ES2384242T3 - 4- (Aminomethyl) piperidinbenzamides substituted with aminosulfonyl as 5HT4 antagonists - Google Patents

Abstract

A compound of formula (I) one of its stereochemically isomeric forms, one of its N-oxide forms, or one of its pharmaceutically acceptable acid or base addition salts, wherein -R1-R2- is a bivalent radical of formula-O -CH2-O- (a-1), - O-CH2-CH2- (a-2), - O-CH2-CH2-O- (a-3), - O-CH2-CH2-CH2- (a -4), - O-CH2-CH2-CH2-O- (a-5), - O-CH2-CH2-CH2-CH2- (a-6), - O-CH2-CH2-CH2-CH2-O - (a-7), - O-CH2-CH2-CH2-CH2-CH2- (a-8), where in said bivalent radicals optionally one or two hydrogen atoms of the same carbon atom or of different carbon atoms can be replace with C1-6 alkyl or hydroxy, R3 is hydrogen, halo, C1-6 alkyl or C1-6 alkyloxy; R4 is hydrogen, halo, C1-6 alkyl; C1-6 alkyl substituted with cyano or C1-6 alkyloxy; C1-6 alkyloxy; cyano, amino or, mono- or di (C1-6 alkyl) amino; R5 is hydrogen or C1-6 alkyl and the radical -OR5 is located at the 3 or 4 position of the piperidine moiety; L is a radical of formula -Alq -R6, wherein Alk is C1-4 alkanediyl; and R 6 is aminosulfonyl or aminosulfonyl substituted with C 1-4 alkyl or phenyl

Description

4- (Aminomethyl) piperidinbenzamides substituted with aminosulfonyl as 5HT4 antagonists

The present invention relates to new compounds of formula (I) that exhibit 5HT4 antagonistic properties. The invention further relates to methods for preparing these new compounds, pharmaceutical compositions comprising these new compounds as well as the use of said compounds as a medicament.

WO-00/37461 discloses bicyclic benzamides of 4- (aminomethyl) piperidine derivatives substituted at the 3 or 4 position having 5HT4 antagonistic properties.

The compounds of the present invention differ structurally from the compounds known in the art cited by the presence of a different radical radical moiety.

Unexpectedly, the present compounds of formula (I) have better metabolic stability properties compared to the compounds described in WO-00/37461.

The present invention relates to compounds of formula (I)

one of its stereochemically isomeric forms, one of its N-oxide forms, or one of its pharmaceutically acceptable acid or base addition salts, where -R1-R2- is a bivalent radical of formula

-O-CH2-O

(a-1),

-O-CH2-CH2

(a-2),

-O-CH2-CH2-O

(a-3),

-O-CH2-CH2-CH2

(a-4),

-O-CH2-CH2-CH2-O

(to 5),

-O-CH2-CH2-CH2-CH2

(a-6),

-O-CH2-CH2-CH2-CH2-O

(a-7),

-O-CH2-CH2-CH2-CH2-CH2

(a-8),

wherein in said bivalent radicals optionally one or two hydrogen atoms of the same carbon atom or of different carbon atoms may be replaced by C1-6 alkyl or hydroxy,

R3 is hydrogen, halo, C1-6 alkyl or C1-6 alkyloxy;

R4 is hydrogen, halo, C1-6 alkyl; C1-6 alkyl substituted with cyano or C1-6 alkyloxy; C1-6 alkyloxy; cyano, amino or, mono- or di (C1-6 alkyl) amino; R5 is hydrogen or C1-6 alkyl and the radical -OR5 is located at position 3 or 4 of the piperidine moiety; L is a radical of the formula -Alq-R6, wherein Alq is C1-4 alkanediyl; Y R 6 is aminosulfonyl or aminosulfonyl substituted with C 1-4 alkyl or phenyl.

As used in the above definitions, halo is a generic term for fluoro, chloro, bromo and iodo; C1-4 alkyl defines saturated straight or branched chain hydrocarbon radicals containing 1 to 4 atoms carbon such as, for example, methyl, ethyl, propyl, butyl, 1-methyl ethyl, 2-methylpropyl and the like; The intention is to that C1-6 alkyl includes C1-4 alkyl and higher homologs thereof containing 5 or 6 carbon atoms, such as, for example, 2-methylbutyl, pentyl, hexyl and the like; C3-6 cycloalkyl is a generic term for cyclopropyl,

cyclobutyl, cyclopentyl and cyclohexyl; C1-12 alkanediyl defines bivalent straight or branched chain hydrocarbon radicals containing from 1 to 12 carbon atoms such as, for example, methanediyl, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5- Pentanediyl, 1,6-hexanediyl, 1,7-heptanediyl, 1,8-octanediyl, 1,9-nonanodiyl, 1,10-decanediyl, 1,11-undecanediyl, 1,12-dodecanediyl and branched isomers thereof. C 1-4 alkanediyl defines bivalent straight or branched chain hydrocarbon radicals containing from 1 to 4 carbon atoms such as, for example, methanediyl, 1,2-ethanediyl, 1,3-proponediyl and 1,4-butanediyl.

The term "aminosulfonyl" refers to a radical of the formula

The term "stereochemically isomeric forms", as used hereinbefore, defines all possible isomeric forms that the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of the compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More particularly, stereogenic centers may have the R or S configuration; Substituents on (partially) saturated bivalent cyclic radicals may have the cis or trans configuration. Compounds containing double bonds may have an E or Z stereochemistry in said double bond. Obviously, it is intended that the stereochemically isomeric forms of the compounds of formula (I) be contemplated by the scope of this invention.

It is intended that the pharmaceutically acceptable acid or base addition salts mentioned hereinbefore comprise the therapeutically active non-toxic acid or base addition salt forms that the compounds of formula (I) are capable of forming. Pharmaceutically acceptable acid addition salts can be conveniently obtained by treating the basic form with a suitable acid. Suitable acids comprise, for example, inorganic acids, such as hydrogen halides, e.g. eg, hydrochloric or hydrobromic, sulfuric, nitric, phosphoric acid and the like; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e., ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic acid , ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like.

Conversely, said salt forms can be converted into the free base form by treatment with a suitable base.

Compounds of formula (I) containing an acidic proton can also be converted into their non-toxic amine or metal addition salt forms by treatment with suitable organic and inorganic bases. Suitable base addition salt forms comprise, for example, ammonium salts, alkali metal or alkaline earth metal salts, e.g. eg, salts of lithium, sodium, potassium, magnesium, calcium and the like, salts with organic bases, e.g. eg, the benzathine, N-methyl-D-glucamine and hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.

The term "addition salt", as used hereinbefore, also comprises the solvates that the compounds of formula (I) are capable of forming as well as their salts. These solvates are, for example, hydrates, alcoholates and the like.

Some of the compounds of formula (I) may also exist in their tautomeric forms. Although these forms are not explicitly indicated in the above formula, they are intended to be included within the scope of the present invention.

It is intended that the N-oxide forms of the compounds of formula (I), which can be prepared in ways known in the art, comprise those compounds of formula (I) in which one or more nitrogen atoms are oxidized in form of N-oxide. Particularly, those N-oxides in which the nitrogen of piperidine is N-oxidized are contemplated.

