SK197A3 - Imidazopyridine-azolidinones, preparation method thereof, pharmaceutical composition containing same and their use - Google Patents

Abstract

PCT No. PCT/EP95/02954 Sec. 371 Date Jan. 28, 1997 Sec. 102(e) Date Jan. 28, 1997 PCT Filed Jul. 26, 1995 PCT Pub. No. WO96/03405 PCT Pub. Date Feb. 8, 1996Imidazopyridine-azolidinones are useful for treating or preventing amenable gastro-intestinal ailments.

Description

SUMMARY OF THE INVENTION

The invention relates to novel imidazopyridinesolidinones which are intended for use in the pharmaceutical industry as active ingredients for the manufacture of pharmaceutical compositions.

BACKGROUND OF THE INVENTION

European patent application EP-A-0 033 094 describes imidazo [1,2-a] pyridines which in the 8-position bear an aryl substituent, which is preferably a phenyl, thienyl, pyridyl radical or chlorine, fluorine, methyl, tert. butyl-, trifluoromethyl-, methoxy- or cyano-substituted phenyl radical. Aryl radicals mentioned as being of particular interest in EP-A-0 033 094 are phenyl, o- or p-fluorophenyl, p-chlorophenyl and 2,4,6-trimethylphenyl radicals, of which phenyl, o- or p- fluorophenyl and 2,4,6-trimethylphenyl. European patent applications EP-A-0 204 285, EP-A-0 228 006, EP-A-0 268 989 and EP-A-0 308 917 disclose imidazo [1,2-a] pyridines which in position 3 carry an unsaturated aliphatic radical, in particular a (substituted) alkynyl radical. European patent application EP-A-0 266 890 discloses imidazo [1,2-] pyridines which are substituted in the 8-position by an alkenyl, alkyl or cycloalkylalkyl radical.

SUMMARY OF THE INVENTION

It has been found that the compounds described in detail below and which differ from those previously known, especially in the substitution at the 8-position, have surprising and particularly advantageous properties.

The invention relates to compounds of formula (I)

or thiocyanate,

halo

R

R ¹

R ²

C _L _ ₄ alkyl, hydroxymethyl,

C ₁ _ ₄ alkyl, hydrogen, C £ _ ₄ alkyl, Cy _ ₄ alkoxy, halogen or triflate ³

R ³ '

R ⁴

R ⁵ is is fluoromethyl, is hydrogen or C 1-4 alkyl, is hydrogen, C 1-4 alkyl or substituted C 1-4 alkyl having one or two identical or different substituents selected from the group consisting of from halo, C _L _ ₄ alkoxy and C ₁ _ ₄ alkoxy-C ₁₄ alkoxy, is hydrogen, C ^ _ ₄ alkyl, C ^^ - alkoxy, halogen or trifluoromethyl, is hydrogen, C ₁ _ ₄ alkyl, C ^ _ ₄ alkoxy or halogen, is 0 (oxygen) is 0 (oxygen) and salts thereof.

C ₁₄ -alkyl or NH a or CH 2 is a linear or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and especially methyl radicals.

Halogen within the meaning of the invention is bromine, fluorine and especially chlorine. C - ^ _ ₄ alkoxy is the oxygen atom, in which one of the abovementioned C ₁ _4 alkyl radicals is attached. Examples which may be mentioned are the methoxy and ethoxy radicals.

C 1-4 -alkoxy-C 1-4 -alkoxy is one of the above-mentioned C 1-4 -alkoxy radicals, which is substituted with another C 1-4 -alkoxy radical. An example that may be mentioned is the methoxyethoxy radical.

Suitable salts for the compounds of formula (I) are preferably all acid addition salts. Particular mention may be made of the pharmacologically tolerable salts of inorganic and organic acids which are commonly used in pharmaceutical technology. Pharmacologically intolerable salts, which may be, for example, the starting products of processes for the preparation of compounds of the invention on an industrial scale, are converted into pharmacologically compatible salts by processes known to those skilled in the art. Water-soluble and water-insoluble acid addition salts 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, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy acid The 2-naphthoic acids are used for the preparation of salts, depending on whether the monobasic or polysulphuric acid and, depending on what salt is desired, in equimolar amounts or different therefrom.

One embodiment are compounds of formula (I) wherein C 1 -C 4 -alkyl, hydroxymethyl or halogen is

R ¹ is C ₁ _ ₄ alkyl,

ABOUT

R 1 ^is C ₁ -C ₄ -alkyl or halogen;

R is hydrogen or C1-4-alkyl,

3 '

R is hydrogen, C ^ _4 alkyl or substituted C - ^ _ ₄ -alkyl having a substituent selected from the group consisting of halogen, C _1-4 -alkoxy and C ₁ _ ₄ -alkoxy-C ₁ _ ₄ alkoxy .

R ⁴ is hydrogen, r ⁵ is hydrogen,

A is (O) oxygen or NH a

Y is (O) oxygen or CH 2, and salts thereof.

Another embodiment are compounds of formula (I) wherein r0 is methyl, hydroxymethyl, chloro or fluoro; I t is methyl, R ² s ^and C ₁ _ ₄ alkyl, and

R is hydrogen or C _1-4 -alkyl, and '

R is hydrogen, C ^ _ ₄ alkyl or substituted C - ^ _ ₄ -alkyl having a substituent selected from the group consisting of C ^ _ ₄ alkoxy and C ^ _ ₄ alkoxy-C - ^ _ ₄ alkoxy,

R ⁴ is hydrogen, R 8 is hydrogen,

A is (O) oxygen or NH a

Y is (O) oxygen or CH 2, and salts thereof.

