CZ91997A3 - Derivatives of phenyl-oxo-alkyl-(4-piperidinyl)benzoates - Google Patents

Abstract

The present invention is concerned with novel benzoate derivatives of the general formula I, N-oxide forms, pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof, wherein Re1 represents a halogen atom or alkylsulfonylamino group, either Re2 represents a hydrogen atom and Re3 represents an alkyl group, an alkenyl group or alkynyl group; or Re2 and Re3 taken together form a bivalent radical of the general formula -CH=CH-, -(CHi2)i2-, or -(CHi)i3-, whereby in the bivalent radicals one or two hydrogen atoms may be replaced by an alkyl group, Alk represents an alkanediyl group Re4 is a hydrogen atom or an alkyloxy group, Re5, Re6 and Re7 each independently represents a hydrogen atom, a halogen atom, an alkyl group an alkyloxy group or Re5 and Re6 taken together may also form a bivalent radical of the general formula -NRe8C(O)NRe9-, -NH-C(NHRe10)=N-, -O-(CHi2)im-O-. In the present invention there are also claimed a pharmaceutical composition comprising

Description

The invention relates to novel benzoate derivatives, to pharmaceutical compositions containing said compounds, to processes for preparing the compounds and compositions, and to their medical use, in particular in the treatment of conditions involving reduced colonic motility.

BACKGROUND OF THE INVENTION

In European patent application EP-0,389,037-A, published September 26, 1990,

N- (3-hydroxy-4-piperldinyl) (dihydrobenzofuran or dihydro-2H-benzopyran) carboxamide derivatives are disclosed as being capable of stimulating gastronotestinal activity.

In European patent application EP-0,445,862-A, published September 11, 1991, there are disclosed

N- (4-piperidinyl) (dihrobenzfuran or dlhydro-2H-benzpyran) carboxamide derivatives are also described as being capable of stimulating gastrolntestinal activity. WO 93/03725 (SmlthKline Beecham), published March 4, 1993, discloses the use as 5HT4 receptor antagonist esters of the formula X-CO-YZ, wherein X may be a substituted phenyl group, Y may be an oxygen atom, and Z may be substituted piperidine residue. WO 94/08995 (SmlthKline Beecham), published April 28, 1994, also discloses 7-benzfurancarboxylates having 5HT4 antagonist activity.

The last two patent applications describe the use of 5HT4 antagonist compounds in the treatment of irritable bowel syndrome, especially its diarrhea.

It has further been discovered that the novel compounds exhibit intestinal pro-climatic activity.

Thus, the disclosed compounds can be used in the treatment of reduced bowel activity, particularly of the colon.

· E e • • • • • • • •

According to the invention

The present invention relates to novel benzoate derivatives of the general formula

N-oxide forms, pharmaceutically acceptable acid addition salts, and their ether-isomerically isomeric forms, wherein:

R ^- * is halogen or alkylsulfonamylová group containing 1 to 6 carbon atoms;

either R ² is hydrogen and R ³ is C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl;

or R ² and R ³ taken together may form a bivalent radical of the formula: -CH-CH- (a)

- <CH ₂ ) 2- (b)

-CH ₂ ) _3- (c) in radicals (a), (b), and (c), one to two hydrogen atoms may be replaced by an alkyl group containing 1 to 6 carbon atoms;

Alk is an alkanediyl group having 1 to 6 carbon atoms;

R ⁴ is a hydrogen atom or an alkyloxy group having 1 to 6 hydrogen atoms;

R ⁵ , R ⁶ and R ⁶ are each independently: a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkyloxy group having 1 to 6 carbon atoms; or R ⁵ and R ⁶ taken together may form • · · ·

a divalent radical of the general formula:

II -NR ⁸ C-NR ⁹ - (d), NH- ^R ° -NH-C = N- ^(e) - ^r ° -0- (CH2) _m -0- (I);

R ⁸ and R ⁹ are independently hydrogen or alkyl of up to 6 carbon atoms;

R ¹⁰ is hydrogen, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkyloxycarbonyl;

m is 1 or 2.

As used in the foregoing definitions, a halogen atom is a generalization for a fluorine, chlorine, bromine and iodine atom. C 1 -C 6 alkyl includes saturated straight and branched chain hydrocarbon radicals having 1 to 6 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl, hexyl, 1-methylethyl, 2-methylpropyl and the like.

The C 2 -C 6 alkenyl group includes straight and branched chain hydrocarbon radicals of 8 with one double bond containing up to 6 carbon atoms such as ethenyl, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3pentenyl a 3-methyl-2-butenyl group, a 3-hexsnyl group, and the like. 2 to 6 carbon atoms include straight and branched chain hydrocarbon radicals β One triple bond containing 2 to 6 carbon atoms, such as ethynyl, 2-propynyl,

3-butynyl, 2-butynyl, 2-pentynyl, 3pentynyl, 3-hexynyl and the like. C 1 -C 6 alkanediyl includes straight-chain and branched divalent hydrocarbon radicals having 1 to 6 carbon atoms, such as methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl , 1,5-pentanediyl, 1,6-hexanediyl.

The pharmaceutically acceptable acid addition salts contain therapeutically active non-toxic acid addition salt forms which have the ability to form compounds of formula (I). Suitable acids are, for example, inorganic acids such as hydrohalic acids, i.e. hydrochloric or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Or it contains organic acids such as acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p toluenesulfonic, pamlamic, salicic, pamoic and similar acids.

The term addition salt also includes eolvates which may be formed both from the compounds of formula (I) and from their salts.

Such solvates are eg hydrates, alcoholates and the like.

Conversely, the salt can be converted to the free base form by reaction of 8 alkali.

