts. One embodiment (mode a), are the compounds of the formula I *, wherein R1 is methyl, one of the substituents R2a and E2b is hydrogen and the other is methoxy, ethoxy, ispropoxy, methoxyethoxy, or methoxypropoxyl, one of the substituents R3a and R3b is hydrogen and the other is hydroxyl, and its salts. An additional embodiment (mode b) are the compounds of the formula I *, wherein R1 is methyl, one of the substituents R2a and R2b is hydrogen and the other is hydroxyl, one of the substituents R3a and R3b is hydrogen and the other is methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, and their salts.

An additional embodiment (mode c) of the invention, are the compounds of the formula I *, wherein R1 is methyl, one of the substituents R2a and R2b is hydrogen and the other is methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, one of the substituents R3a and R3b is hydrogen and the other is methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, and their salts. In a further embodiment (mode d) of the invention, are the compounds of the formula I *, wherein R1 is hydroxymethyl, one of the substituents R2a and R2b is hydrogen and the other is methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, one of the substituents R3a and R3b is hydrogen and the other is hydroxyl, and its salts. A further embodiment (mode e) of the invention, are the compounds of the formula I *, wherein R 1 is hydroxymethyl, one of the substituents R 2a and R 2b is hydrogen and the other is hydroxyl, one of the substituents R 3a and R 3b is hydrogen and the other is, methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, and its salts. An additional embodiment (mode f) of the invention are the compounds of the formula I *, wherein R1 is hydroxymethyl, one of the substulants R2a and R2b is hydrogen and the other is methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, of the substituents R3a and R3b is hydrogen and the other is methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, and their salts.