A group of interesting compounds consists of those compounds of formula (I) in which one or more of the following restrictions apply: a) -R1-R2- is a radical of formula (a-3); I

b) -R1-R2- is a radical of formula (a-5); and / or c) R3 is hydrogen, halo, methyl or methoxy; and / or d) R4 is hydrogen, halo, methyl, cyano, amino or C1-4 alkylamino; and / or e) R4 is fluoro; and / or f) R5 is hydrogen or methyl, and the radical -OR5 is located at position 3 or 4 of the piperidine ring; and / or g) R5 is hydrogen or methyl, and the radical -OR5 is located at position 3 of the piperidine ring; and / or h) R5 is hydrogen, and the radical -OR5 is located at position 4 of the piperidine ring; and / or i) the radical -OR5, in which R5 is hydrogen or methyl, is located at position 3 of the piperidine ring and is in trans position relative to methylene at position 4 of the piperidine moiety; and / or j) the radical -OR5, in which R5 is hydrogen or methyl, is located at position 3 of the piperidine ring and is in a trans position relative to methylene at position 4 of the piperidine moiety and the absolute configuration of said moiety

5 piperidine is (3S, 4S); I k) L is a radical of the formula -Alq-R6 in which Alq is C1-4 alkanediyl and R6 is aminosulfonyl or aminosulfonyl substituted with C1-4 alkyl or phenyl;

Other interesting compounds are those compounds of formula (I) in which

10 -R1-R2- is a bivalent radical of the formula -O-CH2-CH2-O- (a-3), -O-CH2-CH2-CH2-O- (a-5),

R3 is hydrogen, halo, C1-6 alkyl or C1-6 alkyloxy;

R4 is hydrogen, halo, C1-6 alkyl; cyano; amino or mono- or di (C1-6 alkyl) amino; R5 is hydrogen or C1-6 alkyl, and the radical -OR5 is located at the 3 or 4 position of the piperidine moiety; L is a radical of formula

-Alq-R6

20 wherein Alk is C1-4 alkanediyl; and R 6 is aminosulfonyl optionally substituted with C 1-4 alkyl or phenyl.

Particular compounds are those compounds of formula (I) in which the radical -OR5, which preferably represents hydroxide or methoxide, is located in position 3 of the piperidine moiety with trans configuration, that is, the radical -OR5 is in position trans with respect to the methylene of the piperidine residue.

The most particular compounds are those compounds of formula (I) in which the bivalent radical -R1-R2- is a radical of formula (a-3) or (a-5), the radical -OR5 represents hydroxy and is located at position 3 of the 30 piperidine residue with configuration (3S-trans) corresponding to the absolute configuration (3S, 4S) of said piperidine residue.

Preferred compounds are those most particular compounds in which L is a radical of the formula -Aq-R6 in which Alk is C1-4 alkanediyl and R6 is aminosulfonyl or aminosulfonyl substituted with C1-4 alkyl or phenyl.

The compounds of formula (I) can be prepared by reacting an intermediate of formula (II) with a carboxylic acid derivative of formula (III) or optionally a reactive functional derivative thereof such as, e.g. eg, carbonylimidazole derivatives, acyl halides or mixed anhydrides. Said formation of amides can be carried out by stirring the reagents in a suitable solvent, optionally in the presence of a base, such as

40 triethylamine

The compounds of formula (I) can also be prepared generally by N-alkylation of a

Intermediate of formula (V) with an intermediate of formula (IV), wherein W is a suitable leaving group such as, for example, halo, e.g. eg, fluoro, chloro, bromo, iodo or in some cases W can also be a sulfonyloxy group, e.g. eg, methanesulfonyloxy, benzenesulfonyloxy, trifluoromethanesulfonyloxy and similar reactive leaving groups. The reaction can be carried out in an inert reaction solvent such as, for example, acetonitrile, 2-pentanol, isobutanol, dimethylacetamide or DMF, and optionally in the presence of a suitable base such as, for example,

50 sodium carbonate, potassium carbonate, N-methylpyrrolidone or triethylamine. Stirring can increase the speed of the reaction. The reaction is conveniently carried out at a temperature between room temperature and the reflux temperature of the reaction mixture.

Alternatively, compounds of formula (I) can also be prepared by reductive N-alkylation of an intermediate of formula (V) with an intermediate of formula L '= O (VI), in which L' = O represents a derivative of formula LH where two geminal hydrogen atoms are replaced with oxygen, by reductive Nalkylation procedures known in the art.

Said reductive N-alkylation can be carried out in an inert reaction solvent such as, for example, dichloromethane, ethanol, toluene or a mixture thereof, and in the presence of a reducing agent such as, for example, a borohydride, p. eg, sodium borohydride, cyanoborohydride or sodium triacetoxyborohydride. It may also be convenient to use hydrogen as a reducing agent in combination with a suitable catalyst such as, for example,

15 palladium on coal or platinum on coal. In the case where hydrogen is used as a reducing agent, it may be convenient to add a dehydrating agent to the reaction mixture such as, for example, aluminum tert-butoxide. To prevent unwanted hydrogenation of certain functional groups in reagents and reaction products from occurring, it may also be convenient to add a suitable catalyst poisoning agent to the reaction mixture, e.g. eg, thiophene or quinoline-sulfur. To increase the speed of the

In the reaction, the temperature can be raised within a range between room temperature and the reflux temperature of the reaction mixture, and optionally the pressure of the hydrogen gas can be increased.

The intermediates of formula (V) can be prepared by reacting an intermediate of formula (VII), where PG

25 represents a protective group known in the suitable art such as, for example, tert-butoxycarbonyl or a benzyl group or a photoeliminable group, with an acid of formula (III) or a suitable reactive functional derivative thereof such as, for example, carbonylimidazole derivatives, and then protecting the intermediate formed in this way, that is, removing the PG by methods known in the art.

The compounds of formula (Ia), defined as compounds of formula (I) in which R3 is hydrogen and R4 is amino, can generally be prepared by N-alkylation of an intermediate of formula (II) with an acid-type derivative carboxylic of formula (III-a). Said N-alkylation reaction can be carried out by stirring the

Reagents in a suitable solvent, optionally in the presence of a base, such as potassium carbonate or triethylamine. The N-alkylation reaction is followed by hydrogenation processes using a suitable catalyst such as palladium on carbon.

The compounds of formula (I) can also be prepared by interconverting the compounds of formula (I) according to transformation reactions of groups known in the art.

The starting materials and some of the intermediates are known compounds and can be purchased from commercial suppliers or can be prepared according to conventional reaction procedures generally known in the art. For example, intermediates of formula (II) of (VII) can be prepared according to the methods described in WO-99/02156 or WO-00/37461.

The intermediates of formula (VI) can be prepared according to the general method described in WO99 / 02156 or WO-00/37461 for intermediates of formula (VIII) described in said documents.

The compounds of formula (I) prepared in the processes described hereinbefore can be synthesized in the form of racemic mixtures of enantiomers that can be separated by resolution procedures known in the art. The racemic compounds of formula (I) can be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization, and the enantiomers are released from said salts with alkali. An alternative way to separate the enantiomeric forms of the compounds of formula (I) involves the use of liquid chromatography with a chiral stationary phase. These stereochemically pure isomeric forms can also be derived from the corresponding stereochemically pure isomeric forms of the appropriate starting materials, provided that the reaction is stereospecific. Preferably, if it is desired to obtain a specific stereoisomer, said compound will be synthesized by stereospecific methods of preparation. These methods will conveniently employ enantiomerically pure starting materials.

