HRP980147A2 - Tetrahydropyrido compounds - Google Patents

Description

Field of application of the invention

This invention relates to new compounds that are used in the pharmaceutical industry as active compounds for the production of drugs.

Known technical background

US Patent 4,468,400 describes tricyclic imidazo[1,2-a]pyridines with various ring systems attached to an imidazopyridine backbone, which should be suitable for the treatment of peptic ulcer conditions.

Description of the invention

The invention relates to compounds of formula I

[image]

where

R1 represents 1-4C-alkyl,

R2 denotes 1-4C-alkyl or hydroxy-1-4C-alkyl,

R3 means hydrogen or halogen,

one of the substituents R4a and R4b is hydrogen and the other is hydrogen, hydroxy, 1-4C-Alkoxy, 1-4C-Alkoxy-1-4C-Alkoxy or 1-4C-Alkylcarbonyloxy, or R4a and R4b together form O (oxygen) ,

one of the substituents R5a and R5b is hydrogen and the other is hydrogen, hydroxy, 1-4C-Alkoxy, 1-4C-Alkoxy-1-4C-Alkoxy or 1-4C-Alkylcarbonyloxy, or R5a and R5b together form O (oxygen) ,

or in which one of the substituents R4a and R4b on the one hand, and R5a and R5b on the other hand, in each case represents hydrogen, and the other substituents in each case together form a methylenedioxide radical (-O-CH2-O-) or an ethylenedioxide radical ( -O-CH2-CH2-O-), where R4a, R4b, R5a and R5b are not simultaneously hydrogen,

R 6 represents hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-

Alkoxycarbonyl-amino or trifluoromethyl, a

R7 denotes hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy,

and their salts.

1-4C-alkyl represents a straight-chain or branched alkyl radical with 1 to 4 carbon atoms. Examples that may be mentioned are butyl radical, isobutyl radical, sec-butyl radical, tert-butyl radical, propyl radical, isopropyl radical, ethyl radical and methyl radical. The advantage is the methyl radical.

Hydroxy-1-4C-alkyl represents the above-mentioned 1-4C-alkyl radicals which are substituted by a hydroxyl group. Examples that may be mentioned are the hydroxymethyl radical, the 2-hydroxyethyl radical and the 3-hydroxypropyl radical. The hydroxymethyl radical is preferred.

Halogen in the sense of the invention represents bromine, chlorine or iodine.

1-4C-Alkoxy represents radicals that, in addition to the oxygen atom, contain a straight-chain or branched alkyl radical with 1 to 4 carbon atoms. Examples that can be mentioned are butoxy radical, isobutoxy radical, sec-butoxy radical, tert-butoxy radical, propoxy radical, isopropoxy radical, and ethoxy radical and methoxy radical are preferred.

1-4C-Alkoxy-1-4C-Alkoxy represents one of the aforementioned 1-4C-Alkoxy radicals substituted by a further 1-4C-Alkoxy radical. Examples that may be mentioned are 2-(methoxy)ethoxy (CH3-O-CH2-CH2-O) and 2-(ethoxy)ethoxy (CH3-CH2-O-CH2-CH2-O-).

1-4C-alkylcarbonyloxy represents a carbonyloxy group to which one of the aforementioned 1-4C-alkyl radicals is attached. An example that can be mentioned is the acetoxy radical (CH3CO-O-).

1-4C-Alkoxycarbonyl represents a carbonyl group to which one of the aforementioned 1-4C-Alkoxy radicals is attached. Examples that can be mentioned are the methoxycarbonyl radical (CH3O-C(O)-) and the ethoxycarbonyl radical (CH3CH2O-C(O)-).

1-4C-Alkoxycarbonylamino represents an amino radical that is substituted by some of the above-mentioned 1-4C-Alkoxycarbonyl radicals. Examples that can be mentioned are the ethoxycarbonylamino radical and the methoxycarbonylamino radical.

1-4C-Alkoxy-1-4C-Alkoxycarbonyl radical represents a carbonyl group to which one of the aforementioned 1-4C-Alkoxy-1-4C-Alkoxy radicals is attached. Examples that can be mentioned are the 2-(methoxy)ethoxycarbonyl radical (CH3-O-CH2CH2-O-CO-) and the 2-(ethoxy)ethoxycarbonyl radical (CH3CH2-O-CH2CH2-O-CO-).

1-4C-Alkoxy-1-4C-Alkoxycarbonylamino represents an amino radical substituted by some of the aforementioned 1-4C-Alkoxy-1-4C-Alkoxycarbonyl radicals. Examples that may be mentioned are the 2-(methoxy)ethoxycarbonylamino radical and the 2-(ethoxy)ethoxycarbonylamino radical.

Suitable salts of the compounds of formula I - depending on the substitution - are preferably all acid addition salts. Special mention should be made of pharmacologically acceptable salts of inorganic and organic acids, usually used in pharmacy. Suitable acid addition salts are water-soluble and water-insoluble, with acids such as, for example, hydrochloric acid, 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, succinic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3- hydroxy-2-naphthoic acid, whereby the acids are used in the preparation of salts - depending on whether they are mono- or polybasic and depending on the desired salt - in an equimolar quantitative ratio or in a ratio that differs from it.

Pharmacologically unacceptable salts that can initially be obtained as process products, for example in the preparation of compounds according to the invention on an industrial level, are converted into pharmacologically acceptable salts by a process known to experts in the field.

Compounds of formula I have three chiral centers. The invention relates to all eight possible enantiomers in any desired intermixing ratio, including the pure enantiomers which are primarily the subject of the invention.