Preferred compounds of the forms of a, to f, are those in which R3b is hydrogen. Particularly preferred compounds of the forms of a, to f, are those in which R2a and R3b are hydrogen. Preferred compounds within the scope of the invention are those of the a mode, which can be characterized by the formula I ** (I **) wherein one of the substituents Ra and Rb and the other is methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy and their salts. Particularly preferred compounds of the a-mode are those of the formula I **, wherein R a is hydrogen and R b is methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, and their salts. With the help of the general formula I *, the following exemplary preferred compounds according to the present invention can actually be mentioned by means of the meanings of the substituents for R1, R2a, R2b, R3a and R3b, which are found in Table 1 below (Table 1): Table 1 R1 R2a R2b R3a R3b CH3 H OCH3 OH H CH3 H OC2H5 OH H CH3 H OCH (CH3) 2 OH H CH3 H OCH2CH2OCH3 OH H CH3 H OCH2CH2CH2OCH3 OH H CH3 H OH OCH3 H CH3 H OH OC2H5 H CH3 H OH OCH (CH3) 2 H CH3 H OH OCH2CH2OCH3 H CH3 H OH OCH2CH2CH2OCH3 H CH3 H OCH3 OCH3 H CH3 H OC2H5 OC2H5 H CH3 H OCH (CH3) 2 OCH (CH3) 2 H CH3 H OCH2CH2OCH3 OCH2CH2OCH3 H CH3 H OCH2CH2CH2OCH3 OCH2CH2CH2OCH3 H CH2OH H OCH3 OH H CH2OH H OC2H5 OH H CH2OH H OCH (CH3) 2 OH H CH2OH H OCH2CH2OCH3 OH H CH2OH H OCH2CH2CH2OCH3 OH H CH2OH H OH OCH3 H Continuation Table 1 R1 R2a R2b R3a R3b CH2OH H OH OC2H5 H CH2OH H OH OCH (CH3) 2 H CH2OH H OH OCH2CH2OCH3 H CH2OH H OH OCH2CH2CH2OCH3 H CH2OH H OCH3 OCH3 H CH2OH H OC2H5 OC2H5 H CH2OH H OCH (CH3) 2 OCH (CH3) 2 H CH2OH H OCH2CH2OCH3 OCH2CH2OCH3 H CH2OH H OCH2CH2CH2OCH3 OCH2CH2CH2OCH3 H CH3 OCH3 H OH H CH3 OC2H5 H OH H CH3 OCH (CH: 3) 2 H OH H CH3 OCH2CH2 OCH3 H OH H CH3 OCH2CH2 CH2OCH3 H OH H CH3 OH H OCH3 H CH3 OH H OC2H5 H CH3 OH H OCH (CH3) 2 H CH3 OH H OCH2CH2OCH3 H CH3 OH H OCH2CH2CH2OCH3 H CH3 OCH3 H OCH3 H CH 3 OCH (CH: 3) 2 H OCH (CH 3) 2 H CH3 OCH2CH2 OCH3 H OCH2CH2OCH3 H Continuation Table 1 CH3 OCH2CH2CH2OCH3 H OCH2CH2CH2OCH3 H CH2OH OCH3 H OH H CH2OH OC2H5 H OH H CH2OH OCH (CH3) 2 H OH H CH2OH OCH2CH2OCH3 H OH H CH2OH OCH2CH2CH2OCH3 H OH H CH2OH OH H OCH3 H CH2OH OH H OC2H5 H CH2OH OH H OCH (CH3) 2 H CH2OH OH H OCH2CH2OCH3 H CH2OH OH H OCH2CH2CH2OCH3 H CH2OH OCH3 H OCH3 H CH2OH OC2H5 H OC2H5 H CH2OH OCH (CH3) 2 H OCH (CH3) 2 H CH2OH OCH2CH2OCH3 H OCH2CH2OCH3 H CH2OH OCH2CH2CH2OCH3 H OCH2CH2CH2OCH3 H And the salts of these compounds. The compounds according to the present invention can be prepared as will be described by way of example in the examples which follow, or by using analogous steps of the process starting from suitable starting compounds (see, for example, the EP patent). -A-0 299 470 or Kaminski et al., J. Med. Chem. 1985, 28, 876-892). The starting compounds are known, or can be prepared in the form analogous to the known compounds. The compounds according to the present invention can be prepared starting, for example, from 8-amino-imidazo [1, 2-a] pyridines protected by N according to the following reaction scheme: The above scheme represents an example of an enantioselective synthesis. The N-protected 8-aminoimidazo [1, 2-a] pyridines (Piv represents a customary protection group, preferably the pivaloyl group), deprotonated at position 7, is reactivated with a dioxolane enantiomerically pure. This leads initially to a condensation product which can be cyclized under strongly acidic conditions with the removal of the protection groups. Subsequent reduction of the keto group, using sodium borohydride, leads with approximately 90% enantiomeric purity to the indicated 7,8-trans-diol. Subsequent etherification, which is carried out with the known processes, for example, as described in the Examples, leads to the final products of the formula I *, wherein R2a and R3b are hydrogen. The corresponding 7,8-cis compound is obtained from the mother liquor, which is on the left after the separation of the 7,8-trans compound, by chromatographic purification. The substances according to the present invention are isolated and purified in a known manner, for example by distilling the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent, or by subjecting them to one of the usual purification methods, such as by example, column chromatography on a suitable support material. (The salts are obtained by dissolving the free compound in a suitable solvent, for example, in a chlorinated hydrocarbon, such as dichloromethane or chloroform, or a low molecular weight aliphatic alcohol (ethanol, isopropanol), which contains the desired acid, or to which the desired acid is subsequently added The salts are obtained by filtration, reprecipitation, precipitation with a non-solvent during the addition of salt or by evaporating the solvent The salts obtained can be converted by alkalization or by acidification in the compounds free, which in turn can be converted into salts. In this way, the pharmacologically intolerable salts can be converted into pharmacologically tolerable salts. The pure enantiomers, in particular the pure enantiomers of the formula I *, to which the present invention is preferably referred, can be obtained in a manner known to those skilled in the art, for example by enantioselective synthesis (see, for example, the Scheme), by chromatographic separation on chiral separation columns, by derivatization with chiral auxiliary reagents, subsequent separation of diastereomers and removal of the chiral auxiliary group, through the formation of salt with chiral acids, subsequent separation of the salts and release of the desired compound of the salt, or by (fractional) crystallization from a suitable solvent. The trans-products obtained (with R2a and R3b = hydrogen), can be converted (at least partially) to the corresponding cis-products (with R2b and R3b = hydrogen) by placing them under acid conditions (for example, 2 equivalents of acid, such as sulfuric acid), in the corresponding alcohol R2a-OH. In the same way, the obtained cis-products can be converted to the corresponding trans-products. The cis- and trans-products are separated, for example, by chromatography or by crystallization. The examples that follow serve to further illustrate the present invention without restricting it. Likewise, the additional compounds of the formula I, whose preparation is not explicitly described, can be prepared analogously or in a form known to those skilled in the art, using customary process techniques. The abbreviation min, is set for minute (s), h for hour (s) and ee for enantiomeric excess.