Another embodiment are compounds of formula (I) wherein rQ is methyl, hydroxymethyl, or chloro; is methyl, ^{R2 is:} C ₁ _ ₄ alkyl,

Q

R is H or C - ^ _ ₄ alkyl,

R is H, C - ^ _ ₄ alkyl, C ^ _ ₄ alkoxy-C - ^ _ ₄ alkyl, or. C ^ _ ₄ -alkoxy-C ₁ _ ₄ alkoxy-C ^ _ ₄ alkyl,

R ⁴ is hydrogen,

R 6 is hydrogen,

A is (O) oxygen or NH a

Y is (O) oxygen or CH ₂ , and salts thereof.

Exemplary compounds of the invention are listed in the following Table 1:

Table 1

Compounds of formula (I) (see attached sheet of formulas),

with R ¹ = CH ₃ , and R ° r ⁴ = h, r ⁵ = h denote ú: R ² and R ³ next next substituents Y R ³ ' A F ch ₃ H H NH 0 F ch ₃ H H NH CH ₂ F ch ₃ H H 0 0 F ch ₃ H H 0 CH ₂ C1 ch ₃ H H 0 0 C1 ch ₃ H H NH ch ₂ C1 ch ₃ H H 0 ch ₂ ch ₃ C1 H H NH 0 CH ₂ OH C1 H H NH 0 ch ₃ C1 H H 0 0 ch ₃ C1 H H NH ch ₂ C1 C1 H H NH ch ₂ . ch ₂ oh ch ₃ H H NH CH ₂ ch ₃ ch ₃ H CH ₂ OCH ₂ CH ₂ OCH ₃ NH 0 ch ₃ C1 H ch ₂ and ₃ NH 0

and salts of the compounds shown in the table.

Compounds of formula (I) may each have a chiral center of 30 ° at the positions to which substituents and R ^{a are} attached.

In this case of the chiral compounds, the invention thus comprises both the pure enantiomers and diastereomers and mixtures thereof in some mixing ratio containing racemates.

The invention further relates to a process for the preparation of compounds of formula (I) and salts thereof. The method includes:

(a) for the preparation of compounds of formula (I) wherein R ® is hydroxymethyl, reducing compounds of formula (II) wherein, known, or

above with the compounds of formula v

(b) cyclic

and X is

Y have a suitable starting group, as defined by the removal of HX, and, if desired, subsequent conversion of compounds I obtained in their salts, or, if desired, subsequent release of compounds (I) from the obtained salts of compounds (I).

The reduction of compounds (II) is carried out in a manner known per se to the person skilled in the art. It is carried out in inert solvents, for example lower aliphatic alcohols, for example using suitable hydrides, such as sodium borohydride, if desired with the addition of water.

The cyclization of compounds (III) is carried out in a manner known per se to those skilled in the art, for example as described in the following examples, in inert solvents and in the presence of an acid binding reagent (proton acceptor). Said proton acceptors which are, for example, alkali metal hydroxides, such as sodium or potassium hydroxide, or metal hydrides, such as sodium hydride. A suitable starting group is, for example, a halogen atom (preferably chlorine or bromine) or a methanesulfonyloxy group.

A person skilled in the art is required, since his knowledge of the specific reaction conditions is required to carry out the preparation methods.

The isolation and purification of the substances according to the invention is carried out in a manner known per se, for example in such a way that the solvent is distilled off under vacuum and the residue is recrystallized from a suitable solvent, or subjected to one of the usual purification methods such as column chromatography on a suitable carrier material.

The acid addition salts are obtained by dissolving the free base in a suitable solvent, for example water, a chlorinated hydrocarbon such as dichloromethane or chloroform, a lower aliphatic alcohol (ethanol, isopropanol), a ketone such as acetone, or an ether such as THF, or diisopropyl ether which contains the desired acid or to which the desired acid is then added.

The salts are obtained by filtration, reprecipitation, precipitation with a false solvent for the addition salt or evaporation of the solvent. The salts obtained can be converted by alkalization, for example with aqueous ammonia, into the free bases, which can be converted into acid addition salts. In this way, it is possible to convert pharmacologically unacceptable acid addition salts into pharmacologically acceptable acid addition salts.

The starting materials II are obtained by cyclization of those compounds (III) in which Ιΐθ is CHO.

Compounds (III) are obtained, for example, by reaction of the compounds

we, with the compounds Hal-CO-Y-CHR 1 -CHR 1 -X, in which R 1, R, Y and X are as defined above and Hal is a halogen atom (preferably chlorine or bromine).

The starting compounds (IV) are disclosed in EP-A-0 268 989 and EP-A-0 308 917 or can be prepared in a manner analogous to those described above. For example, the starting compounds (IV) can be prepared in a manner known per se from the corresponding nitro compounds by reduction or hydrolysis of suitable N-acyl derivatives.

The following examples serve to explain the details of the preparation of the compounds of the invention. The examples also serve specifically to describe by way of example the preparation of compounds of formula (I) and the preparation of selected starting compounds. Likewise, they may be analogous to, or in a manner known to, the person skilled in the art using conventional techniques. The abbreviation IT stands for room temperature, h stands for hour (s), min stands for minute (s), m.p. stands for melting point, b.v. means boiling point and decomposition. means decomposition.

DETAILED DESCRIPTION OF THE INVENTION

Final products

Example 1

- [2- (2,3-dimethyl-imidazo [1,2-a] pyridin-8-yl] aminomethyl) -3-methylphenyl] oxazolidin-2-one

a) 8- [2- (2-chloroethoxycarbonylamino) -6-methylbenzylamino] -

2,3-dimethylimidaz [l, 2-a] pyridine

2-Chloroethyl chloroformate (12.4 g, 81 mmol) dissolved in dichloromethane (40 mL) was added dropwise at RT, over about 30 minutes, to a solution of 8- (2-amino-6-methylbenzylamino) -

2,3-dimethylimidazo [1,2] pyridine (19.65 g, 70 mmol) in anhydrous dichloromethane (600 mL). The mixture was then stirred at RT for 16 h and then extracted with sodium bicarbonate (4 x 200 mL). After extraction of the aqueous phase with dichloromethane (200 mL), the combined organic extracts were washed with water (2 x 200 mL), dried over magnesium sulfate and concentrated. The crude product remaining (33.9 g) was used directly in the next reaction in Example 1b.