The above stereochemically isomeric forms include all possible isomeric forms which the compounds of formula (I) may possess. Unless otherwise stated, the chemical names of the compounds designate the emesis of all possible stereochemically isomeric forms. Said mixtures comprise all diastereomers and enantiomers of the basic molecular structure. Stereogenic centers may have the R- or S-configuration.

Substituents on divalent cyclic (partially) saturated radicals may have either the C 1- or trans configuration. The C 2 -C 6 alkenyl radicals may have an E- or Z-configuration.

Stereochemically isomeric forms of the compounds of formula (I) are, of course, included within the scope of the invention.

Certain compounds of formula (I) may also exist in their tautomeric forms. Although not specifically mentioned in the above formula, these forms are included within the scope of the invention. For example, compounds of formula (I) wherein R ⁵ and R ⁶ together form a bivalent radical of formula (d), wherein R ® and R ® or both are hydrogen atoms, may exist in their corresponding tautomeric forms.

The N-oxide forms of the compounds of formula (I) include those compounds of formula (I) wherein one or more nitrogen atoms are oxidized to the so-called N-oxide, especially those N-oxides, wherein the piperidine-nitrogen is N-oxidized.

R ¹ is a fluorine, chlorine or bromine atom, preferably chlorine.

• · · ·

R ³ , unless taken together with R ² , is preferably an alkyl group having 1 to 6 carbon atoms, preferably a methyl group.

If there are R ² and R ³ together, js preferably a bivalent radical of formula (b).

Alk is suitably a 1,2-stanediyl group, a 1,3-propanediyl group, or a 1,4-butanediyl group, preferably a 1,3-propanediyl group.

R ^{4 is} suitably a hydrogen atom or a msthoxy group. R ⁸ , R ⁸ and R ⁷ are suitably hydrogen atoms, alkyl of 1 to 6 carbon atoms, alkyloxy of 1 to 6 carbon atoms, or chlorine, preferably methyl, methoxy or hydrogen; or when R @ 8 and R @ 8 are common, a radical of formula (d) or (e), especially a radical of formula (d), is preferred.

The compounds of our interest are compounds of the general formula (I) wherein R 1 is a chlorine atom.

Other compounds of interest are those wherein the Alk Js 1,3-propanedlyl group.

Other compounds of interest of the general formula (I) are those wherein R ² and R ³ , taken together, form a bivalent radical of formula (b).

Preferably the compounds are those wherein R ®, R ® and R ⁷ are methoxy.

Also preferred are compounds wherein R ⁷ is hydrogen, and R ® and R ® taken together form a radical of formula (d), wherein R ® and R ⁹ are hydrogen atoms.

Other preferred compounds are those compounds of interest where R @ 5 and R @ ⁷ are methyl and R @ ⁸ is a methoxy group.

The most preferred compounds are:

cis-3-Methoxy-1- (4-oxo-4- (3,4,5-trimethoxyphenyl) butyl) 4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzfurancarboxylate;

1- {4-Oxo-4- (3,4,5-trimethoxyphenyl) butyl} -4-piperidinyl · 4-amino-5-chloro-2,3-dihydro-7-benzfurancarboxylate;

• · • ·

- (4- {2 _l 3-dihydro-2-oxo-1H-benzimidazol-5-yl) -4-oxobutyl) -4.piperidinyl4- amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate;

1- (4- (4-methoxy-3 _l 5-dimethylphenyl) -4-oxobutyl) -4-piperidinyl-4-amin5- chloro-2,3-dihydro-7-benzofurancarboxylate;

and their stereoisomeric forms and pharmaceutically acceptable acid addition salts thereof.

To simplify the structural representation of the compounds of formula (I) and some of their intermediates, the radical of formula will be

later represented by the symbol D and a radical of the general formula

II

C-Alk— represented by the symbol L.

In the following preparations, the reaction products can be isolated from the reaction mixtures and, if necessary, further purified according to generally known procedures, eg, extraction, distillation, crystallization, trituration and chromatography.

Compounds of formula (I) may be prepared by N-alkylating a piperidine of formula (II) with an intermediate of formula (III), wherein W ^- is a suitable leaving group such as halogen, i.e., chlorine, bromine or iodine, or sulfonyloxy, i.e. methanesulfonyloxy, toluenesulfonyloxy and the like, separating groups. The N-alkylation reaction of (II) β (III) is conveniently conducted by known alkylation procedures.

• ·

N-alkylation

LW ¹ + HD- (I) (IH) dl

Compounds of formula (I) may also be prepared by eeterification of an alcohol of formula (IV), wherein R ⁴ and L are as defined above, with a carboxylic acid of formula (V) wherein R ¹ , R ² and R ² are as defined above, or functional derivatives of a given carboxylic acid such as an acyl halide, symmetric or mixed anhydride or ester, preferably an activated ester, all according to known procedures.

(IV)

It may be beneficial to protect the amino group of the intermediate of formula (V) during the course of the reaction to avoid side reactions. Said amino is removed after completion of the esterification. Suitable protecting groups include readily removable groups such as C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkyloxycarbonyl. C 1-4 alkyl, phenylmethyl and the like protecting groups.

Compounds of formula (I) represented by the general formula (Id) wherein R ⁵ and R ⁶ ee occur together and form a radical of formula (d) can be prepared by reacting an intermediate of formula (VI) β

1,1'-carbonyl-ble-1H-imldazole or functional derivatives thereof, following known procedures.

Alk-D

(VI)

Compounds of formula (I), represented by formula (I-e), wherein R® and R® are taken together to form a radical of formula (e), may be prepared by reacting an intermediate of formula (VI) represented by formula (VI-a). ), wherein R ® and R ® are hydrogen atoms, with an intermediate of formula (VII), following known procedures.

NH

Alk-D + C 1 -alkyl-O-C-NH-R ¹⁰ (VII)

O (I-c)

The compounds of formula (I) may also be converted into one another. E.g. compounds of formula (I) wherein R ^{= 3} is hydrogen can be converted to compounds of formula (I) wherein R ¹⁰ is C 1 -C 6 alkylcarbonyl or C 1 -C 6 alkyloxycarbonyl according to known procedures .