Examples Final Products 1 A. (7R. 8R.9R) -2.3-Dimethyl-8-hydroxy-7-methoxy-9-phenyl-7.8.9.10-tetrahydro-imidazo [1,2-hl- [1, 71-naphthyridine Method a 20 g (65 mmol) of (7R, 8R, 9R) -2,3-dimethyl-7,8-dihydroxyl-9-phenyl-7,8,9, 1-tetahydro-imidazo [1, 2-h] [1, 7] naphthyridine in methanol (350 ml). 1 3.5 g of sulfuric acid are added and the solution is stirred for 48 h at a temperature of 50 ° C. After cooling, the reaction mixture is poured into 250 ml of water. The pH is adjusted through an aqueous solution of saturated sodium hydrogen carbonate until a neutral pH is obtained. The precipitate is collected and purified on silica gel (eluent: diethyl ether). 2.5 g of the titration compound are obtained in the form of colorless crystals with a melting point of 1 64 to 1 65 ° C (2-propanol).

Method b 1 g (32.5 mmol) of (7R, 8R, 9R) -2,3-dimethyl-7,8-dihydroxyl-9-phenyl-7,8,9,1-tetahydro-imidazo [1 is dissolved. , 2-h] [1,7] naphthyridine in 200 ml of dry dimethylformamide. They are added in small portions at temperature environment 1 .9 g of paraffin sodium hydride (80%) available in the market. After 1 h, 9.1 g (65 mmol) of methyl iodide dissolved in 4 ml of dimethylformamide is added, and the mixture is stirred for an additional hour. The reaction mixture is poured into cold water. 20 ml of an aqueous solution of saturated ammonium chloride are added, the yellow precipitate is collected and discarded. The filtrate is extracted several times with ethyl acetate, the combined organic phases are washed several times with water and the solvent is evaporated in vacuo. The solid residue is purified on silica gel (diethyl ether). 2 g of the titration compound are obtained in the form of colorless crystals having a melting point of 1 64-1 65 ° C (2-propanol). 1 B. (7S 8S 9S) -2.3-Dimethyl-8-hydroxy-7-methoxy-9-phenyl-7.8.9.1 0-tetrahydro-imidazo [1,2-hl-M .71naphthyridine The titration compound of melting point from 1 61 to 1 62 ° C is obtained in a manner similar to the procedure described in Example 1, Method a, using (7S, 8S, 9S) -2,3-Dimethyl-7, 8-dihydroxyl-9-phenyl-7,8,9,1-tetahydroimidazo [1, 2-h] [1,7] naphthyridine as starting material. 2A. (7S. 8R. 9R) -2.3-Dimethyl-8-hydroxyl-7-methoxy-9-phenyl-7.8.9.1 0-tetrahydro-imydazo ["1,2-hl-M .7jnaphthyridine 6 g of the titration compound are obtained in the form of a colorless powder of melting point from 1.08 to 11.0 ° C after purification on silica gel according to Example 1A, Method a, starting from (7S). , 8R, 9R) -2,3-Dimethyl-7,8-dihydroxyl-9-phenyl-7,8,9,11-tetahydro-imidazo [1, 2-h] [1,7] naphthyridine. 2B. (7R. 8S. 9S) -2.3-Dimethyl-8-hydroxyl-7-methoxy-9-phenyl-7.8.9.1 0-tetrahydro-imidazo [1, 2-hl- [1,7) naphthyridine The titration compound of melting point of 1 71 to 1 72 ° C, is obtained from the mother liquor of Example 1 B, after purification on silica gel (eluent: diethyl ether). 3. (7R. 8R. 9R) -2.3-Dimethyl-7-ethoxy-8-hydroxyl-9-phenyl-7.8.9.1 0-tetrahydro-imidazole, 2-h1- [1, 71-naphthyridine 500 mg of the titration compound are obtained by the reaction of (7R, 8R, 9R) -2,3-dimethyl-7,8-dihydroxyl-9-phenyl-7,8,9,1-tetahydro-imidazo [1, 2-h] [1, 7] naphthyridine with ethanol and sulfuric acid according to Example 1, Method a, after purification on silica gel (eluent: diethyl ether). Melting point: from 1 88 to 1 90 ° C. 4. (7S. 8R. 9R) -2.3-Dimethyl-7-ethoxy-8-hydroxy-9-phenyl-7.8.9.1 0-tetrahydro-imidazoH, 2-h] - [1, 71-naphthyridine Obtained 800 mg of the titration compound melting point 1 35 ° to 1 37 ° C, in the form of a solid by further purification of the mother liquor of Example 3 on silica gel. 5A. (7R. 8R. 9R) -2.3-Dimethyl-8-hydroxy-7- (2-methoxyethoxy) -9-phenyl-7.8.9.1 0-tetrahydro-imidazoM .2-hU1 .7lnaphthyridine Method a g of the titration compound of melting point of 30-131 ° C are obtained by the reaction of 20 g of (7R, 8R, 9R) -2,3-dimethyl-7,8-dihydroxyl-9-phenyl- 7,8,9,11-tetahydro-imidazo [1, 2-h] [1,7] naphthyridine with 2-methoxy-ethanol according to Example 1, Method a.