The compounds of formula (I), their N-oxide forms, pharmaceutically acceptable acid or base addition salts and stereoisomeric forms have antagonistic properties of 5HT4 as described in Example C.1.

In addition, the compounds of formula (I) have demonstrated improved metabolic stability as described in Example C.2. These beneficial metabolic stability properties reduce the risk of a drug interaction occurring at the level of cytochrome P450 family enzymes such as, e.g. eg, CYP1A2, CYP3A4, CYP2D6, CYP2C9 and CYP2C19, and, therefore, the present compounds have an improved pharmacological safety profile. In addition, these beneficial metabolic stability properties may make it possible for the compounds of formula (I) to be administered once a day instead of the usual administration of the active substance following a dosing schedule of between two or four doses per day, which means an increase in compliance by the patient.

In view of the 5HT4 antagonistic properties of the compounds of the present invention, the compounds in question can generally be used in the treatment or prophylaxis of gastrointestinal conditions such as hypermotility, irritable bowel syndrome (IBS). , IBS with a predominance of constipation or diarrhea, IBS with predominant pain or no pain, intestinal hypersensitivity and pain reduction associated with gastrointestinal hypersensitivity and / or hyperactivity.

It is also believed that the compounds of formula (I) are useful in the prevention or prophylaxis of an interrupted, impeded or impaired digestion such as dyspepsia. The symptoms of dyspepsia are, for example, epigastric pressure, a loss of appetite, feeling of fullness, early satiety, nausea, vomiting, bloating and belching.

The compounds of formula (I) may also be useful in the treatment of other disorders related to 5HT4 such as bulimia and hyperphagia.

In view of the usefulness of the compounds of formula (I), it is concluded that the present invention also provides a method for treating warm-blooded animals, including humans, (generally referred to as patients) suffering from gastrointestinal conditions such as the syndrome of irritable bowel (IBS). Therefore, a method of treatment is provided to relieve patients suffering from conditions such as hypermotility, irritable bowel syndrome (IBS), IBS with a predominance of constipation or diarrhea, IBS with predominantly pain or pain, intestinal hypersensitivity and pain reduction associated with hypersensitivity and / or gastrointestinal hyperactivity.

The compounds of formula (I) may also be potentially useful in other gastrointestinal disorders, such as those associated with the motility of the upper part of the gastrointestinal tract. In particular, they are potentially useful in the treatment of gastric symptoms of gastroesophageal reflux disease, such as heartburn (including episodic heartburn, nighttime heartburn and food-induced heartburn).

In addition, 5HT4 antagonist compounds of formula (I) may also be potentially useful in the treatment or prophylaxis of bladder hypersensitivity, overactive bladder, lower urinary tract symptoms, benign prostatic hypertrophy (BPH), prostatitis, detrusor hyperreflexia, exit obstruction, frequent urination, nocturia, urgent urination, pelvic hypersensitivity, emergency incontinence, urethritis, prostatedynia, cystitis, idiopathic bladder hypersensitivity, urinary incontinence or urinary incontinence associated with irritable bowel syndrome. In this regard, it may be convenient to combine the 5HT4 antagonist compounds of formula (I) with an alpha adrenergic receptor antagonist, such as alfuzosin, indoramine, tamsulosin, doxazosin, terazosin, abanokyl or prazosin, to obtain pharmaceutical compositions comprising an antagonist of alpha adrenergic receptors of this type and a 5HT4 receptor antagonist of formula (I).

Therefore, the present invention provides compounds of formula (I) for use as a medicine and, in particular, the use of compounds of formula (I) in the manufacture of a medicine for treating gastrointestinal conditions such as hypermotility, IBS, IBS with predominance of constipation or diarrhea, IBS with predominant pain or no pain, intestinal hypersensitivity and pain reduction associated with gastrointestinal hypersensitivity and / or hyperactivity. Both therapeutic and prophylactic treatment are contemplated.

In view of the 5HT4 antagonistic properties of the compounds of the present invention, the compounds in question may also be useful for treating or preventing CNS disorders related to 5HT4 in a human being. In particular, the compounds of formula (I) can be used to treat various CNS disorders, including, but not limited to, drug addiction, cognitive disorders such as Alzheimer's disease, senile dementia; behavioral disorders such as schizophrenia, mania, obsessive-compulsive disorder and disorders due to the use of psychoactive substances; mood disorders such as depression, bipolar affective disorder, anxiety disorder and panic; disorders of autonomic function control such as hypertension and sleep disorders; obsessive / compulsive disorders including anorexia and bulimia, and neuropsychiatric disorders, such as Gilles de la Tourette syndrome and Huntington's disease.

To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, in the form of base or acid addition salt, is combined as an active ingredient in intimate admixture with a pharmaceutically acceptable carrier, said carrier can take many forms depending on the Desired form of preparation for administration. These pharmaceutical compositions are desirably presented as unit dosage forms suitable, preferably, for oral, rectal or parenteral injection administration. For example, in the preparation of the compositions as oral pharmaceutical forms, any of the usual pharmaceutical means can be used, for example, water, glycols, oils, alcohols and the like, in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, tablets, capsules and tablets. Due to their easy administration, tablets and capsules represent the most beneficial oral unit dosage form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier usually comprises sterile water, at least in large part, although other ingredients may be included, for example, to promote solubility. For example, injectable solutions may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline solution and glucose solution. Injectable suspensions can also be prepared in which case suitable carriers, suspending agents and the like can be used. In compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and / or a suitable moisturizing agent, optionally combined with suitable additives of any type in minor portions, said additives do not cause any significant detrimental effect on the skin. . Such additives may facilitate cutaneous administration and / or may be useful for preparing the desired compositions. These compositions can be administered in various ways, e.g. eg, as a transdermal patch, as a point dorsal anointing or as an ointment. The acid addition salts of (I) due to

which have a greater water solubility than the corresponding basic form, are obviously more suitable for the preparation of aqueous compositions.

It is especially convenient to formulate the pharmaceutical compositions mentioned above as unit dosage forms so that their administration is simple and dose uniformity is maintained. The term "unit dosage form", as used in the description and claims herein, refers to physically discrete units suitable as unit doses, each unit containing a predetermined amount of active ingredient calculated to produce the associated desired therapeutic effect. with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including slotted or coated tablets), capsules, pills, powder sachets, wafers, injectable solutions or suspensions, coffee spoons, tablespoons and the like, and segregated multiples thereof.

For oral administration, the pharmaceutical compositions may take the form of solid pharmaceutical forms, for example, tablets (both ingestible and chewable forms only), gelatin capsules or capsules, conventionally prepared with pharmaceutically acceptable excipients such as binding agents (e.g. eg, pregelatinized corn starch, polyvinyl pyrrolidone or hydroxypropyl methylcellulose); fillers (eg, lactose, microcrystalline cellulose or calcium phosphate); lubricants (eg, magnesium stearate, talc or silica); disintegrants (eg, potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). The tablets can be coated by methods well known in the art.

Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product to be constituted with water or other suitable vehicle before use. Such liquid preparations may be prepared in a conventional manner, optionally with pharmaceutically acceptable additives such as suspending agents (eg, sorbitol syrup, methylcellulose, hydroxypropylmethylcellulose or hydrogenated edible fats); emulsifying agents (eg, lecithin or acacia); non-aqueous vehicles (eg, almond oil, fatty esters or ethyl alcohol); and preservatives (eg, methyl or propyl phydroxybenzoates or sorbic acid).

Pharmaceutically acceptable sweeteners preferably comprise at least one intense sweetener, such as saccharin, sodium or calcium saccharin, aspartame, potassium acesulfame, sodium cyclamate, alitamo, a dihydrocalconic sweetener, monelin, stevioside or sucralose (4.1 ', 6'- trichloro-4,1 ', 6'-trideoxygalactosacarose), preferably saccharin, sodium or calcium saccharin, and optionally an industrial sweetener such as sorbitol, mannitol, fructose, sucrose, maltose, isomalt, glucose, hydrogenated glucose syrup, xylitol, caramel or honey

Intense sweeteners are conveniently used in low concentrations. For example, in the case of sodium saccharin, the concentration may be between 0.04% and 0.1% (w / v) depending on the total volume of the final formulation, and is preferably 0.06% in the dose formulations low and approximately 0.08% in high dose. The industrial sweetener can be used effectively in large amounts between about 10% and about 35%, preferably between about 10% and 15% (w / v).

Pharmaceutically acceptable flavorings that can mask the taste of the bitter ingredients of the low dose formulations are preferably fruity flavors such as cherry, raspberry, blackcurrant or strawberry flavor. The combination of two flavors can provide very good results. High dose formulations may require stronger flavors such as caramelized chocolate flavor, fresh mint flavor, artificial flavor and similar pharmaceutically strong strong flavors. Each flavor can be present in the final composition in a concentration between 0.05% and 1% (w / v). Preferably, combinations of said strong flavors are used. Preferably, a flavor is used that does not undergo any change or loss of taste and color in the acidic conditions of the formulation.

The formulations of the present invention may optionally include an antiflatulant such as simethicone, alphaD-galactosidosa and the like.

The compounds of the invention can also be formulated as prolonged release preparations. This type of long-acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or in ion exchange resins, or as moderately soluble derivatives, for example, as a moderately soluble salt. .

The compounds of the invention can be formulated for parenteral administration by injection, conveniently intravenous, intramuscular or subcutaneous injection, for example, bolus injection or continuous intravenous infusion. Formulations for injection may be presented in a unit dosage form, e.g. eg, ampoules or in mutildosis containers, with an added preservative. The compositions may take the form of forms such as suspensions, solutions or emulsions in aqueous or oily vehicles, and may contain excipients such as suspending agents, isotonizers, stabilizers and / or dispersants. As an alternative, the active ingredient may be in the form of a powder to be constituted with a suitable vehicle, e.g. eg, sterile pyrogen-free water, before use.

The compounds of the invention can also be formulated as rectal compositions such as suppositories or retention enemas, e.g. eg, containing bases for conventional suppositories such as cocoa butter or other glycerides.

The compounds of the invention can be used for intranasal administration, for example, as a liquid spray, as a powder or in the form of drops.

In general, it is contemplated that a therapeutically effective amount be between about 0.0001 mg / kg and about 1 mg / kg of body weight, preferably between about 0.001 mg / kg and about 0.5 mg / kg of body weight.

Experimental part

In the procedures described below, the following abbreviations are used: "ACN" means acetonitrile; "THF" means tetrahydrofuran; "DCM" means dichloromethane; "DIPE" means diisopropyl ether; "EtOAc" means ethyl acetate; "NH4OAc" means ammonium acetate; "MIK" means isobutyl methyl ketone, "DMF" means dimethylformamide, "DMA" means dimethylacetamide. For some chemical compounds its chemical formula, p. e.g., NaOH for sodium hydroxide, Na2CO3

20 for sodium carbonate, K2CO3 for potassium carbonate, NH3 for ammonia, CuO for copper (II) oxide, CH2Cl2 for dichloromethane, CH3OH for methanol, HCl for hydrochloric acid and KOH for potassium hydroxide, NaBF4 for sodium tetrafluoroborate. Chiralcel AD is a chiral stationary phase column acquired from Daicel Chemical Industries, LTd, Japan.

A. Preparation of intermediates

25 Example A.1

a) Preparation of

intermediate 1)

A mixture of methyl 2,3-dihydroxy-5-methylbenzoate (0.198 mol), 1,3-dibromopropane (0.198 mol) and K2CO3 (0.396 mol) in 2-propanone (360 ml) was stirred and heated to reflux for 6 hours, then cooled and the solvent evaporated. The mixture was poured onto ice water and filtered. The filtrate was extracted with ethyl acetate. The organic layer was separated, dried and filtered, the solvent was evaporated, and purified by silica gel column chromatography (eluent: from 80/20 to 70/30 of cyclohexane / ethyl acetate), to obtain the intermediate 1).

35 b) Preparation of

 intermediate 2)

A mixture of intermediate (1) (0.1129 mol) in a mixture of a 2N solution of NaOH (370 ml) and THF (370 ml) was stirred at room temperature for 15 hours. THF was evaporated and the mixture was acidified with 12N HCl. The precipitate was filtered, washed with water and dried to obtain 21.9 g of intermediate (2) (mp 74 ° C).

Example A.2

45 a) Preparation of

 intermediate (3)

A mixture of 2,3-dihydroxy-4-methylbenzoic acid methyl ester (1.2 mol), 1,3-dibromopropane (152 ml) and K2CO3 (380 g) in 2-propanone (2500 ml) was stirred and heated to reflux for 20 hours. The reaction mixture was cooled and filtered, and the filtrate was evaporated to obtain 300 g of intermediate (3).

b) Preparation of

 intermediate (4)

A mixture of intermediate (3) (1.12 mol) in NaOH (2 M) (1800 ml) and THF (500 ml) was stirred and refluxed for 3 hours. The reaction mixture was cooled and the organic solvent evaporated. The aqueous concentrate was acidified with HCl and the resulting precipitate was filtered, washed with water and dried to obtain 403 g of intermediate.

15 (4).

Example A.3

a) Preparation of

 intermediate (5)

A mixture of 5-chloro-2,3-dihydroxybenzoic acid methyl ester (0.3 mol), 1,3-dibromopropane (0.42 mol) and K2CO3 (0.66 mol) in 2-propanone (500 ml) was stirred and heated at reflux for 20 hours, then it was filtered hot and the filtrate was evaporated. The residue was purified by silica gel column chromatography (eluent: DCM). The desired fractions were collected and the solvent was evaporated. Toluene was added and an azeotrope formed

25 which was removed on the rotary evaporator to obtain 69 g of methyl 8-chloro-3,4-dihydro-2H-1,5-benzodioxepin-6-carboxylate (intermediate 5).

b) Preparation of

 intermediate (6)

A mixture of intermediate (5) (0.25 mol) and KOH (1 mol) in water (650 ml) was stirred and refluxed for 2 hours. The reaction mixture was cooled and acidified with HCl, the resulting precipitate was filtered, washed with water and dried to obtain 48 g of 8-chloro-3,4-dihydro-2H-1,5-benzodioxepin-6 acid. -carboxylic (intermediate 6).