If one of the substituents R4a and R4b on the one hand, and one of the substituents R5a and R5b on the other hand, together form a methylenedioxide radical or an ethylenedioxide radical, the two substituents that form a methylenedioxide radical or an ethylenedioxide radical are preferably in the cis position with each other.

The compounds to be emphasized are those of formula I in which

where

R1 represents 1-4C-alkyl,

R2 denotes 1-4C-alkyl or hydroxy-1-4C-alkyl,

R3 means hydrogen,

one of the substituents R4a and R4b is hydrogen, and the other is hydrogen, hydroxy or 1-4C-alkoxy, or R4a and R4b together form O (oxygen),

one of the substituents R5a and R5b is hydrogen, and the other is hydrogen, hydroxy, 1-4C-alkoxy, or R5a and R5b together form O (oxygen),

where R4a, R4b, R5a and R5b are not simultaneously hydrogen,

R 6 represents hydrogen, halogen, or trifluoromethyl, a

R7 denotes hydrogen or halogen,

and their salts.

The subject of the invention that should be emphasized are the compounds of formula I*

[image]

where

R1 represents 1-4C-alkyl,

R2 denotes 1-4C-alkyl or hydroxy-1-4C-alkyl,

R3 means hydrogen,

one of the substituents R4a and R4b is hydrogen, and the other is hydrogen, hydroxy or 1-4C-alkoxy,

one of the substituents R5a and R5b is hydrogen, and the other is hydrogen, hydroxy or 1-4C-alkoxy,

where R4a, R4b, R5a and R5b are not simultaneously hydrogen,

R6 represents hydrogen, halogen or trifluoromethyl, a

R7 denotes hydrogen or halogen,

and their salts.

The subject of the invention, which should be particularly emphasized, are the compounds of formula I*,

where

R1 represents 1-4C-alkyl,

R2 denotes 1-4C-alkyl or hydroxymethyl,

R3 means hydrogen,

R4a means hydrogen,

R4b denotes hydroxy or 1-4C-alkoxy,

R5a is hydrogen, hydroxy or 1-4C-alkoxy,

R5b means hydrogen,

R6 represents hydrogen, halogen or trifluoromethyl, a

R7 denotes hydrogen or halogen,

and their salts.

Compounds of the formula I* are preferred as the subject of the invention,

where

R1 represents 1-4C-alkyl,

R2 denotes 1-4C-alkyl,

R3 means hydrogen,

R4a means hydrogen,

R4b denotes hydroxy,

R5a denotes hydroxy,

R5b means hydrogen,

R6 represents hydrogen, halogen or trifluoromethyl, a

R7 denotes hydrogen or halogen,

and their salts.

Using the general formula I*, the following compounds can be mentioned as examples according to the invention, with the meaning of the substituents and the positions for the substituents R3, R6 and R7 indicated in the following Table 1 (Tab. 1):

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and salts of compounds listed in Table 1.

The compounds according to the invention can therefore be prepared as described in the following examples, or by applying analogous process steps, starting from the corresponding starting compounds.

The starting compounds are known or can be prepared analogously with known compounds.

Depending on the substitution pattern in positions 7 and 8 (R4a/R4b or R5a/R5b), the compounds according to the invention can be prepared starting from N-protected 8-aminoimidazo[1,2-a]pyridines which are known or can be prepared by a known method (see for example EP-A-0 299 470 or Kaminski et al., J. Med. Chem., 28 (1985) 876-892) according to the following reaction schemes:

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N-protected (Piv in this case, and in the following schemes represents common protecting groups, primarily pivaloyl group) 8-aminoimidazo[1,2-a]pyridine deprotonated in position 7 reacts with cinnamaldehyde. The addition product is first oxidized (e.g. with manganese dioxide) and then epoxidized (e.g. with hydrogen peroxide). Under very basic and then very acidic conditions, the protective group is removed and the ring is closed. Reduction of the keto group, which follows if desired, can be carried out, for example, using sodium borohydride.

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Instead of epoxidizing according to Scheme 1, the ring is closed under strongly acidic conditions and the protecting group is removed. Reduction to alcohol, which follows if desired, is carried out using sodium borohydride.

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The above scheme represents an example of enantioselective synthesis, where the same N-protected imidazo[1,2-a]pyridines as in Scheme 1 are used as starting materials. Reaction of these imidazo[1,2-a]pyridines in deprotonated form with enantiomerically pure dioxolane initially leads to a condensation product that can cyclize under strongly acidic conditions with deprotection. Reduction of the keto group with the use of sodium borohydride (see also Scheme 1) that follows, leads to the final product marked with an enantiomeric purity greater than 90%.

[image]

Starting from the above-mentioned 8-aminoimidazo[1,2-a]pyridine, compounds substituted at the 8-amino group were obtained either by alkylation using a suitable alkylating reagent bearing substituents (e.g. R8a = hydrogen, R8b = halogen), or by reductive by alkylation with appropriately substituted ketones [R8a and R8b together form O (oxygen)] with the help of a reducing agent such as sodium cyanoborohydride, and rings are closed in them with base or acid catalysis, resulting in cyclic ketones, which in turn can be converted into the desired target compounds by suitable chemical transformations (see for example Schemes 1 and 2). If necessary, the CO2R group can be initially reduced (aldehyde step) before cyclization, then 7-hydroxy substituted derivatives are formed, which in turn can be converted to suitable target compounds by oxidation/reduction.