Method b To a solution of 1 00 g of (7R, 8R, 9R) -2,3-Dimethyl-7,8-dihydroxyl-9-phenyl-7,8,9,11-tetahydroimidazo- [1, 2-h] [1, 7] naphthyridine in 1 l of 2-ethoxyethanol, 64 g of concentrated sulfuric acid are slowly added at room temperature under argon atmosphere. The range of addition is such that the temperature of the mixture does not exceed 35 ° C. After 1.5 hours of further stirring at room temperature, the green solution is poured into a mixture of 1 kg of crushed ice and 800 ml of dichloromethane. The pH of the stirred mixture is adjusted to 7.5 by the addition of a 1.0 M aqueous sodium hydroxide solution, the organic layer is separated, the aqueous layer is extracted three times with dichloromethane (200 ml each), the dichloromethane are washed collectively with 500 ml of water (six times) and then dried over sodium sulfate. Upon completion of evaporation of the solvent under reduced pressure, the remaining oil residue is treated with 450 ml of acetone to yield 75 g of off-white crystals consisting of a 1: 1 mixture of the titration compound and its epimer (7S, 8R, 9R ). The mixture is separated by H PLC preparation using methanol as eluent. 28 g of the compound of melting point titre from 128 to 129 ° C after recrystallization from ethyl acetate. 5B. (7S 8S 9S) -2.3-Dimethyl-8-hydroxyl-7 -? / 2-methoxyethoxy) -9-phenyl-7.8.9.1 0-tetrahydro-imidazop .2-h1f-1 .7-naphthyridine The titration compound is obtained of melting point of 1 30 to 1 31 ° C in a manner similar to the procedure described in Example 5A, Method a, using (7S, 8S, 9S) -2,3-Dimethyl-7,8-dihydroxyl-9-phenyl -7,8,9,11-tetahydroimidazo [1, 2h] [1,7] naphthyridine as starting material. 6A. (7S 8R 9R) -2,3-Dimethyl-8-hydroxyl-7 -? / 2-methoxyethoxy) -9-phenyl-7.8.9.1 0-tetrahydro-imidazoM .2-hydroxy-7-naphthyridine 7.8 g of the compound of melting point titration of 1 31 to 1 32 ° C, in the form of a solid from the mother liquor of Example 5A after purification by silica gel (eluent: diethyl ether). 6B. (7R, 8S, 9S) -2.3-Dimethyl-8-hydroxyl-7-? 2-methoxyethoxy) -9-phenyl-7.8.9.1 0-tetrahydro-imidazori. 2-hip .71naphthyridine The titration compound of melting point 1 31 to 1 32 ° C is obtained from the mother liquor of Example 5B, after purification on silica gel (eluent: diethyl ether). 7. (7S. 8R. 9R) -2.3-Dimethyl-8-hydroxy-9-phenyl-7- (2-propoxy) -7.8.9.10-tetrahydro-imidazori .2-hU1 .7lnaphthyridine 1 g of the titration compound of melting point 168 to 169 ° C is obtained by the reaction of 3 g of (7R, 8R, 9R) -2,3-dimethyl-7,8-dihydroxyl-9-phenyl-7 , 8,9, 10-tetahydro-imidazo [1,2-h] [1,7] naphthyridine with 2-propanol according to Example 1, Method a. 8. (7R. 8R.9R) -2.3-Dimethyl-7,8-dimethoxy-9-phenyl-7.8.9.10-tetrahydro-imidazoM .2-h1l1.7lnaphthyridine 8 g of the titration compound of melting point of 155 to 156 ° is obtained C, by reaction of 10 g of (7R, 8R, 9R) -2,3-dimethyl-7,8-dihydroxyl-9-phenyl-7,8,9, 10-tetahydro-imidazo [1, 2-h ] [1, 7] naphthridine with 1.9 g of sodium hydride (80%) and 9.1 g of methyl iodide according to Example 1, Method b.