Compounds of formula (I) wherein R ³ is C 2 -C 6 alkenyl or C 2 -C 6 alkynyl may be converted to compounds of formula (I) wherein R ³ is the corresponding saturated alkyl radical according to known procedures .

The compounds of formula (I) may also be converted to the corresponding compounds. N-oxide forms according to generally known procedures for converting a trivalent nitrogen into its N-oxide forms. Said N-oxidation may be carried out by reacting the starting compounds of formula (I) with a suitable organic or inorganic peroxide

Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali metal peroxides or alkaline earth metal peroxides, i.e. sodium peroxide, potassium peroxide. Suitable organic peroxides may include peracids, such as benzenecarboperoxo acid or a halogen substituted benzenecarboperoxo acid, i.e. 3-chlorobenzenecarboperoxo acid, furthermore peroxyalkanoic acids, i.e. peroxyacetic acid, alkyl hydroperoxides, i. tert-butyl hydroperoxide. Suitable solvents are e.g.

water, lower alcohols, i.e. ethanol and the like, hydrocarbons, i.e. methylbenzene, ketones, e.g.

···· ····

2-butanone, halohydrocarbons, i.e. dichloromethane, and mixtures of these solvents.

Intermediates of formula (II) may be prepared according to generally known procedures by esterification of a suitably substituted piperidine of formula (VIII) with an acid intermediate of formula (V) or functional derivatives thereof, followed by deprotection Ρ. P represents an easily removable protecting group such as a C 1 -C 4 alkylcarbonyl group, a C 1 -C 4 alkyloxycarbonyl group, a phenylmethyl group, and the like.

1. ester formation

- (Π)

2. Removal of P

(VHI)

The preparation of an acid intermediate of formula (V) is outlined in European patent application EP-0,389,037-A.

Intermediates of formula (VI-a) may be prepared by reducing the intermediate of formula (IX) with a suitable reducing agent, eg, by combining platinum on activated carbon and hydrogen 8 with a reaction-inert solvent such as tetrahydrofuran.

Intermediates of formula (IX) may be prepared by N-alkylating a piperidine of formula (II) with an intermediate of formula (X), a leaving group such as a halogen atom is suitable. The preparation proceeds in a similar way to the preparation of compounds of formula (I) from intermediates of formula (II) and (III).

(IX) ·· ··

Intermediates of formula (VIIIa), where P ¹ is P as defined above, as well as hydrogen, can be prepared by reduction of intermediate of formula (XI) according to known procedures. In particular, intermediates of formula (VIII ') wherein R ⁴ is C 1 -C 6 alkyloxy (these intermediates are then represented by formula (VI-T)) and wherein R ⁴ and the hydroxyl group have the cis-configuration may be prepared by reducing the intermediate of formula (XI-a) using a reducing agent such as substituted borohydrides, i.e., lithium tria (sec.butylborohydride), potassium tris (tert.butlyborohydride), substituted aluminum hydrides, lithium-trl-t-butoxyaluminohydrides and the like; a reaction-inert solvent such as tetrahydrofuran.

It may be advantageous to carry out the reaction at a lower temperature, preferably below

-70 * C. By using ether-pure reagents, said reduction can be performed in a stereospecific manner.

The cis and trans diastereomeric racemates of the compounds of formula (I), or any of the other intermediates, may be dissolved into their optical isomers, cia (+), cis (-), trans (+), and trans (-) using generally known procedures. Diastereomers can be separated by physical separation As selective crystallization and chromatographic methods, e.g., countercurrent distribution, and enantiomers can be separated from each other by selective crystallization of their diastereomeric salts with enantiomerically pure salts or their enantiomerically pure derivatives.

The compounds of formula (I) and the intermediates of formula (II) and (VI), the Noxide forms, the pharmaceutically acceptable salts, and their stereolsomeric forms exhibit beneficial gut patency properties. In particular, these compounds exhibit pronounced patency enhancing properties of the small and large intestines. These properties were supported by the results obtained in Guinea Pig lleum Coaxial Stimulation and Colon motility in conscious dog tests.

Both said tests are described later. Some of the compounds also show activity in the Lidamidine test in dogno.

·· ··

I · · <

· ⁴

In view of their useful properties, the compounds of the invention may be formulated into various forms suitable for medical purposes.

In order to prepare the pharmaceutical compositions of this invention, an effective amount of the compound, in the form of an acid or base addition salt, as an active ingredient, is admixed with a pharmaceutically acceptable carrier to form a well-mixed mixture, which carrier may take various forms depending on the method of preparation required for medical use. .

These pharmaceutical compositions are in unit dosage form suitable for oral or oral administration, or by parenteral injection.

For example, any pharmaceutical compositions such as water, glycols, oils, alcohols, and the like, may be used to prepare oral dosage compositions for the preparation of oral fluids such as suspensions, syrups, elixirs, and solutions.

Solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like can be used in the preparation of powder form, pills, capsules and tablets.

Tablets and capsules represent the most advantageous oral dosage form for ease of administration, and solid pharmaceutical carriers are obviously employed. In the case of parenteral compositions, the carrier will usually comprise sterile water, or at least for the most part, although other ingredients, such as those which increase solubility, may also be added. Injectable solutions, for example, may be prepared using a carrier comprising saline, glucose solution or a mixture of saline and glucose solution. Suitable liquid carriers, suspending agents and the like may be employed in the preparation of injectable suspensions. In the case of compositions suitable for percutaneous administration, the carriers may comprise a penetration enhancing agent and / or a suitable wetting agent, optionally combined with a small amount of suitable additives of any nature, provided that the additives must not exhibit a significant deleterious effect on the skin. Said additives may facilitate skin administration and / or may assist in the preparation of the desired compositions. These compositions can be administered in a variety of ways, e.g., as a transdermal patch, topical administration or as an ointment.