b) 3- [2- (2,3-Dimethylimidazo [1,2-a] pyridin-8-ylaminomethyl) -3-methylphenyl] oxazolidin-2-one

Sodium hydride (3.15 g, 80% strength in paraffin) was added portionwise with vigorous stirring over a period of about 30 minutes to a solution of the crude product of Example 1a (33.8 g) in anhydrous ethanol (800 mL). The mixture was then stirred for an additional 30 minutes at RT, then water (200 ml) was added portionwise and the ethanol was distilled off on a rotary evaporator. The precipitate was filtered off with suction, washed with water and dried in vacuo. The crude product was purified by silica gel chromatography (eluent: toluene / dioxane = 4: 1). After concentration of fractions = 0.15 and crystallization from ethyl acetate / diisopropyl ether, the title compound (13.6 g, 63%) was isolated as a beige solid. MP: Mp 139-140 ° C.

c) Reaction of the title compound dissolved in acetone with methanesulfonic acid affords the methanesulfonate of the title compound, m.p. Mp 232-235 ° C.

Example 2

3- [2- (3-chloro-2-methylimidazo [1,2-a] pyridin-8-ylaminomethyl) -3-methylphenyl] oxazolidin-2-one

a) 8- [2- (2-Chloroethoxycarbonylamino) -6-methylbenzylamino] -3-chloro-2-methylamidazo [1,2-a] pyridine

Following the procedure described in Example 1a, 8- (2-amino-6-methylbenzylamino) -3-chloro-2-methylimidazo [1,2-a] pyridine (0.27 g) and 2-chloroethyl chloroformate (0.18 g) in dichloromethane (30 mL) gave the title compound as a brown oil, which was used immediately in the next reaction in 2b.

b) 3- [2- (3-chloro-2-methylimidazo [1,2-a] pyridin-8-ylaminomethyl) -3-methylphenyl] oxazolidin-2-one

Following the procedure described in Example 1b, the crude product 2a (0.37g) and sodium hydride (0.45g, 80% paraffin intensity) in anhydrous ethanol (20ml) gave, after crystallization from ethyl acetate / petroleum ether, the title compound (70mg). , 21%) as a beige solution. MP: 137 to 139 ’C.

Example 3

3- [2- (3-hydroxymethyl-2-methylimidazo [l, 2-a] pyridin-8-ylaminomethyl) -3-methylphenyl] oxazolidin-2-one

a) 8- [2- (chloroethoxycarbonylamino) -6-methylbenzylamino] -3-formyl-2-methylimidazo [1,2-a] pyridine

Following the procedure described in Example 1a, 8- (2-amino-6-methylbenzylamino) -3-formyl-2-methylimidazo [1,2-a] pyridine (2.03 g) and 2-chloroethyl chloroformate (1.01 g) in dichloromethane (120 mL) gave the title compound as a brown oil, which was used directly in the next reaction in Example 3b.

b) 3- [2- (3-formyl-2-methylimidazo [1,2-a] pyridin-8-ylaminomethyl) -3-methylphenyl] oxazolidin-2-one

Following the procedure described in Example 1b, the crude product 3a (0.12 g) and sodium hydride (0.01 g, 80% paraffin intensity) in anhydrous ethanol (10 mL) gave, after crystallization from ethyl acetate / diisopropyl ether, the title compound ( 80 g, 73%) as a beige solid. MP: 196 to 197 ° C

c) 3- [2- (3-hydroxymethyl-2-methylimidazo [1,2-a] pyridin-2-ylaminomethyl) -3-methylphenyl) oxazolidin-2-one

A solution of 3- [2- (3-formyl-2-methylimidazo [1,2-a] pyridin-8-ylaminomethyl) -3-methylphenyl] oxazolidin-2-one (0.18 g, 0.49 alcohol) and sodium borohydride (19 mg, 0.5 mmol) in anhydrous ethanol (20 mL) was stirred while water (75 mL), ethanol was added

IT for 30 minutes. It was then distilled off on a rotary evaporator and the aqueous residue was extracted with ethyl acetate (3 x 50 mL). The organic extracts were treated with water (50 mL), dried over magnesium sulfate, and concentrated. After crystallization from diisopropyl ether, the title compound (120 mg, 66%) was obtained as a beige solid. MP: 152 až

157 “C.

Example 4

3- [2- (3-hydroxymethyl-2-methylimidazo [1,2-a] pyridin-8-yloxymethyl) -3-methylphenyl] oxazolidin-2-one

a) 8- [2- (2-Chloroethoxycarbonylamino) -6-methylbenzyloxy] -3-formyl-2-methylimidazo [1,2-a] puridine

Following the procedure described in Example 1a, 8- (2-amino-6-methylbenzyloxy) -3-formyl-2-methylimidazo [1,2-a] pyridine (2.36 g) and 2-chloroethyl chloroformate (1.3 g) in dichloromethane (150 mL) gave the title compound as a brown oil, which was used immediately in the next reaction in 3b.

b) 3- [2- (3-formyl-2-methylimidazo [1,2-a] pyridin-8-yloxymethyl) -3-methylphenyl] oxazolidin-2-one

Following the procedure described in Example 1b, the crude product 4a (1.14 g) and sodium hydride (0.13 g, 80% paraffin intensity) in anhydrous ethanol (200 mL) gave, after crystallization from ethyl acetate / diisopropyl ether, the title compound ( 0.7 g, 67%) as a beige solid. MP: Mp 242-244 ° C.

c) 3- [2- (3-hydroxymethyl-2-methylimidazo [1,2-a] pyridin-8-yloxymethyl) -3-methylphenyl] oxazolidin-2-one

A solution of 3- [2- (3-formyl-2-methylimidazo [1,2-a] pyridin-8yloxymethyl) -3-methylphenyl] oxazolidin-2-one (1.39 g, 3.8 mmol) and sodium borohydride (0.19 g, 4.75 mmol) in anhydrous ethanol (125 mL) was stirred at RT for 1.5 h. Then water (100 ml) was added, ethanol was distilled off on a rotary evaporator and the aqueous residue was stirred at 4 ° C for 30 min. The precipitate was filtered off, washed with cold water and dried in vacuo. The title compound (1.28 g, 91%) was obtained as a beige solid. MP: 190 to 193 ’C.