35 Example A.4  intermediate (7)

A mixture of 2,3-dihydroxy-4-methoxybenzoic acid methyl ester (0.45 mol), 1,3-dibromopropane (0.72 mol), K2CO3 (155 g) and CuO (3.6 g) in DMF (2500 ml) was stirred at 120 ° C -130 ° C for 7 hours, it was cooled and filtered. The solvent was evaporated. HCl (0.5 N aqueous solution, 1000 ml) was added. The mixture was extracted twice with DCM (750 ml). The organic layer was separated, dried and filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: 70/30/15 hexane / ethyl acetate / DCM). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE to obtain methyl 3,4-dihydro-9-methoxy-2H1,5-benzodioxepin-6-carboxylate (intermediate 7).

b) Preparation of

 intermediate (8)

A solution of NaOH (500 ml, 2 N) was added to a solution of intermediate (7) in THF (250 ml). The mixture was stirred at room temperature overnight. The solvent was partially evaporated. The residue was extracted with DCM. The layers of the mixture were separated. The aqueous layer was acidified with concentrated HCl solution to pH = 1-2. The solid was filtered, washed with water and dried to obtain 35.5 g of 9-methoxy-3,4-dihydro-2H-1,5-benzodioxepin-6-carboxylic acid (intermediate 8).

Example A.5

a) Preparation of

 intermediate (9)

A mixture of 5-chloro-2,3-dihydroxybenzoic acid methyl ester (0.49 mol) in acetic acid (2000 ml) was stirred and heated to reflux. A solution of N-chlorosuccinimide (0.49 mol) in acetic acid (600 ml) was added dropwise at reflux. The reaction mixture was stirred and heated at reflux for 30 minutes. More solution of N-chlorosuccinimide (0.075 mol) in acetic acid (100 ml) was added dropwise at reflux. The reaction mixture was stirred and refluxed for 30 minutes, then cooled and poured onto water (500 ml). The residue was extracted with toluene (3 times). The separated organic layer was washed with water and dried, and the solvent was evaporated. The residue was crystallized from DIPE and petroleum ether to obtain 70 g of intermediate (9).

b) Preparation of

 intermediate (10)

A mixture of intermediate (9) (0.3 mol), 1,3-dibromopropane (0.35 mol) and K2CO3 (0.7 mol) in 2-propanone (1000 ml) was stirred and heated at reflux for 30 hours. The reaction mixture was cooled, diluted with water (2000 ml) and extracted twice with DCM. The separated organic layer was washed with water and dried, and the solvent was evaporated. The residue was crystallized from DIPE and petroleum benzine to obtain 55 g of intermediate (10).

 intermediate (11)

A mixture of intermediate (10) (0.2 mol) and KOH (1 mol) in water (1000 ml) was stirred and heated at reflux for 90

minutes The reaction mixture was cooled and acidified with HCl, and the resulting precipitate was filtered, washed with water and dried to obtain 46 g of intermediate (11).

Example A.6

a) Preparation of

 intermediate (12)

A mixture of 5-chloro-2,3-dihydroxybenzoic acid methyl ester (0.1 mol) in acetic acid (250 ml) and Nbromosuccinimide (0.11 mol) was stirred and refluxed for 4 hours. The reaction mixture was cooled and poured into water (500 ml). The precipitate was filtered and dried to obtain 23 g of intermediate (12).

b) Preparation of

 intermediate (13)

A mixture of intermediate (12) (0.7 mol), 1,3-dibromopropane (0.94 mol) and K2CO3 (1.55 mol) in 2-propanone (1300 ml) was stirred and heated at reflux for 20 hours. The reaction mixture was cooled and filtered, and the solvent was evaporated. The residue was solidified in petroleum ether, filtered and dried to obtain 240 g of intermediate (13).

20 c) Preparation of

 intermediate (14)

A mixture of intermediate (13) (0.053 mol) and KOH (0.2 mol) in water (160 ml) was stirred and refluxed for 90 minutes. The reaction mixture was cooled and the aqueous layer was extracted with DCM. The aqueous layer was acidified with HCl, and the resulting precipitate was filtered, washed with water and dried to obtain 13 g of intermediate (14).

Example A.7

30 a) Preparation of

 intermediate (15)

A mixture of 5-nitro-2,3-dihydroxybenzoic acid methyl ester (0.3 mol), K2CO3 (0.66 mol), 1.3

Dibromopropane (0.42 mol) and tetra-n-butylammonium bromide (4.5 g) in 2-propanone (900 ml) and DMA (600 ml) was stirred and heated at reflux for 30 hours. The reaction mixture was stirred for two days at room temperature and then filtered. The solvent was evaporated and the residue was partitioned between water and DCM. The separated organic layer was dried, filtered and concentrated. The residue was suspended in DIPE, filtered, dried and purified by silica gel column chromatography (eluent: 98/2 of CH2Cl2 / CH3O) to obtain 33.5 g of intermediate (15).

40 b) Preparation of

 intermediate (16)

A mixture of intermediate (15) (0.11 mol) in THF (250 ml) was hydrogenated with 10% palladium on carbon (3 g) as a catalyst in the presence of a thiophene solution (1 ml). After incorporation of hydrogen (3 equivalents), the catalyst was filtered on dicalite and the filtrate was concentrated to obtain 24.7g of intermediate (16).

c) Preparation of

 intermediate (17)

10 Intermediate (16) (0.0448 mol) was added portionwise at 5 ° C to a mixture of concentrated HCl (10 ml) in water (10 ml). The mixture was heated to 0 ° C. A solution of NaNO2 (0.048 mol) in water (10 ml) was added dropwise at 0 ° C. The mixture was stirred at a temperature between 0 ° C and 5 ° C for 1 hour, and then filtered. The filtrate was cooled to 0 ° C and then added to a solution of NaBF4 (0.076 mol) in water (20 ml). The mixture was stirred at 0 ° C for 30 minutes. The precipitate was filtered, washed with a minimum amount of water followed

15 of diethyl ether / water (50/50) and then with diethyl ether, and dried under vacuum at room temperature to obtain

12.10 g of intermediate (17).

d) Preparation of

 intermediate (18)

A mixture of intermediate (17) (0.0387 mol) and sodium fluoride (0.1549 mol) in toluene (120 ml) was stirred and refluxed overnight, and then cooled to room temperature. The precipitate was filtered. The filtrate was washed with toluene and evaporated to dryness. The residue was dissolved in DCM. The solvent was evaporated to dryness. He

The residue was purified by silica gel column chromatography (eluent: DCM) to obtain 2.8 g of intermediate (18).

e) Preparation of

 intermediate (19)

A mixture of intermediate (18) (0.0124 mol) in a solution of NaOH (2 N, 25 ml) and THF (25 ml) was stirred at room temperature overnight. THF was evaporated and ethyl acetate was added. The mixture was extracted with ethyl acetate, then acidified with HCl to pH 2. The precipitate was filtered, washed with water followed by ether.

35 diethyl and dried to obtain 2.16 g of intermediate (19).