Acid addition salts of formulas (i), (II) and (VI) due to their increasing solubility in water over the corresponding base form are, of course, more advantageous for the preparation of aqueous compositions. It is particularly advantageous to prepare the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and requirements refers to physically discrete units suitable as unitary dosages, each containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effects in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including divided or encapsulated tablets), capsules, pills, sachets, cachets, injectable solutions or suspensions, preparations administered in the amount of a teaspoon or tablespoon, and segregated multiples thereof.

In view of their ability to stimulate gastrointestinal motility and in particular to increase colonic motility, the compounds of the invention are useful for stabilizing or improving gastrointestinal movement in patients suffering from symptoms associated with impaired mobility, e.g., reduced peristalsis of the small and large intestine, sometimes associated with delayed gastric emptying.

In view of the use of the compounds of the present invention, methods of treating warm-blooded animals suffering from gastrointestinal mobility disorders such as constipation, obstructive ileus, intestinal atony, postoperative intestinal atony, irritable bowel syndrome (IBS), drug-induced delayed intestinal movement, and in particular Then the damaged per i became tic of the colon. Said methods include the systematic administration of an effective amount of a compound of formula (I), a N-oxide, a pharmaceutically acceptable acid addition salt, or a possible stereoisomeric form thereof. This guarantees the use of the compounds of formula (I) as medicaments, in particular the use of the compounds of formula (I) for the manufacture of medicaments for the treatment of conditions involving reduced mobility of the colon.

The therapeutically effective amount is in the range of 0.001 mg / kg to approx. 10 mg / kg body weight, preferably from 0.02 mg / kg to 5 mg / kg body weight. The treatment method may also include administering the active ingredient on a diet two to four times a day.

In the following examples, the abbreviations "THF" for tetrahydrofuran and "

DIPE 'for diisopropyl ether.

«· · · · · · · · ·

DETAILED DESCRIPTION OF THE INVENTION

A. Preparation of intermediates

Example 1.

a) Add sodium borohydride (7.7g) to a stirred solution of 3-Methoxy-1 (phenylmethyl) -4-piperidinone (44.8g) in ethanol (610ml). The mixture was then cooled to room temperature and stirring was continued for three hours at room temperature. Concentrate the reaction mixture to about 150 mL. Add water (300ml) to the concentrate and evaporate all ethanol. After cooling, the mixture was extracted with diethyl ether. Wash the extract with water, dry, filter and evaporate. The oily residue was purified by column chromatography over silica gel using CHCl 3 / CH 3 OH 96/4 as eluent. Collect pure fractions and evaporate the eluent. The residue was separated by column chromatography over silica gel using hexane / CHCl 3 / CH 3 OH / NH 3) 50/50/1 as eluent. Collect the first fraction and evaporate the eluent. The yield was 11.5g (25.5%) of trans-3-methoxy-1- (phenylmethyl) -4-piperidinol (interm. 1). Collect the second fraction and evaporate the eluent. Yield: 7.7g (17.1%) of cis-3-methoxy-1- (phenylmethyl) -4-piperidinol (interm. 2).

and ´) A solution of 3-Methoxy-1- (phenylmethyl) -4-piperidinone (4.4g) in THF is cooled to

-75 ° C. Lithium tri-sec-butylborohydride was added dropwise and the reaction mixture was stirred for 2 hours at -70 ° C. A 10% acetic acid solution (100ml) was added dropwise at room temperature. The organic solvent was evaporated. The aqueous residue was basified with ammonium hydroxide, then the layer was washed with water, dried over magnesium sulfate, filtered and the solvent was evaporated. The residue was purified by short column chromatography, eluting with CH 2 Cl 2 ^{/ CH} 3 OH 95/5 to 98/2, yielding 1.3g (29.4%) of cis-3-methoxy-1- (phenylmethyl) -4-plperidinol (interm. 2).

b) A mixture of intermediate (2) (11.5g) and methanol (150ml) was hydrogenated at normal pressure and room temperature with two grams of 10% palladium on carbon catalyst. After obtaining the calculated amount of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue is purified by silica gel column chromatography using 85/15 CHCl 3 / (CH 3 OH / NH 3) as eluent. The pure fraction was collected and the eluent was evaporated. Yield: 3.6g (53%) of cis-3-methoxy-4-piperidinol as an oil

I of the remainder (intermediate 3).

c) A solution of bls (1,1'-dimethylethyl) dicarbonate (65.5g) in CHCl 3 (10ml) was added dropwise to a solution of intermediate (3) (34g) in CHCl 3 (350ml) and the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture is washed with water and ammonia, then with water. The separated organic layer was dried over magnesium sulfate, filtered and the solvent was evaporated. The residue (79g) was purified by column chromatography over silica gel using eluent

CH 2 Cl 2 ^/ (CH 3 OH / NH ₃ ) in a ratio of 97/3 to 95/5.

Pure fractions were collected and the solvent was evaporated, yielding 58g of (±) -1,1-dimethylethyl C 18 -4-hydroxy-3-methoxy-1-piperidinecarboxylate (96.4% of the unpurified residue) (interm. 4).

d) Sodium hydride (4g) was added to a solution of intermediate (4) (19.4g) in 400 ml of tetrahydrofuran. The mixture was stirred and refluxed for three hours (solution I). 1,1'-carbonyl bie-1H-imidazole (13.6g) was added to a suspension of 4-amino-5-chloro-2,3-dlhydro-2,2-dimethyl-7-benzfurancarboxylic acid (16g) in acetonitrile (400ml) . The mixture was stirred at room temperature for 2 hours. The solvent was evaporated.