13 Example 5

5-Chloromethyl-3- [2- (2,3-dimethyl-imidazo [1,2-a] pyridin-8-ylaminomethyl) -3-methyl-phenyl] -oxazolidin-2-one

a) A mixture of 150 g (1.14 mol) 1,3-dichloropropanol and 90.2 g (1.14 mol) pyridine was added dropwise at 5-8 ° C over 2 h to 591 ml (1.14 mol). mol) of a solution of phosgene in toluene (1.93 mol / L) and the mixture was stirred for another 24 h at 20 ° C. Aerated with pyridine hydrochloride was filtered off, the filtrate was washed with water and dried with magnesium sulfate, and after fractional distillation, 102 g (47%) of 2-chloro-1-chloromethylchloroformate were obtained. Bp 140-145 ° C / 18 mbar.

b) A solution of 2.0 g (7.13 mmol) of 8- (2-amino-6-methylbenzylamino) -

2,3-dimethylimidazo [1,2-a] pyridine and 1.5 g (7.84 mmol) of the title compound in 80 mL of dichloromethane were stirred for 2 days at RT. The organic solution was washed with saturated magnesium carbonate solution and water, dried with magnesium sulfate, and concentrated in vacuo. 3.4 g of crude 8- (2 - [(2-chloro-1-chloromethylethoxy) carbonylamino] -6-methylbenzylamino) -2,3-dimethylaimidazo [1,2-a] pyridine was obtained as an oil which was used in the next stage.

c) A solution of 0.48 g of 85% potassium hydroxide in 4 ml of ethanol was added dropwise at 20 ° C to a solution of the preceding compound in 30 ml of ethanol, and the mixture was stirred for another 5 h. It was concentrated in vacuo, the residue was treated with water, the mixture was extracted and the dry organic layer of magnesium sulfate was concentrated in vacuo. The residue was treated with 5 mL of ethanol and cooled in an ice bath. 1.2 g of the title compound are obtained. MP: M.p. 141-143 ° C.

Example 6

3- [2- (2,3-Dimethylimidazo [1,2-a] pyridin-8-ylaminomethyl) -314 methylphenyl] -5-methyloxazolidin-2-one hydrochloride

a) Analogously to Example 5a, 2-chloro-1-propanol and phosgene yield 2-chloro-1-methylethylchloroformate. Bp 55 DEG-56 DEG C./17 mbar.

b) Analogous to Example 5b, 2.0 g (7.13 mmol) of 8- (2-amino-6-methylbenzylamino) -2,3-dimethylimidazo [1,2-a] pyridine and 1.23 g were reacted. (7.85 mmol) of the title compound to give 3.1 g of crude 8- (2 - [(2-chloro-1-methylethoxy) carbonylamino] -6-methylbenzylamino) -2,3-dimethylimidazo [1,2-a] ] -pyridine, as a formless solid.

b) A solution of 0.48 g 85% KOH in 15 ml ethanol was added dropwise at RT to 2.9 g of the preceding compound in 15 ml ethanol and the mixture was additionally stirred for 12 h. It was concentrated in vacuo, the residue was treated with water, the mixture was extracted with dichloromethane and the dry organic layer of magnesium sulfate was concentrated in vacuo. The residue was treated with 0.3 mL concentrated hydrochloric acid and acetone to give 1.5 g of the title compound. MP: 274 DEG -275 DEG C. (dec.).

Example 7

3- (2- (2,3-dimethyl-imidazo [l, 2-a] pyridin-8-ylaminomethyl) -3-methylphenyl] -4-methyl oxazolidin-2-one

a). Similar to Example 5b, 2-chloropropylpropyl chloroformate and 8- (2-amino-6-methylbenzylamino) -2,3-dimethylimidazo [1,2-a] pyridine afford 8- [2- (2-chloropropoxycarbonylamino) -6-methylbenzylamino]. -2,3-dimethylimidazo [1,2-a] pyridine.

b) The preceding compound and a solution of sodium hydroxide in ethanol gave, analogously to Example 5c, the title compound.

Example 8

- [2- (2,3-Dimethylimidazo [1,2-a] pyridin-8-ylamino-methyl-3-methylphenyl) -5-methoxymethyloxazolidin-2-one

a) Similar to Example 5b, 8- [2- (1-chloromethyl-2-methoxy-

-ethoxycarbonylamino) -6-methylbenzylamino] -2,3-dimethylimidazo [1,2-a] pyridine was obtained from 1-chloromethyl-2-methoxyethyl chloroformate (Helv. Chim. Acta 44, 105, 1961) and 8- (2- amino-6-methylbenzylamino) -2,3-dimethylimidazo [1,2-a] pyridine.

b) The preceding compound and a solution of potassium hydroxide in ethanol gave, analogously to Example 5c, the title compound.

Example 9

1- [2- (2,3-dimethyl-imidazo [1,2-a] pyridin-8-ylaminomethyl) -3-methylphenyl) pyrrolidin-2-one

a) 8- [2- (4-Chlorobutyrylamino) -6-methylbenzylamino] -2,3-dimethylimidazo [1,2-a] pyridine

0.88 mL (7.85 mmol) of 4-chlorobutyryl chloride was added dropwise at 0-5 ° C with stirring to a solution of 2.2 g (7.85 mmol) of 8- (2-amino-6-methylbenzylamino) -2 3-dimethylimidazo [1,2-a] pyridine and 0.63 ml (7.85 mmol) pyridine in 30 ml dichloromethane and stirred for a further 2 h at 0-20 ° C. It was adjusted to pH 7 with water and potassium bicarbonate, the mixture was extracted by shaking, and the organic layer was dried with magnesium sulfate and concentrated in vacuo. The residue was recrystallized from toluene and petroleum ether (50/70 ° C). Yield: 2.6 g (86%) of the title compound.