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In a variant of the procedure described above in Scheme 4, where R5a and R8a = H (hydrogen) and R5b and R8b together = O (oxygen), 8-aminoimidazo[1,2-a]pyridine is initially reacted with ester derivatives of epoxycinnamic acid with regioselective epoxy opening (A). The products cyclize under basic aprotic conditions (C). Alternatively, the mixture may hydrolyze and the free carboxylic acid derivatives cyclize under acidic conditions (D). In both cases, the keto group can then be reduced to the alcohol (G), as indicated in Scheme 1, for example using sodium borohydride. If 8-aminoimidazo[1,2-a]pyridine reacts with protected epoxycinam-aldehyde derivatives (B), the ring can be closed in the products under acidic conditions after removal of the acetal protecting group (F). Reduction of the ester function and acid cyclization is also possible (E). Both the reduction of the keto function and the ring closure in the aldehyde stage can be carried out enantioselectively, and with the use of a suitable enantiomerically pure epoxy derivative, an enantioselective synthesis is possible.

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In a further version of Scheme 4, the enantioselective synthesis is outlined above. The dihydroxycinnamic acid derivative is activated in the benzylic position either directly or after the introduction of a protective group on the second hydroxyl group. The thus obtained products react with 8-amino-imidazo[1,2-a]pyridine. The ring is then closed, e.g. under basic conditions. The step that then follows as desired (reduction) is carried out analogously to Scheme 3.

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8-haloimidazo[1,2-a]pyridines (X = halogen) react with appropriately substituted β-phenyl-β-amino acids with a heavy metal as a catalyst (preferably Pd), resulting in substituted amines, which in turn cyclize according to Scheme 4. Instead of the COOR group, an aldehyde group (as already mentioned in Scheme 4) can be used, if desired in the form of an acetal. Y stands for H (hydrogen) or a protecting group that can be removed after ring closure.

[image]

Starting from imidazoles that are known or can be prepared in an analogous way, ring closure is favored by the presence of an enamine structure (equilibrium!). After introducing the double bond by oxidation, reduction of the keto group to an alcohol can be carried out as outlined in Scheme 1.

In the above schemes, “R” is 1-4C-alkyl. In the ester group mentioned in the example (-COOR or -CO2R) there may be another releasing group instead of the radical -OR or it may also be a group that can be used according to its functionality instead of the ester group.

Compounds of formula I in which R4a/R4b or R5a/R5b are 1-4C-Alkoxy, 1-4C-Alkoxy-1-4C-Alkoxy or 1-4C-Alkylcarbonyloxy can be prepared by conventional derivatization methods known to those skilled in the art. (eg alkylation or acylation), from the corresponding compounds in which R4a/R4b or R5a/R5b means a hydroxyl group.

Substances according to the invention are isolated and purified in a manner known per se, for example by distilling the solvent in vacuo and recrystallization of the residue obtained from a suitable solvent, or by subjecting the residue to one of the usual cleaning methods, such as column chromatography on a suitable support material.

Salts are obtained by dissolving the free compound in a suitable solvent, e.g. in a chlorinated hydrocarbon such as methyl chloride or chloroform, or in an aliphatic alcohol of low molecular weight (ethanol, isopropanol) containing the desired acid, or to which the desired acid is subsequently added. Salts are obtained by filtration, reprecipitation, precipitation with the addition of a substance that is not a solvent for the addition salt, or evaporation of the solvent. The resulting salts can be converted into free compounds by alkylation or acidification, and the free compounds can be converted into salts. In such a way, pharmacologically unacceptable salts can be converted into pharmacologically acceptable salts.

Pure enantiomers, especially pure enantiomers of the formula I*, to which the invention primarily relates, can be obtained in a manner known to a specialist in the field, for example by enantioselective synthesis (see for example Scheme 3), chromatographic separation on chiral separation columns, derivatization with chiral auxiliary reagents , then by separation of diastereomers and removal of the chiral auxiliary group, salt formation on chiral acids, then separation of the salt and liberation of the desired compound from the salt, or by (fractional) crystallization from a suitable solvent.

The invention further relates to the processes and process intermediates described in the above schemes, especially those process intermediates from Schemes 1, 2, 3, 4, 5, 6 and 7, which can be isolated before the cyclization step.

The following examples serve to further illustrate the invention, without limiting it. Similarly, further compounds of formula I, the preparation of which is not explicitly described, can be prepared analogously or in a manner known to a person skilled in the art, using conventional process techniques.

Examples

FINAL PRODUCTS

1. 2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo-[1,2-h][1,7]naphthyridin-7-one

A solution of 2,3-dimethyl-7-(3-phenyl-1-oxo-2-propenyl)-8-pivaloyl-aminoimidazo[1,2-a]pyridine in 30 ml of dioxane was treated with 20 ml of conc. hydrochloric acid, refluxed for 8 hours, adjusted to pH 7.0 using 2 M sodium hydroxide solution with cooling and extracted three times with 50 ml of ethyl acetate. The combined extracts were washed with water, dried over potassium carbonate and concentrated in vacuo. The remaining viscous oil was chromatographed on silica gel using ethyl acetate/petroleum ether (1:1) as eluent. 2.6 g of the title compound, melting point 138-40 °C, were obtained.

2. 9-(2-chlorophenyl)-2,3-dimethyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-7-one

The title compound, mp 80-2 °C, was obtained from 7-[3-(2-chlorophenyl)-1-oxo-2-propenyl]-8-pivaloylamino-2,3-dimethylimidazo[1,2-a]-pyridine in 73% utilization analogous to example 1.

3. 9-(2,6-dichlorophenyl)-2,3-dimethyl-7,8,9,10-tetrahydroimidazo-[1,2-h][1,7]naphthyridin-7-one

The title compound, mp 248-9 °C, was obtained from 7-[3-(2,6-dichloro-phenyl)-1-oxo-2-propenyl]-8-pivaloylamino-2,3-dimethylimidazo-[1,2- a] pyridine in a 41% recovery analogously to example 1.