Dissolving the residue in tetrahydrofuran (400ml) θθ gives solution II. Solution IIe is poured into solution I at room temperature and the reaction mixture is stirred for 2 hours at room temperature. The solvent was evaporated. The residue was partitioned between CH 2 Cl 2 and H 2 O. The organic layer was separated and the aqueous layer was extracted twice with CH2Cl2.

The separated organic layer was dried over magnesium sulfate, filtered and the solvent was evaporated.

The residue was purified by column chromatography over silica gel, eluting with CH 2 Cl 2 / CH 3 OH 98/2. The desired fractions were collected and the solvent was evaporated. There was obtained 32g of (±) - cis - 1 - ((1,1-dimethylethylethoxy) carbonyl) -3-methoxy-4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzfurancarboxylate (87%) (interm. 5). ).

• · · ·

θ) A mixture of intermediate (5) (32g) in tetrahydrofuran (500ml) and hydrochloric acid (50ml) was stirred and heated to reflux for 30 min. The reaction mixture was cooled and basified with ammonium hydroxide. The layers were separated. The aqueous layer was extracted with tetrahydrofuran. The separated organic layer was evaporated and the residue purified by column chromatography over silica gel using CH 2 Cl 2 / CH 3 OH / NH 3 93/7. The pure fraction was collected and the solvent was evaporated. The residue crystallized from acetonitrile. The precipitate is filtered, desiccated in vacuo (80 C ^e). The yield was 6.4g of (+) - 18-methoxy-4-piperidinyl-4-amine-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzfurancarboxylate (26%) (interm. 6).

Example 2.

a) A mixture of 4-amino-5-chloro-2,3-dihydro-7-benzfurancarboxylic acid (# 3g) in thionyl chloride (100ml) and CHCl 3 (200ml) was stirred and refluxed for two hours. Cool the mixture and evaporate the solvent. Add toluene and evaporate again. Yield: 4.8g of 4-amino-5-chloro-2,3-dihydro-7-benyfurancarbonyl chloride (100% unpurified residue) (interm. 7).

b) Stir a solution of 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate (4.02g) and N, N-dimethyl-4-pyridinamine (3.7g) in dichloromethane (200ml) at room temperature. A solution of intermediate (7) (4.8g) in CH 2 Cl 2 (200ml) was poured into solution. Stir the reaction mixture for three hours at room temperature. Wash the mixture with water, 5% sodium hydroxide solution and again with water. Separate the organic layer, dry over magnesium sulfate and filter, and evaporate the solvent. The residue (7.4g) was purified by column chromatography over silica gel using CH 2 Cl 2 / CH 3 OH 98/2 as eluent. Pure fractions Collect and evaporate the solvent. Yield: 4.7g of 1,1-dimethylethyl 4 - (((4-amino-5-chloro-2,3-dihydro-715- (benzfuranyl) carbonyl) oxy) -1-piperidinecarboxylate (59%) (intermediate 8) .

c) Stir and heat the mixture of intermediate (8) (7g) in tetrahydrofuran (20ml) and hydrochloric acid (20ml) for two hours. Cool the reaction mixture and basify with ammonium hydroxide. Remove the organic layer by decantation and evaporate the solvent. The residue is purified by column chromatography over silica gel using eluent (92/92/92). Pure fractions were collected and the solvent was evaporated. Purify the residue (5.5g) by high performance liquid chromatography (column: 200g Kromasil, 1µm, 100 Aeluent: 0.5% NH 4 OAc in water / methanol 70/30). Collect pure fractions and extract with NH3 / CH2Cl2 · Evaporate the extract. The residue was crystallized from acetonitrile. Filter the precipitate and dry (vacuum, 70 ° C). The yield was 2.60g of 4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benfurancarboxylate (54%) (interm. 9).

Example 3.

a) A mixture of cyclopropyl (4-amino-3-nitrophenyl) methanone (80g), prepared as described in US-3,657,267, and 420ml of concentrated hydrochloric acid are stirred and heated to reflux for 30min. Cool the reaction mixture and add water. The precipitate was filtered off, washed with water and dried. Yield

It is 80g (84.5%) of 1- (4-amino-3-nitrophenyl) -4-chloro-1-butanone, m.p. 150 DEG C. (interm. 10).

b) A mixture of intermediate (9) (14.8g), intermediate (10) (12.13g) and N, N-diethylethanamine (8.3ml) in Ν, Ν-dimethylformamide (150ml) was stirred for 20 hours at a temperature of about 70 C. Evaporate the solvent . Dilute the residue with water and extract twice with CH 2 Cl 2. Wash the separated organic layer with water, dry over magnesium sulfate, filter, and evaporate the solvent. The residue was purified by column chromatography over silica gel using CH 2 Cl 2 / CH 3 OH 90/10 as eluent. Collect the desired fractions and evaporate the solvent. The residue (10 g) was crystallized from diisopropyl ether. Filter and dry the precipitate. Yield: 8.3g (33%) of 1- (4- (4-amino-3-nitrophenyl) -4-oxobutyl) -4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzfurancarboxylate (interm. 11) .

c) A mixture of intermediate (11) (8.2g) in tetrahydrofuran (150ml) is hydrogenated with platinum on activated carbon (5%) (2g). After obtaining H2 (3), the catalyst is filtered off over dicalite and the filtrate is evaporated. Dilute the residue with water and extract twice with CH 2 Cl 2. Wash the separated organic layer with water, dry over magnesium sulfate, filter, and evaporate the solvent. The residue (8g) was purified by column chromatography over elicica gel using CH 2 Cl 2 / CH 2 OH / NH 4 (92/8) as eluent. Collect pure fractions and evaporate the solvent. The residue (7.5g) was crystallized from CH 3 CN. Filter and dry the precipitate. Yield: 5.43g (70.5%)

- (4- (3,4-diaminophenyl) -4-oxobutyl) -4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzfurancarboxylate, m.p. 173.4 ^e C (interm. 12).