Start Compounds A1. 2, 3-Di meti lo-7-r (2R.3S) -2.3-O-isopropylidene-3-phenylpropane-1-on-1-phenyl-8-p-valoylamino-imidazop .2-alp indine They were dissolved 60 g (0.245 mol) of 2,3-dimethyl-d-pivaloylaminoimidazo [1,2-a] pyridine in 1.51% diethyl ether anhydride excluding the mixture and under an argon atmosphere and cooled to a -75 ° C. By means of a pressure needle, 408 ml (0.612 mol) of tert-butillitium solution (1.5 M in n-pentane) were added dropwise, so that the temperature did not exceed -65 ° C (30 ° C). min). A red suspension was formed. Once the addition was complete, the suspension was stirred at a temperature of -75 ° C for an additional 30 minutes.

Subsequently, 1/3 of a solution of 145 g of methyl (2R, 3S) -2,3-O-isopropylidene-3-phenylpropionate (ee: 99.05%, Daicel Chiralcel HPLC) was added slowly in the form of drops. ml of dry THF, at a temperature below -65 ° C during the course of 30 minutes. Subsequently, the residual amount is added briskly (5 min), with a rise in temperature to -60 ° C. Once the addition is complete, the cooling bath is removed. Upon reaching an internal temperature of -30 ° C, 20 ml of methanol are added, and 200 ml of distilled water is added at an internal temperature of 0 ° C. The aqueous phase is separated in a separating funnel, the organic phase is washed five times with 100 ml of distilled water each time, then the organic phase is extracted three times with 10% of sulfuric acid of resistance (200 ml, 50 ml, 50 ml). The sulfuric acid phases, treated with 200 ml of dichloromethane, are combined and adjusted to a pH of 2.3 with 1 0 N of a sodium hydroxide solution and cooled with ice and vigorous stirring. The organic layer is separated. The aqueous phase is extracted with 30 ml of dichloromethane. The combined dichloromethane phases are washed twice with a little distilled water. Subsequently, it is dried over anhydrous sodium sulfate and the solvent is completely removed in vacuo. A brown oil is obtained which is treated with 50 ml of diethyl ether. After germination, crystals are formed which are filtered after remaining overnight and washed with diethyl ether. After drying under vacuum, 57.7 g (52.5%, ee> 99%, Daicel Chiralcel HPLC) of the titration compound of melting point 76 to 80 ° C, in the form of a pale yellow powder, are obtained.

A2. 2.3-Dimetil-7-r? 2R.3S) -2.3-O-isopropylidene-3-phenylpropane-1-on-1-iH-8-pivaloylamino-imidazole "1,2-alpyridine The titration compound is obtained (ee: 98.3%, Daicel Chiralcel HPLC) , similar to the procedure described in Example A1, using methyl (2S, 3R) -2,3-O-isopropylidene-3-phenylpropionate (ee: 98%, Daicel Chiralcel HPLC) in the form of an agent of testing B1 (8R. 9R) -2.3-Dimethyl-8-hydroxyl-9-phenyl-7.8.9.1 0-tetrahydroimidazole, 2-hlH, 71naphthyridin-7-one 0.8 g (24 mmol) of 2.3 are introduced. -dimetílo-7 - [(2R, 3S) -2,3-O-isopropilideno-3-phenylpropane-1-on-1 -yl] -8-pivaloylaminoimidazo [1, 2-a] pi ridine (ee > 95 %, Daicel Chiralcel HPLC) in 50 ml of 70% strength sulfuric acid with ice cooling over the course of 4 minutes. A suspension is formed during this course, which becomes an orange solution after 30 minutes. Once the addition is complete, the ice bath is removed and the mixture is stirred at room temperature. After 50 h the reaction solution is added to the ice water and dichloromethane is added, then the mixture is adjusted to a pH of 8 using 6N of sodium hydroxide solution and a saturated sodium hydrogen carbonate solution. The organic phase is separated. The aqueous phase is extracted twice with dichloromethane. The organic phases are combined and washed with a little distilled water. Subsequently, the organic layer is dried over anhydrous sodium sulfate, filtered and concentrated in a rotary vacuum operator. The concentrated residue is chromatographed on silica gel (eluent: dichloromethane / methanol 100/1).