MP: 138-140 ° C.

b) 1- [2- (2,3-Dimethylimidazo [1,2-a] pyridin-8-ylaminomethyl) -3-methylphenyl] pyrrolidin-2-one

A solution of 0.41 g (6.25 mmol) of 85% KOH in 15 mL of ethanol was added dropwise at RT to a solution of 2.4 g (6.24 mmol) of the title compound in 60 mL of ethanol and stirred for an additional 4 h . It was concentrated in vacuo to about 30 ml, the residue was diluted with water and the mixture was extracted several times by shaking with ethyl acetate. The organic layer was dried with magnesium sulfate and concentrated in vacuo, and the residue was crystallized using diisopropyl ether. 2.0 g (92%) of the title compound were obtained. MP: 138-141 C.

Example 10

1- [2- (3-chloro-2-methylimidazo [1,2-a] pyridin-8-ylaminomethyl) -3-methylphenyl] phenyl] pyrrolidin-2-one

a) 8- [2- (4-chlorobutyrylamino) -6-methylbenzylamino] -3-chloro-2-methylimidazo [1,2-a] pyridine

Following the procedure outlined in Example 9a), the title compound was obtained by reaction of 8- (2-amino-6-methylbenzylamino) -3-chloro-2-methylimidazo [1,2-a] pyridine and 4-chlorobutyryl chloride as a beige powder after crystallization from ethyl acetate. / cyclohexane. Yield 66%; mp 127-130 ° C.

b) 1- [2- (3-chloro-2-methylimidazo [1,2-a] pyridin-8-ylaminomethyl) -3-methylphenyl] pyrrolidin-2-one

Following the procedure outlined in Example 9b), the title compound was obtained as a beige powder by reacting the preceding compound with potassium hydroxide in ethanol followed by crystallization from diisopropyl ether. The yield was 77%; mp 265 DEG-267 DEG.

Starting compounds

A1. 3-chloro-3-mety1-8-pivaloylaminoimidazo [1,2-a] pyridine

5.0 g (18.6 mmol) of 2-methyl-8-pivaloylaminoimidazo [1,2-a] pyridine hydrochloride prepared from 8-amino-2-methylimidazo [1,2-a] pyridine and pivaloyl chloride, m.p. 229-230 ° C, dissolved. in glacial acetic acid (ml) and chlorine gas were slowly pumped in at 15 ° C until the reaction was complete by TLC control (about 20 minutes). The solvent was then distilled off, the residue was added to ethyl acetate / water (30 ml in each case) and the basic solution was extracted with saturated sodium bicarbonate solution. The extract was then extracted again with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with water (50 mL), dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: toluene / dioxane = 9: 1). After concentration of fractions Rf = 0.2, the title compound (4.1 g, 83%) was obtained as a colorless mass. MP: Mp 117-118 ° C.

A2. 8-amino-3-chloro-imidazo [1,2-a] pyridine

A suspension of 3-chloro-2-methyl-8-pivaloylaminoimidazo [1,2-a] pyridine (4.0 g, 15 mmol) in 60% sulfuric acid (25 mL) was stirred at 100 ° C for 1 h. After cooling to IT, water (100 mL) was added and the mixture was adjusted to pH 10 using 10 N sodium hydroxide solution. It was then extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water (50 mL), dried over magnesium sulfate and concentrated. The residue was added to boiling toluene, purified with silica gel and crystallized. The title compound was isolated as a beige solid. Yield 1.9 g (70%), m.p. 126-127 ° C.

BI. 8- (6-methyl-2-nitro-benzylamino) -2,3-dimethyl-imidazo [1,2-a] pyridine

Sodium carbonate (15.0 g) and sodium carbonate (31.0 g) were added to a solution of 8-amino-2,3-dimethylimidazo [1,2-a] pyridine (14.7 g) and 6-methyl-2-nitrobenzylchloride at IT. (18.6 g) in 100 ml of acetone, and the mixture was then heated under boiling under stirring

- 18 reflux for 6 h. After cooling the solution to IT and concentration, the residue was dissolved in a mixture of 200 mL of ethyl acetate and 200 mL of water and the organic phase was separated. After three further extractions with 100 mL of ethyl acetate, each of the combined organic phases was dried over magnesium sulfate and then concentrated to 80 mL. 12.1 g of the title compound crystallized as a slightly yellow solid. The mother liquor was concentrated. Chromatographic purification of the residue on silica gel (eluent: toluene / dioxane = 6: 1) gave an additional 14 g of crystalline product. Recrystallization of both fractions from ethyl acetate gave 21.5 g (76%) of the title compound, m.p. 160 to 162 ’C.

B2. 8- (6-methyl-2-nitro-benzyloxy) -2,3-dimethyl-imidazo [1,2-a] pyridine

A suspension of 8-hydroxy-2,3-dimethylimidazo [1,2-a] pyridine (7.46 g, 46 mmol), 6-methyl-2-nitrobenzyl chloride (9.35 g, 50.4 mmol). , sodium carbonate (11.24 g, 105 mmol) and sodium iodide (7.63 g, 50.4 mmol) in acetone (750 mL) was heated at reflux for 8 h. After cooling to IT, water (200 mL) was added and acetone was distilled off on a rotary evaporator. The aqueous residue was then stirred at 4 ° C for 30 minutes. The pale brown precipitate was then filtered off, washed with water and dried in vacuo. Further purification was performed by silica gel chromatography (eluent: toluene / dioxane = 5: 1). Fractions Rf = 0.2 were concentrated and recrystallized from ethyl acetate / cyclohexane. The title compound was isolated as a yellow solid. Yield 8.31 g (50%), m.p. 168 to 171 ’C.