B. Preparation of end products

Example 4.

A mixture of intermediate (6) (2.3g), 4-chloro-1- (3,4,5-trimsthoxyphenyl) -1-butanone (2g), sodium carbonate (2.1 g) and potassium iodide (catalytic amount) in 4-methyl Stir -2-psntanone (150ml, previously dried over magnesium sulphate) and heat at reflux overnight. The reaction mixture was cooled, washed with water, dried over magnesium sulfate, filtered and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using CH 2 Cl 2 to CH 2 Cl 2 / (CH 3 OH / NH 3) 97/3 as eluent. Collect pure fractions and evaporate the solvent. Dissolve the residue in methanol and convert to ethanedioic acid β by ethanedioic acid (0.6g). Boil the mixture, cool and filter the precipitate and recrystallize from 2-propanol. Dissolve the precipitate in aqueous NH 4 OH / CH 2 Cl 2. Separate the organic layer, dry over magnesium sulfate, filter, and evaporate the solvent. Stir the residue in the boiling diisopropyl ether, cool and filter the resulting precipitate (vacuum, 80C). The yield is 1.1 g of (±} - C 18 -3-methoxy-1- {4-oxo-4- (3,4,5-trimethoxyphenyl) butyl) -4-piperidinyl-4-amino-5-chloro-2,3-dihydro -7-benzfurancarboxylate (28%), m.p.

132.3 ° C (compound 1).

In a similar way we prepare:

1- (4-Oxo-4- (3,4,5-trimethoxyphenyl) butyl) -4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzfurancarboxylate: ethanedioate (1: 1), b. mp 177.8 ° C (compound 2);

1- {4- (4-Ethylphenyl) -4-oxobutyl) -4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzfurancarboxylate, mp 121.3 ° C (Compound 3);

- (4- (3,5-Dichlorophenyl) -4-oxobutyl) -4-piperidinyl-4-amino-5-chloro-2,3-dihydrobenzfurancarboxylate, m.p. 122.6 ° C (compound 4);

- (4- (3,4-Dimethoxyphenyl) -4-oxobutyl) -4-piperidinyl-4-amine-5-chloro-2,3-dihydro-7-benzfurancarboxylate, m.p. 156.3 ° C (compound 5);

1- (4- {4-Methoxyphenyl) -4-oxobutyl-4-piperidinyl-4-amine-5-chloro-2,3-dihydro-7-benzfurancarboxylate, m.p. 136.4 ° C (compound 6);

1- (4- (4-Methoxy-3,5-dimethylphenyl) -4-oxobutyl) -4-piperidinyl-4-amine-5-chloro-2,3-dihydro-7-benzfurancarboxylate (E) -2-butenedioate, b mp 171.2 ° C (compound 7);

Example 5.

Add 4- <4-Hydroxy-1-piperidinyl) -1- (3,4,5-trimethoxyphenyl) -1-butanone (3.3g) to a solution of sodium hydride (0.4g) in tetrahydrofuran (10ml) (solution I) in the presence of nitrogen. A mixture of 5-amino-6-chloro-3,4-dihydro-2H-1-benzpyran-8-carboxylic acid (2: 14g) and 1,1'-carbonylbis-1H-imidazole (2g) in acetonitrile (100ml) was stirred for for two hours at room temperature and evaporate the solvent. Dissolve the residue in tetrahydrofuran (10ml) (solution II). Pour solution (II) into solution (I) at room temperature and stir the reaction mixture for four hours. Evaporate the solvent. Dilute the residue with water and extract twice with CH 2 Cl 2. Wash the separated organic layer with water, dry over magnesium sulfate, filter, and evaporate the solvent.

The residue was purified by column chromatography over ell-gel using eluent

CH 2 Cl 2 / hexane / (CH 3 OH / NH 3) 50/42/3. Desired fractions Collect and evaporate the solvent. Purify the residue (2.3g) by high performance liquid chromatography over silica gel using CH 2 Cl 2 / CH 3 OH 90/10 as eluent. Pure frakoe Collect and evaporate the solvent. Allow the residue (1.2g) to crystallize from diisopropyl ether. Filter the precipitate and dry. Yield: 0.93 g of 1- {4-oxo-4- _(3-I 4 ₁ 5-trimethoxyphenyl) butyl) -4-piperidinyl-5-amino-6-chloro-3,4-dihydro-2H-benzopyran-8-carboxylate, b. M.p. 112.7¾ (compound 8).

In a similar way we prepare:

1- (4-Oxo-4- (3,4,5-trimethoxyphenyl) butyl) -4-piperidinyl-4-amino-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzfurancarboxylate, m.p. 154.2 ° C (compound 9);

1- {4-Oxo-4- (3,4,5-trimethoxyphenyl) butyl} -4-piperidinyl-4-amino-5-chloro-2-methoxybenzoate monohydrate, m.p. 90 ° C (compound 10); 1- (4-Oxo-4- (3,4,5-trimethoxyphenyl) butyl) -4-piperidinyl-4-amino-5-chloro-2-methyl-7-benzfurancarboxylate, m.p. 128.6 ° C (compound 11).

Example 6.

A mixture of intermediate (12) (2.4g) and hydrochloric acid (a few drops) in water (50ml) was stirred at room temperature. Add a solution of potassium isocyanates (2.5g) in water (50ml) and stir the resulting reaction mixture and heat at reflux for two hours. Cool the reaction mixture, basify with ammonium hydroxide and then extract with CH 2 Cl 2.