Example A.8

a) Preparation of

 intermediate (20)

A mixture of 5-bromo-2,3-dihydroxybenzoic acid methyl ester (0.397 mol) and K2CO3 (0.87 mol) in 1,3-dibromopropane (49 ml) and 2-propanone (1000 ml) was stirred and heated at reflux for 22 hours, then the reaction mixture was cooled and filtered over dicalite, and the solvent was evaporated. The residue was partitioned between NaHCO3 (5%, aq.) And DCM. The organic layer was separated, dried and filtered over dicalite, and the solvent was evaporated to obtain 112 g of intermediate (20).

b) Preparation of

 intermediate (21)

A mixture of intermediate (20) (0.14 mol) in THF (200 ml) and 2 N NaOH solution (300 ml) was stirred at 30-60 ° C for 4 hours. The organic solvent was then evaporated and the aqueous concentrate was cooled on ice and extracted with DCM. The aqueous layer was cooled again on ice and acidified to pH = 1, and the solid residue

10 was filtered and dried to obtain 33 g of intermediate (21).

c) Preparation of

 intermediate (22)

A mixture of intermediate (21) (0.33 mol) and copper cyanide (I) (2.7 mol) in DMA (800 ml) was stirred at 140 ° C for 20 hours, then the reaction mixture was cooled and FeCl3 was added .6H2O (130 g), HCl (33 ml) and water (200 ml). The mixture was stirred at 60 ° C for 20 hours, cooled and poured into water. Ethyl acetate was added and the layers were filtered to remove insoluble salts. The organic layer was separated, washed with water,

20 dried and filtered, and the solvent was evaporated. The residue was dissolved in water and a 5% NaOH solution was added, then the mixture was extracted with DIPE, acidified with HCl and extracted with ethyl acetate. The organic layer was separated and dried, and the solvent was evaporated. The residue was purified by short column chromatography (eluent: 95/5 CH2Cl2 / CH3OH + 2 ml acetic acid) to obtain 7 g of intermediate (22).

25 Example A.9

a) Preparation of

 intermediate (23)

A mixture of 5-nitro-2,3-dihydroxybenzoic acid methyl ester (0.3 mol), potassium carbonate (0.66 mol), 1,3-dibromopropane (0.42 mol) and tetra-n-butylammonium bromide (4.5 g) in 2-propanone (900 ml) and DMA (600 ml) was stirred and heated at reflux for 30 hours. The reaction mixture was stirred for two days at room temperature and then filtered. The solvent was evaporated and the residue was partitioned between water and DCM. The separated organic layer was dried, filtered and concentrated. The residue was suspended in DIPE, filtered, dried and purified by

35 silica gel column chromatography (eluent: 98/2 CH2Cl2 / CH3OH) to obtain 33.5g of intermediate (23).

b) Preparation of

 intermediate (24)

A mixture of intermediate (23) (0.11 mol) in THF (250 ml) with 10% palladium on carbon (3 g) is catalyzed as a catalyst in the presence of a thiophene solution (1 ml). After incorporation of hydrogen (3 equivalents), the catalyst was filtered on dicalite and the filtrate was concentrated to obtain 24.7 g of intermediate (24).

45 c) Preparation of

 intermediate (25)

Intermediate (24) (0.11 mol) was dissolved in trichloromethane (500 ml) and the mixture was cooled in an ice bath until

5 a temperature below 10 ° C. Trifluoroacetic acid anhydride (0.14 mol) was added dropwise at the same temperature and then the reaction mixture was stirred for 1 hour at room temperature. The residue was crystallized from DIPE at room temperature overnight to obtain 5.8 g of intermediate (25).

d) Preparation of 10

 intermediate (26)

60% NaH (0.171 mol) was added portionwise at room temperature to a mixture of intermediate (25) (0.131 mol) in DMF (450 ml) in a stream of nitrogen. The mixture was stirred at room temperature for 1 hour. Be

15 added iodoethane (0.171 mol) drop by drop. The mixture was stirred at a temperature between 50 and 60 ° C for 2 days, then cooled to room temperature, poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried, filtered and the solvent evaporated. The residue was purified by silica gel column chromatography (eluent: 90/10 of toluene / ethyl acetate) to obtain 26.5 g of intermediate (26).

20 e) Preparation of

 intermediate (27)

25 Lithium hydroxide monohydrate (0.264 mol) was added portionwise at room temperature to a mixture of intermediate (26) (0.063 mol) in water (150 ml). The mixture was stirred at room temperature for 18 hours. Water (150 ml) was removed by evaporation. The mixture was acidified with 3 N HCl until pH = 4 and then extracted with ethyl acetate. The organic layer was separated, dried, filtered and the solvent evaporated to obtain 14 g of intermediate (27).

Example A.10

Preparation of

 intermediate (28)

A mixture of intermediate (23) (0.12 mol) in 1 N NaOH (200 ml) was stirred and refluxed for 4 hours. The reaction mixture was allowed to stand overnight at room temperature, then cooled on an ice bath and a 1 N solution of HCl (200 ml) was added. The mixture was allowed to warm to room temperature and the

The precipitate formed was filtered to obtain 26.7 g of intermediate (28).

Example A.11

a) Preparation of

 intermediate (29)

97% sulfuric acid (80 ml) was added carefully to a mixture of 9- (acetylamino) -3,4-dihydro-2H-1.5

5 methyl benzodioxepin-6-carboxylate (0.51 mol) in methanol (1000 ml). The mixture was stirred at 60 ° C for 1 hour and then cooled. The solvent was evaporated. The residue was dissolved in DCM. The mixture was washed with a solution of KHCO3. The organic layer was separated, dried and filtered, and the solvent was evaporated. The residue was suspended in DIPE and a small amount of ACN. The precipitate was filtered, washed and dried to obtain 105 g of intermediate (29).

10 b) Preparation of

 intermediate (30)

A mixture of intermediate (29) (0.24 mol) in water (240 ml) was stirred at 0 ° C. HCl (120 ml) was added dropwise at 0

15 ° C The mixture was stirred for 15 minutes. A mixture of sodium nitrite (0.24 mol) in water (120 ml) was added dropwise at 0 ° C. The mixture was stirred at 0 ° C for 30 minutes to obtain mixture A. A mixture of copper chloride (0.24 mol) in HCl (120 ml) was stirred at room temperature. The mixture A was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. The precipitate was filtered, washed and dried to obtain 55.8 of intermediate (30).

20 c) Preparation of

 intermediate (31)

A mixture of intermediate (30) (0.22 mol) and KOH (2.2 mol) in water (1000 ml) was stirred and refluxed for 30 minutes and then cooled. The mixture was acidified with a concentrated HCl solution. The precipitate was filtered, washed and dried to obtain 48 g of intermediate (31).

 intermediate (32)

A mixture of intermediate (31) (0.01 mol) in sulfuric acid (20 ml) was cooled to -30 ° C, then a mixture of nitric acid (0.01 mol) in sulfuric acid (20 ml) was added dropwise at -30 ° C and the reaction mixture was stirred for 5 minutes. The mixture was poured onto ice water, and the resulting precipitate was filtered and washed with water to obtain intermediate (32).