The main fraction is concentrated and treated with ethyl acetate, and the titration compound crystallizes in the course of this in the form of a yellow solid. This precipitate is filtered with dried suction to obtain a constant weight in a vacuum drying oven at a temperature of 50 ° C. 4.22 g (57%, ee> 95%, Daicel Chiralcel HPLC) of the titration compound of melting point 231 to 234 ° C are obtained.

B2. (8S. 9S) -2.3-Dimethyl-8-hydroxyl-9-phenyl-7.8.9.1 0-tetrahydroimidazop, 2-h H .71naphthyridine-7-one The titration compound is obtained (ee: 94.0%, Daicel Chiralcel HPLC) according to the procedure described in example B 1, starting from 2,3-dimethyl-7 - [(2S, 3R) -2,3-O-isopropylidene-3-phenylpropane-1-on-1-yl ] -8-pivaloylaminoimidazo [1, 2-a] pyridine.

C1. (7R 8R 9R) -2.3-Dimethyl-7,8-dihydroxyl-9-phenyl-7.8.9.1 0-tetrahydro-imidazoM, 2hlf1, 71naphthyridine 6 g (1 9.52 mmol) of (8R, 9R) -2 are suspended, 3-dimethyl-8-hydroxyl-9-phenyl-7,8,9,11-tetrahydroimidazo- [1, 2-h] [1,7] naphthyridine-7-one (ee> 90%, Daicel Chiralcel HPLC) in 60 ml of methanol and cooled to a temperature of from -5o to 0 ° C in a methanol-ice bath. At this temperature, sodium borohydride (0.81 g, 21 .47 mmol) is added by means of a spatula, during the course of 0.5 hours (evolution of gas). Once the addition is complete, the mixture is stirred for an additional 10 minutes, and then concentrated in a rotary evaporator under vacuum at a bath temperature of 40 ° C. The oily residue obtained is taken in water distilled and extracted three times with chloroform. The organic phases are combined and washed with a little water, then dried using anhydrous sodium sulfate and filtered. The filtrate is concentrated in a rotary evaporator under vacuum and is evaporated together with acetone; the titration compound crystallizes in the course of this. The precipitate is filtered, washed with acetone and dried to a constant weight at a temperature of 50 ° C in a vacuum drying oven. 5.15 g (85.3%, ee> 90%, Daicel Chiralcel HPLC) of the titration compound are obtained in the form of a colorless crystalline of melting point of 206 to 209 ° C.

C2. (7S, 8S, 9S) -2.3-Dimethyl-7.8-dihydroxyl-9-phenyl-7.8.9.10-tetrahydroimidazofl, 2hl, 1 .7] naphthyridine The title compound is obtained from melting point of 207 to 208 ° C (ee: 98.7%, Daicel Chiralcel, HPLC), according to the procedure described in example C1 using (8S, 9S) -2,3-dimethyl-8-hydroxyl-9-phenyl-7.8, 9, 10-tetrahydroimidazo [1, 2-h] [1,7] naphthyridine-7-one as the starting material.

D. (7S. 8R.9R) -2.3-Dimethyl-7.8-dihydroxyl-9-phenyl-7.8.9.10-tetrahydro-imidazoM .2-h1i1 .71naphthyridine Silica gel was chromatographed with 2 g of mother liquor of Example C1 (eluent: ethyl acetate / methanol 19/1) to yield 0.35 g of the titration compound in the form of an oil which crystallizes upon the addition of ethyl acetate. Melting point: from 199 to 200 ° C (ethyl acetate).