Dry the separated organic layer over magnesium sulfate, filter, and evaporate the solvent. Mix the residue (2.5g) with β-1'-carbonylbis-1 Himidazole (0.93g) in tetrahydrofuran (80ml). Stir and heat the reaction mixture for two hours. Evaporate the solvent. Dilute the residue with water and extract this mixture twice with CH 2 Cl 2. The separated organic layer was washed with water, dried over magnesium sulfate, filtered and the solvent was evaporated. The residue was crystallized from 2-propanol / methanol. Filter and dry the precipitate.

Yield: 0.53g of 1- (4- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -4-oxobutyl) -4-piperidinyl-4-amino-5-chloro-2,3-dihydro- 7-Benzfurancarboxylate (21.2%), m.p.

272.7 'C (compound 12).

Example 7.

A mixture of intermediate (12) (1.8g), methyl U-imino-α-methoxymethylcarbamate (0.5g) and acetic acid (0.75ml) in CHCl 3 (10ml) was stirred and heated under reflux for two days. Basify the reaction mixture with ammonium hydroxide. Separate the organic layer and extract the aqueous layer 8 CH 2 Cl 2 · Wash the combined organic layers with water, dry over magnesium sulfate, filter, and evaporate the solvent. The residue was crystallized from methanol. Filter and dry the precipitate. The yield is 0.4g of 1- (4- (2 - ((methoxycarbonyl) amine) -1H-benzimidazol-5-yl) -4-oxobutyl) -4-piperidinyl-4-amino-5-chloro-2,3-dihydro- 7-benzfurancarboxylate monohydrate (18.7%), m.p. 201.6 ° C (compound 13).

C. Pharmacological examples

Example 8: Guinea Pig lleum Coaxial Stimulation

Dunkin Hartley guinea pigs of both sexes (body weight ± 500g) are killed by decapitation. Remove the intestine and clean with a warm and oxygenated Henaeleite solution. Inside, intact bowel segments 4.5 cm in length was suspended vertically β preload of 1 g in 100 ml Krebs-Heneeleitova solution (37.5 ° C), carbonated mixture of 95% O ₂ and 5% _of CO. Along the entire length of the intestinal segment, tranemural excitation is applied using two platinum electrodes, the anode being passed through the intestinal lumen and the cathode inserted into the bath. The preparation is excited by a simple rectangular stimulus from the programmable emulator (1 msec, 0.1 Hz, submaximal sensitivity - current to 80% maximum sensitivity). Contraction ee is measured isometrically.

During the 30 min stabilization period, the ee segments are repeatedly stretched to 2 g to obtain a stable 1 g voltage. Prior to electrical stimulation, the cumulative dose sensitivity acetylcholine curve is given. Electrical stimulation is initiated at supramaximal current to determine the maximum amplitude of the response twitches. When these twitches stabilize, ee-max stimulation is introduced to obtain the desired 80% maximum response until the twitch responses are constant for at least 15 min. One portion of the test compound is then added to the bath. The amplitude of the twitch responses five minutes after administration of the test compound is compared to the amplitude before administration of the test compound. Compounds 1, 2, 7 and 13 showed an increase in the amplitude of the tubular responses by more than 5% at concentration

3.10 ^-9 M.

Example 9: Mobility of conscious dogs

Female beagles weighing 7-17 kg are implanted under general anesthesia and aseptic conditions with isometric force transducers sewn to the intestine at 8, 16, 24 and 32 cm from the ileocecal valve. Dogs are in convalescence after at least two weeks. Experiments may start after ± 20 hours of fasting, ad libitum water.

During experiments, dogs can move freely in the cage due to the telemetry (wireless) system. The cages are housed in a specially adapted room provided with glass that transmits light in one direction only, ie the observer sees the dogs while they do not see him. In this way it is possible to observe changes in the behavior of dogs and their defecation. Information issued by power converters in digital form is transmitted by means of a small special carrier, placed in a vest, which the dog is wearing. Signals They are received via a microphone above each cage and transmitted to a central computer system.

One of the parameters examined in this assay is the dog defecation that is observed during the first three hours after administration of the test compound. Compounds 1,2, 5, 6, 12 and 13 have been shown to induce defecation in at least 50% of the test animals at a dosage of 0.31 mg / kg during the first three hours.

D. Examples of composites

The following preparations are exemplary pharmacological composites in dosage form suitable for continuous or occasional administration to warm-blooded animals and are in accordance with the invention.

The active ingredient (A.1) used in the following examples relates to a compound of formula (I), an N -oxide form, a pharmaceutically acceptable acid addition salt, or an ether-isomerically isomeric form thereof.

Example 10: Oral Solutions

Dissolve 9 g of methyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxybenzoate in 4 l of boiling purified water. Dissolve the first 10g of 2,3dihydroxybutanedioic acid in 3L of this solution and then 20g of A.l. Mix this solution with the rest of the original solution and add 11 1,2,3-propanetriol and 3 L of 70% sorbitol. Dissolve 40g of sodium saccharin in 0.5I of water and add 2ml of raspberry and 2ml of gooseberry essences. Mix this solution with the original solution, add water q.s. to a volume of 20I to obtain an oral solution containing 5 mg A.l. for One teaspoon (5ml). The resulting solution is filled into suitable containers.

Example 11: Capsules

Mix 20g A.I., 6g lauryl sodium sulfate, 56g starch, 56g lactose, 0.8g colloidal silica and 1.2g magnesium stearate thoroughly. The resulting mixture is then filled into 1000 suitable hardened gelatin capsules, each containing 20mg of A.I.