B3. 3-chloro-2-methyl-8- (6-methyl-2-nitro-benzylamino) -imidazo [1,2-a] pyridine

From 8-amino-3-chloroimidazo [1,2-a] pyridine (9.26 g), 6-methyl-2-nitrobenzyl chloride (10.5 g), sodium carbonate (13.7 g) and sodium iodide (8 g). 55 g) in acetone (380 ml) according to the procedure described in Example B1, after chromatography on silica gel (eluent: toluene / dioxane = 20: 1) and crystallization from ethyl acetate / cyclohexane, 10.6 g (63 g). %) of the title compound with mp 142 to 144 ’C.

B4. 8- (2-tert-butoxycarbonylamino-6-methylbenzylamino) -2,3-dimethylimidazo [1,2-a] pyridine

From 8-amino-2,3-dimethylimidazo [1,2-a] pyridine (4.8 g), 2-tert-butoxycarbonylamino-6-methylbenzyl chloride (9.2 g), sodium iodide (5.5 g) and sodium carbonate (8.0 g) in acetone (250 mL) similarly using the procedure of Example BI, obtained after chromatography on silica gel (toluene / dioxane = 20: 1 eluent) and recrystallization from diisopropyl ether, 7.1 g (62%) of the title compound. compounds with mp 149 to 152 ’C.

B5. 8- (2-tert-butoxycarbonylamino-6-methyl-benzyloxy) -2,3dimetylimidazo [1,2-a] pyridine

From 8-hydroxy-2,3-dimethylimidazo [1,2-a] pyridine (1.6 g), 2-tert-butoxycarbonylamino-6-methylbenzyl chloride (3.1 g), sodium iodide (1.8 g) g) and sodium carbonate (2.7 g) in acetone (350 ml) similarly using the procedure of Example BI, obtained after chromatography on silica gel (toluene / dioxane = 5: 1 eluent) and recrystallization from cyclohexane, 3.0 g ( 78%) of the title compound mp 128-131 C.

B6. 8- (2-tert-butoxycarbonylamino-6-methyl-benzylamino) -3formyl-2-methylimidazo [1,2-a] pyridine

From 8-amino-3-formyl-2-methylimidazo [1,2-a] pyridine (4.0 g), 2-tert-butoxycarbonylamino-6-methylbenzyl chloride (7.0 g), sodium iodide (4.1 g) ) and sodium carbonate (6.1 g) in acetone (250 mL) analogously using the procedure of Example B1, after chromatography on silica gel (toluene / dioxane = 9: 1 eluent) and recrystallization from diisopropyl ether, 7.3 g (81 g) were obtained. %) of the title compound mp 210-212 ° C.

- 20 Β7. 8- (2-tert-butoxycarbonylamino-6-methylbenzyloxy) -3-formyl-2-methylimidazo [1,2-a] pyridine

From 3-formyl-8-hydroxy-2-methylimidazo [1,2-a] pyridine (2.4 g), 2-tert-butoxycarbonylamino-6-methylbenzyl chloride (4.2 g), sodium iodide (2.5 g) g) and sodium carbonate (3.7 g) in acetone (400 ml) analogously using the procedure of Example B1, after recrystallization from diisopropyl ether / ethyl acetate, 4.4 g (80%) of the title compound were obtained. Mp 189-191 ° C.

C1. 8- (2-Amino-6-methylbenzylamino) -2,3-dimethylimidazo [1,2-a] pyridine

Method A:

A solution of 8- (6-methyl-2-nitrobenzylamino) -2,3-dimethylimidazo [1,2-a] pyridine (61 g) in methanol (5.5 L) is hydrogenated at IT and under atmospheric pressure for 1, 5 h in the presence of 15 g of palladium on activated carbon (5%) as a catalyst. After filtering off the catalyst and concentrating, the residue was dissolved in boiling ethyl acetate (2.7 L). After cooling to IT, 51 g (82%) of the title compound was isolated, m.p. Mp 206-208 ° C.

Method B:

6.7 g of 8- (2-tert-butoxycarbonylamino-6-methylbenzylainino) 2,3-dimethylimidazo [1,2-a] pyridine was added portionwise at 25-30 ° C to a mixture of trifluoroacetic acid (30 mL) and anisole. (3 mL). After stirring at RT for 30 min, the solution was poured into 100 mL of ice water and then treated with 75 mL of 6N sodium hydroxide solution. The precipitate was filtered off and purified by silica gel chromatography (solution: toluene / dioxane = 8: 1). Recrystallization from ethyl acetate gave 3.1 g (62%) of the title compound. Mp 206-208 ° C.

C2. 8- (2-amino-6-methyl-benzylamino) -3-formyl-2-methylimidazo [1,2-a] pyridine

From 8- (2-tert-butoxycarbonylamino-6-methylbenzylamino) -3-formyl-2-methylimidazo [1,2-a] pyridine (3.6 g), trifluoroacetic acid (15 ml) and anisole (5 ml) according to the procedure described in Example C1 (Method B), after chromatography on silica gel (eluent: toluene / dioxane = 9: 1) and crystallization from ethyl acetate / cyclohexane, 2.3 g (76%) of the title compound are obtained. Mp 230-234 ° C.

C3. 8- (2-amino-6-methyl-benzyloxy) -3-formyl-2-methylimidazo [1,2-a] pyridine

From 8- (2-tert-butoxycarbonylamino-6-methylbenzyloxy) -3-formyl-2-methylimidazo [1,2-a] pyridine (5.0 g) and trifluoroacetic acid (40 ml) similarly using the procedure of Example C1 (Method B). ) to give 3.57 g (96%) of the title compound 1.1. 144 to 150 ’C (dec.).