Commercial Utility The compounds of the formula I and their salts have useful pharmacological properties which make them commercially utilizable. In particular, said compounds exhibit a marked inhibition of gastric acid secretion and an excellent gastric and intestinal protective action in animals, in particular humans. In this context, the compounds according to the present invention are distinguished by a high selectivity of action, an advantageous duration of action, a particularly good enteral activity, the absence of significant side effects and a great therapeutic breathing. The "gastric and intestinal protection" in relation to this, is understood as the prevention and treatment of gastrointestinal diseases, in particular of gastrointestinal inflammatory diseases and lesions (such as, for example, stomach ulcers, duodenal ulcer, gastritis, hyperacid or functional gastropathy). related to medicaments), which can be caused, for example, by microorganisms (for example, Helicobacter pylori), bacterial toxins, drugs (for example, certain anti-inflammatories and antirheumatics), chemicals (for example ethanol), gastric acid or tension. Within its excellent properties, the compounds according to the present invention surprisingly prove to be clearly superior to the compounds known from the prior art in various models, in which the anti-ulcer and anti-segregation properties are determined. Taking into account these properties, the compounds of the formula I and their pharmacologically tolerable salts are suitable for use in human and veterinary medicine, where they are used, in particular, for the treatment and / or prophylaxis of diseases of the stomach and / or intestine. Therefore, the present invention further relates to the compounds according to the same, for use in the treatment and / or prophylaxis of the aforementioned diseases. Likewise, the present invention comprises the use of the compounds according to the same for the production of medicaments that are used for the treatment and / or prophylaxis of the aforementioned diseases. Additionally, the present invention comprises the use of the compounds according to the same, for the treatment and / or prophylaxis of the aforementioned diseases. Additionally, the present invention relates to medicaments containing one or more compounds of the formula I and / or their pharmacologically tolerable salts. The drugs are prepared by known processes, which are known to those skilled in the art. As medicaments, the pharmacologically active compounds according to the present invention (active compounds) are used either as such or preferably in combination with pharmaceutically suitable auxiliaries or excipients in the form of tablets, coated tablets, capsules, suppositories, patches (e.g. , as TTS), emulsions, suspensions or solutions, where the content of the active compound is conveniently between 0.1 and 95%, and where, through the With suitable choice of auxiliaries and excipients, a pharmaceutical administration form (e.g., a delayed release form or an enteric form) suitable in an exact manner to the active compound and / or to the triggering of the desired action can be achieved. The person skilled in the art is familiar on the basis of his experience, with auxiliaries or excipients which are suitable for the desired pharmaceutical formulations. In addition to solvents, gel-forming agents, suppository bases, tablet auxiliaries and other transporters of the active compound, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corregidores, preservatives, solubilizers, dyes or in particular , impregnation promoters and agents to elaborate complexes (for example cyclodextrins).

The active compounds can be administered orally, parenterally or percutaneously. In general, advantages in human medicine have been approved for administering the active compound (s) in the case of oral administration, in a daily dosage from about 0.01 to about 20, preferably from 0.05 to 5, in particular from 0.1 to 1. .5 mg / kg body weight, if appropriate in the form of several, preferably 1 to 4, individual doses to achieve the desired result. In the case of similar parenteral treatment or (in particular in the case of intravenous administration of the active compounds), lower doses may be used as a rule. The optimal dose and the manner of administration of the active compounds required in each case can be easily determined by any person skilled in the art based on his or her experience.

If the compounds according to the present invention and / or their salts are to be employed for the treatment of the aforementioned diseases, the pharmaceutical preparations may also contain one or more pharmacologically active constituents of other pharmaceutical groups. Examples that may be mentioned are: tranquilizers (for example from the group of benzodiazapines, for example diazepam), ipsic spasmol (for example, bietamiverin or camilofin), anticholinergics (for example, oxyphencyclimine or fencarbamide), local anesthetics (for example tetracaine or procaine), and if appropriate, also enzymes, vitamins or amino acids. In particular, it should be emphasized in relation to this, the combination of the compounds according to the present invention, with pharmaceuticals that inhibit the secretion of acid, such as, for example, H2 blockers (for example, cimetidine, ranitidine), H + / K + -ATPase inhibitors (for example, omeprazole, pantoprazole), or in addition with the so-called peripheral anticholinergics (by example, pirenzepine, telenzepine), and with gastrin antagonists in order to increase the main action of a sense of addition or superaddition and / or of elimination or reduction of side effects, or additionally the combination with antibacterially active substances (for example, cephalosporins, tetracyclines, pinicilins, macrolides, nitroimidazoles or alternatively bismuth salts) for the control of Helicobacter pylori. The antibacterially active combination components that may be mentioned are, for example, mezlocillin, ampicillin, amoxicillin, cafalotin, cefoxitin, cefotaxime, imipenem, gentamicin, amikacin, erythromycin, ciprofloxacin, metronidazole, clarithromycin, azithromycin, and combinations thereof (eg, clarithromycin + metronidazole).