Example 12: Encapsulated tablets

a) Content preparation

The mixture of 10 g A.I., 570 g lactose and 200 g starch is well mixed and then moistened with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone in approx. 200ml water. Sieve the wet powder mixture, dry and sieve again. Then add 10g of microcrystalline cellulose and 15g of hydrogenated vegetable oil. Mix well and compress into tablets. We get 10,000 tablets, each containing 10mg A.l.

b) Packaging

To a solution of 10g methylcellulose in 75 ml of denatured alcohol, add a solution of 5g of ethylcellulose in 150ml of dichloromethane. Then add 75 ml of dichloromethane and 2.5 ml of 1,2,3-propanetriol. Melt 1 g of polyethylene glycol and dissolve it in 75 ml of dichloromethane. Add this solution to the original solution. Next, add 2.5g of magnesium octane decanoate, 5g of polyvinylpyrrolidone and 30ml of concentrated color suspension and homogenize everything. The thus obtained coating is used to coat the contents of tablets in

Example 13: Injectable solutions

1.8 g of methyl 4-hydroxybenzoate and 0.2 g of propyl 4-hydroxybenzoate are dissolved in about 0.5 l of boiling water. After cooling to approx. 50 ‘C add 4g lactic acid, 0.05g propylene glycol and 4g A.l. Cool the solution to room temperature and make up to a volume of 11 with water. We obtain a solution of 4mg / ml A.l. Sterilize the solution by filtration (U.S.P.XVII p. 811) and fill into sterile containers.

Example 14: Suppositories

3g A.l. dissolve in a solution of 3g 2,3-dihydroxybutanedioic acid in 2ml polyethylene glycol 400.

Melt the surface active agent 12 G with triglycerides q.s. k 300g.

Mix this mixture thoroughly with the original solution.

The mixture thus obtained is poured into molds at a temperature of 37-38 C. We obtain 100 suppositories, each containing 30mg A.l.

• · · · · ·

Claims (10)

PATENT CLAIMS 1. Compound of formula (I) N-oxide form, pharmaceutically acceptable acid addition salts or stereochemical derivatives thereof, characterized in that it is a halogen atom or an alkylsulfonylamino group; either R ² is a hydrogen atom and R ³ is an alkyl group of up to 6 carbon atoms, an alkenyl group of 2 to 6 carbon atoms or an alkynyl group containing 2 to 6 carbon atoms; or R ² and R ³ together form a bivalent radical of the formula: -CH = CH- (a), - (CH ₂₎ 2 (b) - (CH ₂ ) ₃ - (c); in the bivalent radicals of formula (a), (b) or (c), one or two hydrogen atoms may be replaced by an alkyl group containing up to 6 carbon atoms; Alk is an alkanediyl group having 1 to 6 carbon atoms; R ⁴ is hydrogen or C 1 -C 6 alkyloxy; R ³ , R ® and R? are independently hydrogen, halogen, C1-C6alkyl, C1-C6alkyloxy; or R ³ and R ® together may form a bivalent radical of the formula: • · · ··· · »« (Φ. O II-NR ^{S *} -C-NR ⁹ n-R ¹⁰ -NH-C = N- ( ^c ) ^-or -O- (CH ₂ ) _m -O- (s); R ⁸ and R ⁹ are independently hydrogen or C 1 -C 6 alkyl; R ¹⁰ is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyloxycarbonyl; m is 1 or 2. Compound according to claim 1, characterized in that R 6 is a chlorine atom. 3. A compound according to claim characterized in that R ² and R ³ together form a bivalent radical of formula (b). 4. A compound according to claim 1, wherein: Alk is 1,3-propanediyl. A compound according to claim 1 wherein the compound is cis-3-Methoxy-1- (4-oxo-4- (3,4,5-trimethoxyphenyl) butyl) -4-piperidinyl-4-amino-5-chloro -2,3-dihydro-7-benzfurancarboxylate; 1- {4-Oxo-4- (3,4,5-trimethoxyphenyl) butyl) -4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzfurancarboxylate; - (4- (2,3-Dihydro-2-oxo-1Abenzimidazol-5-yl) -4-oxobutyl) -4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzfurancarboxylate; 1- (4- (4-Methoxy-3,5-dimethylphenyl) -4-oxobutyl) -4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzfurancarboxylate; and the ether-isomeric forms thereof, or a pharmaceutically acceptable acid addition salt thereof. • «• · · · A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier. 7. A process for preparing a pharmaceutical composition according to claim 1 wherein the compound of claim 1 is intimately mixed with a pharmaceutically acceptable carrier. A compound according to claim 1 for use as a medicament. Use of a compound according to claim 1 for the manufacture of a medicament for the treatment of intestinal disorders including reduced colonic motility. N-oxide forms, pharmaceutically acceptable acid addition salts, or 8-isomeric forms thereof, characterized in that: R ¹ to R ⁴ , r ⁷ _and Alk are as defined in claim 1. Process for preparing a compound according to claim 1, characterized in that (a) the piperidine of formula (II) is N-alkylated with an intermediate of formula (III); LW ¹ + h — D (ΙΠ) (II) / N-alkylation - (I) characterized by being a suitable leaving group, L is a radical of the general formula • · o ιι C-Alkyl characterized in that Alk and R ® to R ⁷ are as defined in claim 1, and D is a radical of the formula R ^q characterized in that R ¹ to R ⁴ are as defined in claim 1; b) an alcohol of formula (IV) reacted with a carboxylic acid of formula (V) or a functional derivative thereof, such as an acyl halide, symmetrical or mixed anhydride or ester; L - b / OH (IV) (0 c) an intermediate of formula (VI) reacted with 1,1'-carbonylbis-1 Himidazole or a functional derivative thereof, and the compound of formula (1-d) thus prepared; (VI) (1-d) d) an intermediate of formula (VI-a) reacted with an intermediate of formula (VIIa) and the compound of formula (i-e) thus prepared; • · · · · · · I · · ⁴ About NH II li C-Alk-D + C 1-6 alkyl-OC-NH-R ¹⁰ (VII) and optionally converting compounds of formula (I) into themselves by a functional group transformation reaction; and, if desired, converting a compound of formula (I) into a pharmaceutically acceptable acid addition salt, or vice versa, converting the acid addition salt into the free base form with alkali, and / or preparing stereochemically isomeric forms thereof.