C4. 8- (2-amino-6-methyl-benzylamino) -3-chloro-2-methylimidazo [1,2-a] pyridine hydrochloride

A solution of 8- (2-nitro-6-methylbenzylamino) -3-chloro-2-methylimidazo [1,2-a] pyridine (2.0 g, 6 mmol) in methanol (175 mL) and dioxane (175 mL) was added. treated with platinum on carbon catalyst (5% intensity) and hydrogenated at IT under atmospheric pressure for 2 h. After 2 h, 2N hydrochloric acid (5 mL) was added and the mixture was hydrogenated again under the same conditions for 1 h. The catalyst was then filtered off, the filtrate was adjusted to pH 8.5 using 2N sodium hydroxide solution and the solvent was distilled off on a rotary evaporator. The residue was dissolved in boiling ethyl acetate (400 mL). After cooling to IT, diisopropyl ether (250 mL) was added and the mixture was stirred at 4 ° C for 30 minutes to complete the crystallization. The precipitate was then filtered off with suction, washed with diisopropyl ether and dried under vacuum. The title compound (1.66 g, 92%) was isolated as a beige solid. MP: 243-246 ’C.

Industrial use

The compounds of formula (I) and their salts have good pharmacological properties which make them industrially useful. In particular, they have a marked inhibition of gastric acid secretion and an excellent gastric and intestinal protective effect in warm-blooded animals. The compounds of the invention are distinguished herein by high selectivity of action, relatively long duration of action, good intrinsic efficacy, absence of significant side effects, and a wide therapeutic range.

Gastric and intestinal protection in this connection is understood to be a significant prevention and treatment of gastrointestinal diseases, especially gastrointestinal inflammatory disorders and lesions (such as gastric ulcer, duodenal ulcer, gastritis, too acidic or drug-related functional gastropathy) that may be caused by gastropathy. for example microorganisms (for example Helicobacter pylori), bacterial toxins, drugs (for example some anti-fever and anti-rheumatic agents), chemicals (for example ethanol), stomach acid or stressful situations. In this case, the compounds of the invention also have intrinsic activity against Helicobacter pylori microorganisms.

Surprisingly, in their excellent properties, the compounds of the present invention have proven to be clearly superior in various models in which anti-ulcer and antisecretory properties have been determined, compared to those known in the art. Because of these properties, the compounds of formula (I) and their pharmacologically tolerable salts are particularly suitable for use in human and veterinary medicine, where they are particularly used for the treatment and / or prevention of gastric and / or intestinal diseases.

The invention therefore further relates to the compounds of the invention for use in the treatment and / or prevention of the aforementioned diseases.

The invention likewise encompasses the use of the compounds of this invention for:. manufacture of medicaments which are used for the treatment and / or prevention of the aforementioned diseases.

The invention further encompasses the use of the compounds of the invention for the treatment and / or prevention of the aforementioned diseases.

The invention further relates to medicaments comprising one or more compounds of formula (I) and / or their pharmacologically acceptable salts.

The pharmaceutical compositions are prepared by methods known per se and well known to those skilled in the art. As medicaments, the pharmacologically active compounds of the invention (= active compounds) are either used alone or preferably in combination with suitable pharmaceutical excipients or vehicles in the form of tablets, coated tablets, capsules, suppositories, coatings (e.g. as TTS), emulsions, suspensions or solutions, the active compound content is preferably between 0.1 and 95% by weight, and this can be achieved by appropriately selecting excipients and vehicles, a pharmaceutical dosage form that directly meets the active compound and / or desired efficacy goal (e.g., supportive or enteric). formulation).

Those skilled in the art will be able to determine which excipients and vehicles are suitable for the desired pharmaceutical formulations. In addition to solvents, gelling agents, suppository bases, tabletting aids and other active agent vehicles, for example, antioxidants, dispersants, emulsifiers, antifoams, flavoring agents, preservatives, solubilizers, colorants or, in particular, stability agents and complexing agents may be used (e.g., cyclodextrins).

The active agents may be administered orally, parenterally or percutaneously.

In general, it has proven advantageous to administer the active substance (s) in human medicine in the case of oral administration at a daily dose of about 0.01 to about 20, preferably 0.05 to 5, in particular 0.1 to 1.5 mg / kg body weight , in an appropriate distribution, preferably 1 to 4, of the individual dose to achieve the desired result. In the case of parenteral treatment, a similar or (especially in the case of intravenous administration of the active substances) generally lower dose may be used. The skilled artisan can readily determine the optimum dosage and mode of administration of the active ingredients required in each case for his knowledge in the art.

When the compounds and / or salts of the present invention are to be used to treat the aforementioned diseases, the pharmaceutical compositions may also contain one or more pharmacologically active ingredients from other pharmaceutical groups, such as antacids, for example aluminum hydroxide, magnesium aluminate; tranquilizers such as benzodiazepines such as diazepam; spasmolytics, such as bietamiverine, camylophin, anticholinergics, such as oxyphenycycline, fencarbamide; local anesthetics such as tetracaine, procaine; and preferably also enzymes, vitamins or amino acids.

Particular emphasis is placed on the combination of a compound of the invention with drugs that inhibit acid secretion such as H ₂ blockers (e.g. cimetidine, ranitidine), H ⁺ / K ⁺ ATPase inhibitors (e.g. omeprazole, pantoprazole), or further with so-called peripheral anticholinergics (e.g. pirenzepine, telenzepine) as well as gastrin antagonists, in order to increase the main action in an additive or superadditive sense and / or to eliminate or reduce side effects, or further to combine with antibacterial agents (such as cephalosporins) , tetracyclines, nalidixinic acid, penicillins or even bismuth salts) to inhibit Helicobacter pylori.

pharmacology

The excellent gastric protective effect and gastric acid with the secretory-inhibitory effect of the compounds of this invention can be ascertained by investigating in experimental animals 25 animals. The compounds of the invention investigated in the models below have been designated with numbers that correspond to those of the compounds in the examples.