4. 9-(2-trifluoromethylphenyl)-2,3-dimethyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridin-7-one

The title compound, mp 184-5 °C, was obtained from 7-[3-(2-trifluoro-methylphenyl)-1-oxo-2-propenyl]-8-pivaloylamino-2,3-dimethyl-imidazo[1,2-a ]pyridine in a 41% recovery analogously to example 1.

5. 7-hydroxy-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo-[1,2-h][1,7]naphthyridine

A suspension of 1 g of 2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo-[1,2-h][1,7]naphthyridin-7-one in 15 ml of methanol was treated at room temperature with 450 mg of sodium borohydride in small portions. The resulting yellowish solution was stirred for 2 hours and then diluted with ice water. The resulting precipitate was filtered off by suction and washed with a little cold 2-propanol. 800 mg of a compound with a melting point of 210-12 °C were obtained.

6. 9-(2-chlorophenyl)-7-hydroxy-2,3-dimethyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine

The title compound, mp 150-2 °C, was obtained from 9-(2-chlorophenyl)-2,3-dimethyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine-7- it is in 73% utilization analogously to example 5.

7. 9-(2,6-dichlorophenyl)-7-hydroxy-2,3-dimethyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine

The title compound, mp 155-7 °C, was obtained from 9-(2,6-dichlorophenyl)-2,3-dimethyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine- 7-one in 72% utilization analogously to example 5.

8. 9-(2-trifluoromethylphenyl)-7-hydroxy-2,3-dimethyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine

The title compound, mp 145-7 °C, was obtained from 9-(2-trifluoromethyl-phenyl)-2,3-dimethyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]-naphth -ridin-7-one in 72% recovery analogously to example 5.

9. 8-hydroxy-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo-[1,2-h][1,7]naphthyridine

A solution of 2,3-dimethyl-7-(2,3-epoxy-1-oxo-3-phenylpropyl)-8-pivaloylaminoimidazo[1,2-a]pyridine in 5 ml of dry ethanol was treated with vigorous stirring with 95 mg of lithium hydroxide, and after mixing at room temperature, it was cooled to 0 °C in an ice bath for 2 hours. The precipitated crystals were filtered off with suction and washed with a little cold ethanol. After drying in a high vacuum, the solid was introduced into 5 ml of 90% strength sulfuric acid at room temperature and stirred for 1 hour. It was then neutralized with a cooled sodium hydroxide solution of 40% strength while cooling with ice. The resulting precipitate was filtered off and dried in a vacuum. 145 mg of the title compound was obtained, melting point 232-4 °C.

10. 7,8-dihydroxy-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydro-imidazo-[1,2-h][1,7]naphthyridine

700 mg of 8-hydroxy-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridin-7-one was suspended in 15 ml of methanol and treated with 200 mg of sodium borohydride in portions, at room temperature with stirring. After stirring for 2 hours, the mixture was poured into 100 ml of ice water. The resulting precipitate was filtered off, briefly dried in vacuo and recrystallized from a little 2-propanol. 500 mg of the title compound with a melting point of 150-2 °C were obtained.

11. (8R,9R)-2,3-dimethyl-8-hydroxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridin-7-one

10.8 g (24 mmol) 2,3-dimethyl-7-[(2S,3R)-2,3-O-isopropylidene-3-phenylpropan-1-on-1-yl]-8-pivaloylaminoimidazo[1,2- a]pyridine (ee: >95% HPLC) was introduced into 50 ml of a 70% strength sulfuric acid solution cooled with ice for 4 minutes. This resulted in a suspension that turned into an orange solution after 30 minutes. After the addition was complete, the ice bath was removed and the mixture was stirred at room temperature. After 50 hours, analysis was performed using TLC. For processing, the reaction solution was added to ice water, dichloromethane was added, then the mixture was adjusted to pH 8 using a 6 M sodium hydroxide solution and a saturated sodium bicarbonate solution. The organic phase is separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with a little distilled water. The organic layer was then dried over anhydrous sodium sulfate, filtered and concentrated in a rotavapor. The concentrated residue was chromatographed by vacuum chromatography on silica gel using the eluent dichloromethane/methanol 100/1. The major fraction was concentrated and treated with ethyl acetate, during which the title compound crystallized as a yellow solid. The precipitate was filtered off with suction and dried to a constant mass in a vacuum drying oven at 50 °C. Amount: 4.22 g (57.2 %), ee: >95 % (HPLC), mp: 231-4 °C.

12. (7R,8R,9R)-2,3-dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine

6 g (19.52 mmol) (8R,9R)-2,3-dimethyl-8-hydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine-7 -one (ee: >95 %, HPLC) was suspended in 60 ml of methanol and cooled to -5 °C in a methanol ice bath. At this temperature, sodium borohydride (0.81 g, 21.47 mmol) was added with a spatula over 0.5 hours (gas evolution). After the addition was complete, the mixture was stirred for a further 10 minutes, and then concentrated in a rotavapor at a bath temperature of 40 °C. The obtained oily residue was taken up in distilled water and extracted three times with chloroform. The organic phases were combined and washed with a little water, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated on a rotavapor and coevaporated with acetone; the title compound crystallized during this procedure. The precipitate was filtered off with suction and washed with acetone and diethyl ether, and dried to a constant mass at 50 °C in a vacuum drying oven. The title compound was obtained as a colorless crystal with a melting point of 206-9 °C. Quantity: 5.15 g (85.3 %); the compound has a diastereomeric purity of 97.4 % and an enantiomeric excess of ee: 93.8 % (HPLC).

13. (7S,8R,9R)-2,3-dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine

2 g of motherwort from example 12 was chromatographed on silica gel (eluent: ethyl acetate/methanol 19/1), resulting in 0.35 g of the title compound in an oily form, which crystallized with the addition of ethyl acetate. Melting point: 199-200 °C (ethyl acetate).