Example A.12

35 a) Preparation of

 intermediate (33)

Acetone (1000 ml) was stirred and heated at reflux for 24 hours. The reaction mixture was cooled and filtered, and the solvent was evaporated. The residue was dissolved in DCM, and washed with water and 2 N NaOH solution. The organic layer was dried and filtered, and the solvent was evaporated to obtain 30.5 g of intermediate (33).

b) Preparation of

 intermediate (34)

A solution of intermediate (33) (0.146 mol) in NaOH (2 N) (400 ml) and THF (400 ml) was stirred and refluxed for 18 hours. The reaction mixture was cooled and THF was removed by evaporation. The residue was acidified with 10 concentrated HCl. The resulting solid was filtered, washed and dried to obtain 26.5 g of intermediate (34).

Example A.13

a) Preparation of

 intermediate (35)

Intermediate (43) (0.086 mol) was added portionwise to a solution of concentrated HCl (18 ml) in water (18 ml). The mixture was cooled to 5 ° C. A solution of sodium nitrite (0.086 mol) in water (18 ml) was added dropwise. The mixture was stirred at 10 ° C for 1 hour. The precipitate was filtered. The filtrate was cooled, then added to a

20 solution of NaBF4 (0.146 mol) in water (36 ml). The mixture was stirred for 30 minutes. The precipitate was filtered, washed with water followed by diethyl ether and dried under vacuum at 40 ° C for 12 hours to obtain 20 g of intermediate (35).

b) Preparation of 25

 intermediate (36)

A mixture of intermediate (35) (0.0649 mol) and sodium fluoride (0.259 mol) in toluene (250 ml) was stirred and refluxed for two days. The solvent was evaporated to dryness. The residue was purified by chromatography on

30 silica gel column (eluent: 80/20 cyclohexane / EtOAc). The pure fractions were collected and the solvent was evaporated to obtain 7.6 g of intermediate (36).

 intermediate (37)

A mixture of intermediate (36) (0.0358 mol) and lithium hydroxide (0.0716 mol) in THF (70 ml) and water (70 ml) was stirred at room temperature overnight. The solvent was evaporated. The residue was acidified with 6N HCl. The precipitate was filtered, washed with water, then dissolved in CH2Cl2 / CH3OH. The organic layer was separated, dried and filtered, and the solvent was evaporated to obtain 6.22 g of intermediate (37).

40 Example A.14

a) Preparation of

 intermediate (38)

8-Chloro-2,3-dihydro-1,4-benzodioxy-5-carboxylic acid methyl ester (0.44 mol) was dissolved in sulfuric acid (850 ml). This solution was cooled to a temperature below 0 ° C. Nitric acid (smoker, 0.44 mol) in sulfuric acid (200 ml) was added dropwise in 2 hours. The reaction mixture was stirred for 45 minutes at -10 ° C, then poured into ice water. After extracting with DCM, intermediate (38) was obtained.

b) Preparation of

 intermediate (39)

A mixture of intermediate (38) (0.20 mol) in THF (1000 ml) and NaOH (2N, 1000 ml) was stirred at room temperature for 5 hours. THF (700 ml) was removed by evaporation at 35 ° C. The aqueous layer was extracted with ethyl acetate (2 x 750 ml). The separated aqueous layer was cooled in an ice bath and acidified with concentrated HCl. He

The precipitate was filtered, washed with water and dried to obtain 52 g of intermediate (39).

Example A.15

a) Preparation of

 intermediate (40)

A mixture of 5-amino-2,3-dihydroxybenzoic acid (0.62 mol) in sulfuric acid (110 ml) and methanol (1100 ml) was stirred and refluxed for 24 hours. The reaction mixture was kept standing overnight at room temperature. Then, the mixture was concentrated and the residue was partitioned between DCM and water. The layer

The separated aqueous was washed with DCM and the separated organic layers were collected, dried, filtered and concentrated. The product was dried to obtain 120 g of intermediate (40).

b) Preparation of

 intermediate (41)

A mixture of intermediate (40) (0.35 mol), K2CO3 (0.77 mol) and tetrabutylammonium bromide (5 g) in 1,2-dibromoethane (42 ml), DMA (680 ml) and 2-propanone (1000 ml) was stirred and It was heated at reflux (70 ° C) for 20 hours. More DMA (250 ml), tetrabutylammonium bromide (5 g) and 1-bromo-2-chloroethane (29 ml) were added. Mix

The reaction was stirred and heated at reflux for 44 hours. Then, the reaction mixture was allowed to cool to room temperature over the weekend. The suspension was filtered and the filtrate was concentrated. The concentrate was partitioned between water and toluene. The separated aqueous layer was washed several times with DCM. The separated organic layers were combined, dried, filtered and concentrated. The residue was crystallized from DIPE and ACN to obtain 26 g of intermediate (41) (mp 140 ° C).

40 c) Preparation of

 intermediate (42)

A mixture of intermediate (41) (0.063 mol) in 1 N NaOH (100 ml) was stirred and refluxed for 4 hours. The reaction mixture was cooled in an ice bath. A 1N solution of HCl (100 ml) was added to the precipitate formed. This reaction mixture was allowed to warm to room temperature and the precipitate formed was filtered and dried to obtain 14.5 g of intermediate (42) (mp 234 ° C).

Example A.16

a) Preparation of

 intermediate (43)

A mixture of intermediate (41) (0.089 mol) in methanol (500 ml) was hydrogenated at 50 ° C with palladium on carbon (10%; 3 g) as catalyst in the presence of a thiophene solution (1 ml). After incorporation of hydrogen (3 equivalents), the catalyst was filtered on dicalite and the filtrate was evaporated to obtain 20.9 g of intermediate (43).

b) Preparation of

 intermediate (43a)

20 Trifluoroacetic acid anhydride (0.11 mol) was added to a mixture of intermediate (43) (0.1 mol) in trichloromethane (130 ml). The reaction mixture was stirred for 1 hour and the mixture was concentrated. The residue was purified on silica gel on a glass filter (eluent: 90/10 CHCl2 / MeOH). Fractions containing product were collected and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: 98/2 CH2Cl2 / MeOH). The pure fractions were collected and the solvent was evaporated to obtain 11.0 g

25 of intermediate (43a).

c) Preparation of

 intermediate (44)

The intermediate (43a) (0.036 mol) in DMF (100 ml) was stirred at room temperature in a stream of nitrogen. 60% sodium hydride in paraffin (0.0432 mol) was added portionwise in a stream of nitrogen. This reaction mixture was heated to 50 ° C. Then, iodomethane (0.0432 mol) was added dropwise at 50 ° C in a stream of nitrogen. This reaction mixture was stirred at 50 ° C overnight, then the mixture was left.

Cool to room temperature and pour over water (680 ml) and then extract with toluene. The separated organic layer was dried, filtered and concentrated to obtain 10.8 g of intermediate (44). d) Preparation of

 intermediate (45)

A mixture of intermediate (44) (0.0338 mol) in 1 N NaOH (0.07 mol) and water (60 ml) was stirred and refluxed for 1 hour. The reaction mixture was allowed to cool to room temperature, then tert-butyl dicarbonate (0.041 mol) was added and the reaction mixture was stirred overnight at room temperature. Then 1N HCl (0.07 mol) was added and the residue was extracted with DCM. The separated organic layer was dried, filtered and

45 concentrated to obtain 10.0 g of intermediate (45).