Pharmacology The excellent gastric protective action and the action of gastric acid secretion inhibitor of the compounds according to the present invention, can be demonstrated in experimental animal models. The compounds according to the present invention, investigated in the model will be mentioned below, have been supplied with numbers corresponding to the numbers of these compounds in the examples.

Preparation of the test for the inhibition of secretion in the perfused rat stomach. Table A below shows the effects of the compounds according to the present invention on the secretion of pentagastrin-stimulated acid from the rat stomach perfused in vivo after intravenous administration.

Table A Methodology The abdomen of anesthetized rats (CD rats, female, 200-250 g, 1.5 g / kg i .m urethane) was opened after the tracheotomy by means of an abdominal incision in the upper middle part, and fixed a transoral PVC catheter in the esophagus and another through the pylorus, so that the ends of the tube were only projected just inside the gastric lumen. The catheter led from the pylorus outward into the right abdominal wall through the lateral opening. After a complete rinse (50-100 ml), a solution of physiological hardened NaCl was passed continuously at a temperature of 37 ° C through the stomach (0.5 ml / min, pH 6.8-6.9, Braun-Unita I). In the effluent, collected in each case at an interval of 15 minutes, the pH was determined (pH meter 632, glass electrode EA 147, f = 5 mm, Metrohm) and, by titration with a freshly prepared 0.01 N NaOH solution until obtaining a pH of 7 (Dosimat 665 Metrohm), the HC l segregated. The gastric secretion was simulated by continuous infusion of 1 μg / kg (= 1.65 ml / h) of pentagastrin i .v. (left femoral vein) for approximately 30 minutes after the operation is finished (for example, after the determination after the 2 preliminary fractions.) The substances that were tested were administered intravenously in 1 volume of 1 ml fluid. / kg for 60 minutes after starting the continuous infusion of pentagastrin The body temperature of the animals was maintained at a constant temperature of 37.8-38 ° C, by irradiation of infrared rays and heat pads (automatic continuous control by means of a rectal temperature sensor).

Claims (9)

1. CLAIMS A compound of the formula I wherein R1 is methyl or hydroxymethyl, one of the substituents R2a and R2b is hydrogen and the other is hydroxyl, methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, one of the substituents R3a and R3b is hydrogen and the other is hydroxyl, methoxy , ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, wherein R2a or R2b on the one hand and R3a or R3b on the other hand are not simultaneously hydroxyl, and their salts.
2. A compound according to claim 1, characterized formula I * wherein R1 is methyl or hydroxymethyl, one of the substituents R2a and R2b is hydrogen and the other is hydroxyl, methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, one of the substituents R3a and R3b is hydrogen and the other is hydroxyl, methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy; wherein R2a and R2b on the one hand and R3a and R3b on the other, are not simultaneously hydroxyl and their salts.
3. 3. A compound of the formula 1 * according to the claim 2, in which R1 is methyl, one of the substituents R2a and R2b is hydrogen and the other is methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy; one of the substituents R3a and R3b is hydrogen and the other is hydroxyl and its salts.
4. 4. A compound of the formula 1 * according to the claim 2, in which R1 is methyl, One of the substituents R2a and R2b is hydrogen and the other is methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, One of the substituents R3A and R3b is hydrogen and the other is methoxy, ethoxy, isopropoxy , methoxyethoxy or methoxypropoxyl, and their salts.
5. 5. A compound of the formula 1 * according to claims 2, 3 or 4, wherein R3b is hydrogen.
6. 6. A compound of the formula 1 * according to claims 2, 3 or 4, wherein R2a and R3b are hydrogen.
7. 7. A compound according to claim 1, characterized by the formula 1 ** wherein one of the substituents Ra and Rb is hydrogen and the other is methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy and their salts.
8. 8. A compound of the formula 1 ** according to the claim 7, in which Ra is hydrogen and Rb is methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, and their salts.
9. 9. A compound according to claim 1, which is (7R, 8R, 9R) -2,3-Dimethyl-8-hydroxy-7- (2-methoxyethoxy) -9-phenyl-7,8,9, 1 -tetrahydro-imi-dazo [1, 2} h] [1, 7] naphthyridine and its salts. 1 0. A medicament comprising a compound as described in claim 1 and / or a pharmacologically tolerable salt thereof together with the usual auxiliaries and / or excipients. eleven . The use of a compound as described in claim 1 and its pharmacologically tolerable salts for the production of medicaments for the prevention and treatment of gastrointestinal diseases.