14. (8R,9R)-3-formyl-8-hydroxy-2-methyl-7-oxo-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine

(8R,9R)-8-hydroxy-2,3-dimethyl-7-oxo-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine (1 g) was dissolved in 20 ml of dried chloroform, and 5 g of potassium permanganate was added. After stirring the reaction mixture at room temperature for 40 days, the solids were filtered off. The filtrate was chromatographed twice on silica gel (eluent: dichloromethane/methanol 13/1), resulting in 0.07 g of the title compound in the form of a semi-solid.

15. (7R,8R,9R)-3-hydroxymethyl-7,8-dihydroxy-2-methyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine

0.07 g (8R,9R)-3-formyl-8-hydroxy-2-methyl-7-oxo-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine was dissolved in 5 ml of dry methanol, and 0.1 g of sodium borohydride was added. The mixture was stirred for 30 minutes and concentrated in vacuo. The oily residue was partitioned between water and chloroform. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated. The product was purified by vacuum chromatography on silica gel (eluent: dichloromethane/methanol 9/1), resulting in 0.05 g of the title compound as a semi-solid.

1H NMR (CD3OH, 400 MHz), δ = 1.90 (s, 3H, 2-CH3), 3.87 (dd, J8,9 = 9.5 Hz, J8,7 = 8.0 Hz, 1H, 8-H), 4.45 (d , J9,8 = 9.4 Hz, 1H, 9-H), 4.79 (bs, 2H, 3-CH2), 5.42 (d, J7,8 = 8.0 Hz, 1H, 7-H), 7.03 (d, J6, 5 = 6.9 Hz, 1H, 6-H), 7-35-7.42 (m, 3H, 9-Ph), 7.55 (d, J = 7.0 Hz, 2H, 9-Ph), 7.77 (d, J5,6 = 7.0 Hz, 1H, 5-H).

16. (7S,8R,9R)-7,8-isopropylidenedioxy-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine

0.3 g of (7S,8R,9R)-2,3-dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine was dissolved in 5 ml of dry acetone and 10 ml of dry N,N-dimethylformamide. 2,2-dimethoxypropane (20 ml) and p-toluenesulfonic acid monohydrate (0.68 g) were added, and the mixture was stirred for 20 hours at room temperature. The reaction mixture was partitioned between water and dichloromethane. The organic layer was separated, washed with water and dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (eluent: ethyl acetate/methanol 20/1), resulting in 0.2 g of the title compound in the form of colorless needles, melting point 231-232 °C (decomp. diethyl ether).

RESULTING COMPOUNDS

A. 2,3-dimethyl-7-(3-phenyl-1-oxo-2-propenyl)-8-pivaloylamino-imidazo[1,2-a]pyridine

Method A

a) 7-tributylstannyl-2,3-dimethyl-8-pivaloylaminoimidazo-[1,2-a]pyridine

A solution of 1 g of 2,3-dimethyl-8-pivaloylaminoimidazo[1,2-a]pyridine in 40 ml of diethyl ether was treated drop by drop at -78 °C with 8 ml of a 1.5 M solution of t-butyllithium in n-pentane. The mixture was stirred for 15 minutes and then treated with 3.3 ml of tri-n-butyltin chloride. The internal temperature was then allowed to rise to room temperature, the mixture was poured into ice water and extracted three times with ethyl acetate, the combined extracts were washed with a little water and dried over potassium carbonate, the solvent was removed in vacuo, and the resulting oily residue was chromatographed on silica gel. with the use of ethyl acetate/petroleum ether (1:3) as eluent. 1.3 g of 7-tributylstannyl-2,3-dimethyl-8-pivaloylaminoimidazo[1,2-a]pyridine was obtained in the form of a viscous oil.

b) 2,3-dimethyl-7-(3-phenyl-1-oxo-2-propenyl)-8-pivaloylamino-imidazo[1,2-a]pyridine

A solution of 1 g of 7-tributylstannyl-2,3-dimethyl-8-pivaloylamino-imidazo[1,2-a]pyridine in 15 ml of tetrahydrofuran was treated successively with 85 mg of lithium chloride, 60 mg of bis(acetonitrile)-palladium(II ) chloride and 340 mg of cinnamoyl chloride. The mixture was stirred at 60°C for 3 hours. After cooling to 0°C, the yellowish precipitate was filtered off with suction and washed with a little tetrahydrofuran and diethyl ether. After drying in vacuo, 720 mg of the title compound were obtained as the hydrochloride salt, m.p. 263-5 °C (decomposition).

Method B

a) 2,3-dimethyl-7-(3-phenyl-1-hydroxy-2-propenyl)-8-pivaloyl-aminoimidazo[1,2-a]pyridine

A vigorously stirred solution of 41 g of 8-pivaloylamino-2,3-dimethyl-imidazo[1,2-a]pyridine was treated dropwise at -78 °C under argon as a protective gas with 320 ml of a commercially available 1.5 M solution of t- butyllithium in n-pentane, so that the temperature does not exceed -70 °C. After stirring at -78 °C for a further 15 minutes, a solution of 61 g of cinnamaldehyde in 50 ml of dry diethyl ether was added dropwise (internal temperature < -68 °C). The mixture was then allowed to warm to room temperature, and was carefully poured into ice water and extracted three times with a total of 500 ml of ethyl acetate, the reddish-colored organic phase was washed with distilled water and dried over sodium sulfate, and the solvent was removed in vacuo. The residue, a yellowish suspension, was treated with diethyl ether. The obtained crystals were filtered off by suction. 30 g of 2,3-dimethyl-7-(3-phenyl-1-hydroxy-2-propenyl)-8-pivaloylamino-imidazo[1,2-a]pyridine, melting point 194-5 °C, were obtained.