Assay for secretory-inhibitory effect on rat perfusion stomach

Table A, which follows, shows the effect of the compounds of the invention after intravenous administration on pentagastrin-stimulated acid secretion in the perfused rat stomach in vivo.

Table A

No. Dose (pmol / kg) i. in . Acid secretion inhibition (%) lb 3 100 9b 3 100

method

After tracheotomy, the abdomen of anesthetized rats (CD rats, females, 200-25 g; 1.5 g / kg im urethane) was opened by central abdominal incision and the PVC catheter was fixed transorally in the esophagus and another was fixed through the porter in such a way that the ends of the tubes just passed into the stomach lumen. The catheter, led outward from the porter, led out through the side opening in the right abdominal wall.

After complete rinsing (about 50-100 mL), warm saline NaCl at 37 ° C was passed continuously through the stomach (0.5 mL / min, pH 6.8-6.9; Braun-Unita I). The effluate was collected at 15 minute intervals and was subjected to pH determination (pH meter 632, EA 147 glass electrode;

diameter = 5 mm, Metrohm) and titration of the precipitated HCl with freshly prepared 0.01 N NaOH solution to pH 7 (Dosimat 665 Metrohm).

Stimulation of gastric acid secretion was performed by continuous infusion of 1 gg / kg (= 1.65 ml / h) i.v. pentagastrin (left femoral vein) within about 30 minutes after the end of the operation (i.e. after determining 2 pre-fractions). Test substances were administered intravenously in a liquid volume of 1 ml / kg 60 minutes after the start of continuous infusion of pentgastrin.

Animal body temperature was maintained at 37.8-38 ° C by irradiation with an infrared heater and a heated pad (automatic, continuous regulation by rectal temperature sensor).

The table indicates the dose that results in maximal inhibition of acid secretion of about 100%.

Claims (9)

PATENT CLAIMS A compound of formula (I) wherein, R® is a C _L _ ₄ alkyl, hydroxymethyl, halogen or thiocyanate, R ¹ is C ₁₄ -alkyl, R is hydrogen, C ^ _ ₄ alkyl, C ^ _ ₄ alkoxy, halogen or trifluoromethyl, and R is hydrogen or C1-6alkyl, R ^J is hydrogen, _C-L _ ₄ alkyl or substituted C ₁₄ -alkyl, - having one or two identical or different substituents selected from the group consisting of halogen, C ₁ _ ₄ alkoxy, C ₁ _ ₄ -alkoxy-C ₁ _ ₄ alkoxy R is H, C ^^ - alkyl, C ^ _ ₄ alkoxy, halogen or trifluoromethyl, R5 is hydrogen, C £ _ ₄ alkyl, C ^ _ ₄ alkoxy or halogen, A is (O) oxygen or NH a Y is (O) oxygen or CH 2, and salts thereof. Second . A compound of formula (I) according to claim 1, wherein R is a C _1-4 -alkyl, hydroxymethyl or halogen, R ¹ is a C ₁ _ ₄ alkyl, R ² is a C _1-4 -alkyl or halogen R ³ is a hydrogen or C _1-4 alkyl, R ³ is a hydrogen, C _1-4 -alkyl or substituted C 1-6 alkyl, having a substituent selected from the group consisting of halogen, C ^ - ^ - alkoxy and C _{L_-4-alkoxy-C} ~ ₄ alkoxy, R ⁴ is hydrogen, R ³ is hydrogen, A is (O) oxygen or NH a Y is (O) oxygen or Cl 2, and salts thereof. A compound of formula (I) according to claim 1, wherein 11θ is methyl, hydroxymethyl, chlorine or fluorine, R ² is methyl, ^{R 2} is C ₁ _ ₄ alkyl, Q R is hydrogen or C ₁ _ ₄ alkyl, R ^J is hydrogen, C - ^ _ ₄ alkyl or substituted C £ _ ₄ -alkyl having a substituent selected from the group consisting of C ^ _ ₄ alkoxy and C2_ ₄ -alkoxy-C ^ _ ₄ - alkoxy, R ⁴ is hydrogen, R ³ is hydrogen, A is (O) oxygen or NH a Y is (O) oxygen or CH 2, and salts thereof. A compound of formula (I) according to claim 1, wherein rQ is methyl, hydroxymethyl, or chloro, R is methyl, ^{R2 is: C} l-4 ^alk y ^1> Q R is H or C - ^ _ ₄ alkyl, -p R is H, C - ^ _ ₄ alkyl, C - ^^ - alkoxy-C - ^^ - _ ₄ alkoxy or alkoxy-C ₄ -alkoxy-C ₄ alkyl, R ⁴ is hydrogen, R ⁵ is hydrogen, is (O) oxygen or NH, and is (O) oxygen or CH 2, salts thereof. A compound of formula (I) according to claim 1, wherein r 0 is fluoro. A process for the preparation of compounds of their salts, characterized in that t (I) according to claim 1, characterized in that it comprises: a) for the preparation of compounds of formula (I), in xymethyl, reducing compounds of which R ® is hydro (II) of the formula in claim b) the cyclized compounds of formula (III) in claim 1 and X is a suitable starting group, with removal HX and, if desired, subsequent conversion of compounds (I) obtained in their salts, or, if desired, subsequent release of compounds (I) from the obtained salts of compounds (I). 7. A pharmaceutical composition comprising a compound according to claim 1 and / or a pharmaceutically acceptable salt thereof together with the usual pharmaceutical excipients and / or vehicles. Use the compound of claim 1 and pharmaceutically acceptable salts thereof for the prevention and treatment of gastrointestinal diseases. Use of the compounds of claim 1 and pharmaceutically acceptable salts thereof for the manufacture of a medicament for the prevention and treatment of gastrointestinal diseases.