b) 2,3-dimethyl-7-(3-phenyl-1-oxo-2-propenyl)-8-pivaloylamino-imidazo[1,2-a]pyridine

A solution of 35.5 g of 2,3-dimethyl-7-(3-phenyl-1-hydroxy-2-propenyl)-8-pivaloylaminoimidazo[1,2-a]pyridine in 900 ml of trichloromethane was treated with 60 g of manganese dioxide and strongly stirred at room temperature for 20 hours. The mixture was then filtered, the filtrate was concentrated to dryness in vacuo and the resulting oil was treated with a little diisopropyl ether. The crystals obtained by this procedure were filtered out by suction. 31.5 g of the title compound, melting point 108-9 °C, were obtained.

B. 7-[3-(2-chlorophenyl)-1-oxo-2-propenyl]-8-pivaloylamino-2,3-dimethylimidazo[1,2-a]pyridine

The title compound, melting point 158-60 °C, was obtained in 42% yield in the form of hydrochloride, analogously to Example A, Method A, by appropriate reaction with 2-chlorocinnamoyl chloride.

C. 7-[3-(2,6-dichlorophenyl)-1-oxo-2-propenyl]-8-pivaloylamino-2,3-dimethylimidazo[1,2-a]pyridine

The title compound, melting point 218-19 °C, was obtained in 51% yield in the form of hydrochloride, analogously to Example A, Method A, by appropriate reaction with 2,6-dichlorocinnamoyl chloride.

D. 7-[3-(2-trifluoromethylphenyl)-1-oxo-2-propenyl]-8-pivaloyl-amino-2,3-dimethylimidazo[1,2-a]pyridine

The title compound of melting point 206-8 °C was obtained in 12% yield in the form of hydrochloride, analogously to Example A, Method A, by appropriate reaction with 2-trifluoromethylcinnamoyl chloride.

E. 2,3-dimethyl-7-(2,3-epoxy-1-oxo-3-phenylpropyl)-8-pivaloyl-aminoimidazo[1,2-a]pyridine

A mixture of 4 g of 2,3-dimethyl-7-(3-phenyl-1-oxo-2-propenyl)-8-pivaloylaminoimidazo[1,2-a]pyridine in 60 ml of acetone and 400 mg of sodium hydroxide in 12 ml of water was treated is drop by drop with vigorous stirring at 30 °C with 5.6 ml of commercially available aqueous hydrogen peroxide of 30% strength (20 minutes). After stirring at 30 °C for a further 30 minutes, the mixture was cooled to 0 °C and treated with a mixture of 60 ml of water, 13 g of sodium thiosulfate and 30 ml of ethyl acetate. After phase separation, the aqueous phase was extracted with 20 ml of ethyl acetate. The organic phases were combined, washed with a little water and dried over sodium carbonate. After removing the solvent in vacuo, the remaining oil was dried under high vacuum. 4 g of the title compound were obtained in the form of an amorphous mass.

F. 2,3-dimethyl-7-[(2S,3R)-2,3-O-isopropylidene-3-phenylpropan-1-on-1-yl]-8-pivaloylaminoimidazo[1,2-a]pyridine

60 g of 2,3-dimethyl-8-pivaloylaminoimidazo[1,2-a]pyridine was dissolved in 1.5 l of anhydrous diethyl ether with exclusion of moisture and under argon, and cooled to -75 °C in a cooling bath composed of dry ice - acetone. Using a plastic needle, 408 ml (0.612 mol) of tert-butyllithium solution (1.5 M in n-pentane) was added drop by drop, so that the temperature did not exceed -65 °C (30 minutes). A red suspension was formed. After the addition was complete, the suspension was stirred at -75 °C for a further 30 minutes. Then 1/3 of a solution of 145 g of methyl-(2S,3R)-2,3-O-isopropylidene-3-phenylpropionate (ee: 99.05 %) in 150 ml of absolute THF was added drop by drop, at a temperature of -65 °C for 30 minutes. The remaining amount was then quickly added drop by drop (5 min) with the temperature rising to -60 °C. After the addition was complete, the cooling bath was removed. After reaching an internal temperature of -30 °C, 20 ml of methanol was added, and at an internal temperature of 0 °C, 200 ml of distilled water was added. The aqueous phase was separated in a separatory funnel, the organic phase was washed five times with 100 ml of distilled water, then the organic phase was extracted three times with 10% sulfuric acid (200 ml, 50 ml, 50 ml). The sulfuric acid phases were combined, treated with 200 ml of dichloromethane and adjusted to pH 2.3 (balanced electrode) using 10 M sodium hydroxide solution with vigorous stirring.

The aqueous phase was extracted with 30 ml of dichloromethane. The combined dichloromethane phases were washed twice with a little distilled water. The organic phase was then dried over anhydrous sodium sulfate, and the solvent was removed in vacuo. A brown oil was obtained, which was treated with 50 ml of diethyl ether. After germination, crystals were formed, which were filtered off after standing overnight and washed with diethyl ether. After drying in vacuo, the title compound was obtained as a light yellow powder, melting point 76-80 °C. Amount 57.7 g (52.5 %), ee: >99 % (HPLC).

MARKET APPLICATION

The compounds of formula I and their salts show useful pharmacological properties, which make them commercially applicable. First of all, they show a marked inhibition of gastric acid secretion and an excellent gastric and intestinal protective action in warm-blooded animals. In this context, the compounds according to the invention are characterized by high selectivity of action, suitable duration of action, especially good enteral activity, absence of significant side effects and wide therapeutic range.

"Gastric and intestinal protection" in this case means the prevention and treatment of gastrointestinal diseases, primarily gastrointestinal inflammatory diseases and lesions (for example, gastric ulcer, duodenal ulcer, gastritis, hyperacidity or medicinally conditioned functional gastropathy), which can be caused, for example, by micro-organisms (on e.g. Heliobacter pylori), bacterial toxins, medications (e.g. some anti-inflammatory drugs and antirheumatic drugs), chemicals (e.g. ethanol), stomach acid or stressful situations.

In their excellent properties, the compounds according to the invention surprisingly significantly surpassed the compounds known from the prior art in various models in which antiulcerogenic and antisecretory properties were determined. According to these properties, the compounds of formula I and their pharmacologically acceptable salts are extremely suitable for use in human medicine and veterinary medicine, where they are particularly used for the treatment and/or prophylaxis of gastric and/or intestinal disorders.

Therefore, the invention further relates to compounds according to the invention for use in the treatment and/or prophylaxis of the above-mentioned diseases.

The invention also includes the use of the compounds according to the invention for the production of drugs that are used in the treatment and/or prophylaxis of the above-mentioned diseases.

The invention also includes the use of compounds according to the invention in the treatment and/or prophylaxis of the above-mentioned diseases.

The invention also relates to drugs containing one or more compounds of formula I and/or their pharmacologically acceptable salts.

The drugs are prepared by procedures known per se, which are well known to those skilled in the art. As drugs, the pharmacologically active compounds according to the invention (= active compounds) are applied either as such, or preferably in combination with suitable pharmaceutical excipients or additives in the form of tablets, coated tablets, capsules, suppositories, patches (e.g. as TTS), emulsion, suspension or solution, where the content of the active compound is preferably between 0.1 and 95%, and where the administration of the pharmaceutical preparation (e.g. slow-release method or an enteric method) is precisely adapted to the active compound and/or the desired action.

An expert in the field knows based on his own knowledge which auxiliary and additional agents are suitable for the desired pharmaceutical formulations. In addition to solvents, gel-forming agents, suppository bases, auxiliaries in tablets and other carriers of the active compound, it is possible to use, for example, antioxidants, dispersants, emulsifiers, anti-foaming agents, flavor additives, preservatives, dissolving reagents, dyes or, above all, strengthening agents permeation and complexing agents (eg cyclodextrins).

The active compound can be administered orally, parenterally or percutaneously.

In general, in human medicine it has been shown to be suitable for achieving the desired results to administer the active compound(s) orally in a daily dose of approximately 0.01 to approximately 20, preferably 0.05 to 5, and especially 0.1 to 1.5 mg/kg of body weight, if it is suitable in in the form of several, preferably 1 to 4 individual doses. In the case of parenteral treatment, similar or (primarily in the case of intravenous administration of active compounds) generally lower doses can be used. The optimal dose and form of administration of the active compound, required in each individual case, can easily be determined by an expert based on his own knowledge.

If the compounds according to the invention and/or their salts are to be used for the treatment of the aforementioned diseases, the pharmaceutical preparations may also contain one or more pharmacological ingredients from other pharmaceutical groups. Examples include: sedatives (for example from the benzodiazepine group, e.g. diazepam), antispasmodics (e.g. bietamiverine or camilofin), anticholinergics (e.g. oxyphencycline or phenylcarbamide), local anesthetics (e.g. tetracaine or procaine ), and if appropriate, enzymes, vitamins or amino acids.

In this regard, it should be emphasized first of all the combination of the compounds according to the invention with pharmaceutical preparations that inhibit acid secretion, such as for example H2 blockers (e.g. cimetidine, ranitidine), H+/K+-ATPase inhibitors (e.g. omeprazole, pantoprazole), or further with so-called peripheral anticholinergics (e.g. pirenzepi, telenzepine), and with gastrin antagonists with the purpose of enhancing the main effect in an additive or superadditive sense and/or eliminating or reducing side effects, or further a combination with antibacterial active substances (e.g. cephalosporins , tetracyclines, penicillins, macrolides, nitroimidazoles or alternatively bismuth salts) to control Heliobacter pylori. Antibacterial active combination components that should be mentioned are, for example, mezlocillin, ampicillin, amoxicillin, cephalothin, cefoxitin, cefotaxime, imipenem, gentamicin, amikacin, erythromycin, ciprofloxacin, metronidazole, clarithromycin, azithromycin and their combinations (eg clarithromycin + metronidazole).

PHARMACOLOGY

The excellent gastric protective action and inhibition of gastric acid secretion of the compounds according to the invention can be demonstrated in experimental animal models. The compounds according to the invention tested in the model below are described with numbers corresponding to the numbers of the compounds in the examples.

Examination of the inhibitory effect on secretion in the filled stomachs of rats

Table A shows the effects of compounds of the invention on pentagastrin-stimulated acid secretion in filled rat stomachs in vivo following intravenous administration of the compounds.

Table A

[image]

Methodology

Abdomen of anesthetized rats (CD rats, females, 200-250 g; 1.5 g/kg i.m. urethane) was opened after tracheotomy through a medial upper abdominal incision and a PVC catheter was transorally fixed into the esophagus and the other through the pylorus, so that the ends of the tube just reached into gastric lumen. The catheter from the pylorus led outward into the right abdominal wall through an opening on the side.

After thorough washing (about 50-100 ml), warm physiological NaCl solution at 37 °C (0.5 ml/min, pH 6.8-6.9; Braun-Unita I) was continuously passed through the stomach. Excreted HCl was determined in the eluent, always collected at intervals of 15 minutes, by measuring pH (pH meter 632, glass electrode EA 147; Φ = 5 mm, Metrohm) and titrating with freshly prepared NaOH solution to pH 7 (Dosimat 665 Metrohm).

Gastric secretion was stimulated by continuous infusion of 1 μg/kg (= 1.65 ml/h) pentagastrin i.v. (left femoral vein) about 30 minutes after the end of the experiment (i.e. after the determination of the two preliminary fractions). The tested substances were administered intravenously in volumes of 1 ml/kg, 60 minutes after the start of the continuous infusion of pentagastrin.

The body temperature of the animals was kept constant at 37.8-38 °C using infrared radiation and heating pads (automatic continuous control using a rectal temperature sensor).

Claims (10)

1. Compound of formula I [image] indicated by the fact that in it R1 represents 1-4C-alkyl, R2 denotes 1-4C-alkyl or hydroxy-1-4C-alkyl, R3 means hydrogen or halogen, one of the substituents R4a and R4b is hydrogen and the other is hydrogen, hydroxy, 1-4C-Alkoxy, 1-4C-Alkoxy-1-4C-Alkoxy or 1-4C-Alkylcarbonyloxy, or R4a and R4b together form O (oxygen) , one of the substituents R5a and R5b is hydrogen and the other is hydrogen, hydroxy, 1-4C-Alkoxy, 1-4C-Alkoxy-1-4C-Alkoxy or 1-4C-Alkylcarbonyloxy, or R5a and R5b together form O (oxygen) , or in which one of the substituents R4a and R4b on the one hand, and R5a and R5b on the other hand, in each case represents hydrogen, and the other substituents in each case together form a methylenedioxide radical (-O-CH2-O-) or some ethylenedioxide radical (-O-CH2-CH2-O-), where R4a, R4b, R5a and R5b are not simultaneously hydrogen, R6 represents hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonyl-amino or trifluoromethyl, and R7 denotes hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy, and their salts. 2. Compound of formula I according to claim 1, characterized in that R1 represents 1-4C-alkyl, R2 denotes 1-4C-alkyl or hydroxy-1-4C-alkyl, R3 means hydrogen, one of the substituents R4a and R4b is hydrogen, and the other is hydrogen, hydroxy or 1-4C-alkoxy, or R4a and R4b together form O (oxygen), one of the substituents R5a and R5b is hydrogen, and the other is hydrogen, hydroxy or 1-4C-alkoxy, or R5a and R5b together form O (oxygen), where R4a, R4b, R5a and R5b are not simultaneously hydrogen, R 6 represents hydrogen, halogen, or trifluoromethyl, a R7 denotes hydrogen or halogen, and their salts. 3. Compound according to claim 1, formula I*, [image] indicated by the fact that in it R1 represents 1-4C-alkyl, R2 denotes 1-4C-alkyl or hydroxy-1-4C-alkyl, R3 means hydrogen, one of the substituents R4a and R4b is hydrogen, and the other is hydrogen, hydroxy or 1-4C-alkoxy, one of the substituents R5a and R5b is hydrogen, and the other is hydrogen, hydroxy or 1-4C-alkoxy where R4a, R4b, R5a and R5b are not simultaneously hydrogen, R6 represents hydrogen, halogen or trifluoromethyl, a R7 denotes hydrogen or halogen, and their salts. 4. Compound of formula I* according to claim 3, characterized in that in it R1 represents 1-4C-alkyl, R2 denotes 1-4C-alkyl or hydroxymethyl, R3 means hydrogen, R4a means hydrogen, R4b denotes hydroxy or 1-4C-alkoxy, R5a means hydrogen, hydroxy or 1-4C-alkoxy, R5b means hydrogen, R6 represents hydrogen, halogen or trifluoromethyl, a R7 denotes hydrogen or halogen, and their salts. 5. Compound of formula I* according to claim 3, characterized in that in it R1 represents 1-4C-alkyl, R2 denotes 1-4C-alkyl, R3 means hydrogen, R4a means hydrogen, R4b denotes hydroxy, R5a denotes hydroxy, R5b means hydrogen, R6 represents hydrogen, halogen or trifluoromethyl, a R7 denotes hydrogen or halogen, and their salts. 6. The compound according to claim 1, characterized in that it is selected from the group comprising 7,8-dihydroxy-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1 ,7]naphthyridine, 2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-7-one, 9-(2-chlorophenyl) -2,3-di-methyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-7-one,9-(2,6-dichlorophenyl)-2,3- dimethyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-7-one, 9-(2-trifluoromethyl)-2,3-dimethyl-7,8,9 ,10-tetrahydroimidazo[1,2- h][1,7]naphthyridin-7-one,7-hydroxy-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine, 9-(2-chlorophenyl)-7-hydroxy-2,3-dimethyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine,9-(2,6- dichlorophenyl)-7-hydroxy-2,3-dimethyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine,9-(2-trifluoromethyl)-7-hydroxy- 2,3-dimethyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine and 8-hydroxy-2,3-dimethyl-9-phenyl-7,8,9,10 -tetrahydroimidazo[1,2-h][1,7] naphthyridine, or their salts. 7. The compound according to claim 1, characterized in that its chemical name is (7R,8R,9R)-7,8-dihydroxy-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[ 1,2-h][1,7]naphthyridine, and its salts. 8. Medicine characterized in that it contains the compound according to claim 1 and/or its pharmacologically acceptable salt, together with usual pharmaceutical auxiliaries and/or additives. 9. The compound according to claim 1 and its pharmacologically acceptable salt, characterized in that they serve to prevent gastrointestinal diseases. 10. Application of the compounds according to claim 1 and their pharmacologically acceptable salts, characterized by the fact that they serve the production of drugs for the prevention and treatment of gastrointestinal diseases.