Example A.17

Preparation of

 intermediate (46)

A mixture of 1,1-dimethylethyl (trans) -3-hydroxy-4 - [[(phenylmethyl) amino] methyl] -1-piperidinecarboxylate [described in WO-00/37461 as intermediate (1-d) was hydrogenated. ] (0.023 mol) in methanol (100 ml) with palladium on carbon (10%, 1 g) as catalyst. After incorporation of hydrogen (1 equivalent), the catalyst was filtered and the filtrate was evaporated. The residue was solidified in DIPE + ACN, filtered and dried to obtain 4 g of 1,1-dimethylethyl (trans) -4- (aminomethyl) -3-hydroxy-1-piperidinecarboxylate (intermediate 46, mp 178 ° C).

10 Example A.18

a) Preparation of

 intermediate (47)

[1,1-Dimethylethyl-1,1-dimethyl ethyl [1- (phenylmethyl) amino] methyl] -1-piperidinecarboxylate [described in WO00 / 37461 as intermediate (1-d)] (2.73 mol) and purified by chiral column chromatography in Chiralcel AD (eluent: 80/20 hexane / ethanol). The desired fractions were collected and the solvent was evaporated. Toluene was added and an azeotrope was formed which was removed on the rotary evaporator to obtain 377 g of 1,1-dimethylethyl (3S-trans) -3-hydroxy-4 - [[(phenylmethyl) amino] methyl] -1-piperidinecarboxylate ( intermediate 47).

20 b) Preparation of

 intermediate (48)

A mixture of intermediate (47) (0.028 mol) in methanol (100 ml) was hydrogenated with charcoal on palladium (10%, 2 g) as catalyst. After incorporation of hydrogen (1 equivalent), the catalyst was filtered and the filtrate was evaporated to obtain 4.7 g of 1,1-dimethylethyl (3S-trans) -4- (aminomethyl) -3-hydroxy-1-piperidinecarboxylate ( intermediate (48); [α] D20 = + 4.37 ° (c = 24.03 mg / 5 ml in CH3OH)).

30 Example A.19

a) Preparation of

35 Reaction under nitrogen atmosphere. Sodium hydride (0.3 mol) was added to a solution of 1,1-dimethylethyl trans-3-hydroxy-4 - [[[(4-methylphenyl) sulfonyl] oxy] methyl] -1-piperidinecarboxylate [described in WO-00/37461 as intermediate (1-c)]

(0.27 mol) in THF (1300 ml). The mixture was stirred for 30 minutes. Methyl iodide (0.54 mol) was added and the resulting reaction mixture was stirred for 90 minutes. A small amount of water was added. Solvent

40 was evaporated and the residue was partitioned between water and DCM. The organic layer was separated, dried and filtered, and the solvent was evaporated to obtain trans 1,1- [[(4-methylphenyl) sulfonyl] oxy] methyl] -3-methoxy-1-piperidinecarboxylate of 1,1- dimethyl ethyl (intermediate 49).

b) Preparation of

 intermediate (50)

A mixture of intermediate (49) (0.065 mol) in THF (250 ml) was treated with liquid NH3 in an autoclave at 125 ° C

5 for 16 hours. The reaction mixture was filtered and the filtrate was evaporated. The residue was partitioned between a 5% aqueous solution of NaOH and DCM. The organic layer was separated, dried and filtered, and the solvent was evaporated to obtain 16 g of 1,1-dimethylethyl (trans) -4- (aminomethyl) -3-methoxy-1-piperidinecarboxylate (intermediate 50).

Example A.20

10 a) Preparation of

 intermediate (51)

A mixture of tert-butyl 4-oxo-1-piperidinecarboxylate (0.1 mol) and nitromethane (0.1 mol) in methanol (200 ml) is

15 stirred at 10 ° C. Sodium methanolate (0.11 mol) was added dropwise at 10 ° C. The reaction mixture was stirred for 20 hours at room temperature. The solvent was evaporated. The residue was dissolved in water, then neutralized with acetic acid and then extracted twice with DCM. The separated organic layer was washed with water, dried and filtered, and the solvent was evaporated. The residue was suspended in DIPE, filtered, washed and dried to obtain 17.2 g of intermediate (51) (mp 160 ° C).

20 b) Preparation of

 intermediate (52)

A mixture of intermediate (51) (0.058 mol) and acetic acid (12 ml) in methanol (250 ml) was hydrogenated at 14 ° C with palladium on carbon (10%, 1 g) as catalyst. After incorporation of hydrogen (3 equivalents), the catalyst was filtered and the filtrate was evaporated. Ice / water was added to the residue, then made alkaline with potassium hydroxide and K2CO3 was added to remove salts. This mixture was extracted twice with DCM. The separated organic layer was dried and filtered, and the solvent was evaporated. The residue was suspended in DIPE, filtered, washed and dried.

30 to obtain 7.5 g of intermediate (52).

c) Preparation of

35 Triethylamine (0.0373 mol, 5.2 ml) was added followed by ethyl chloroformate (0.0373 mol) dropwise at a temperature between 0 ° C and 5 ° C to a mixture of intermediate (8) (0.0373 mol) in DCM ( 100 ml) in a stream of nitrogen. The mixture was stirred at this temperature for 45 minutes (first mixture). Triethylamine (0.0373 mol, 5.2ml) was added at room temperature to a mixture of intermediate (52) (0.0373 mol) in DCM (100 ml). The mixture was stirred at room temperature for 45 minutes, then added dropwise at a temperature of

40 between 0 ° C and 5 ° C at the first mixture. The reaction mixture was stirred at this temperature for 1 hour, then heated to room temperature, stirred for 1 hour and poured into ice water. DCM was added. The mixture was extracted with DCM. The organic layer was separated, dried and filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: 97/3 / 0.1 of CH2Cl2 / CH3OH / NH4OH). The pure fractions were collected and the solvent was evaporated to obtain 12 g of intermediate (53).

45 d) Preparation of

 intermediate (54)

A mixture of intermediate (53) (0.0275 mol) in HCl / 2-propanol (12 ml) and 2-propanol (120 ml) was stirred at 50 ° C overnight, then cooled to room temperature. The precipitate was filtered, washed with diethyl ether and dried to obtain 8.2 g of intermediate (54). Intermediate (55) was prepared analogously.

Example A.21

a) Preparation of

Triethylamine (0.03 mol) was added to a mixture of intermediate (8) (0.03 mol) in trichloromethane. Then, ethyl chloroformate (0.03 mol) was added at a temperature below 10 ° C. The mixture was stirred for 45 minutes to obtain the mixture (I). A mixture of 1,1-dimethylethyl cis-3-hydroxy-4 - [[[((4-methylphenyl) sulfonyl] oxy] methyl] -1-piperidinecarboxylate [described in WO-00/37461 as intermediate (1-f) ] (0.03 mol) in trichloromethane

20 on a mixture (I) and the reaction mixture was stirred for 30 minutes, washed with a 5% aqueous NaOH solution followed by water, dried and filtered, and the solvent was evaporated to obtain 14 g of intermediate. (56).

b) Preparation of

A mixture of intermediate (56) (0.03 mol), HCl / 2-propanol (30 ml) and 2-propanol (300 ml) was stirred and heated at reflux for 30 minutes. The mixture was cooled and the solvent evaporated. The residue was acidified with a 5% solution of HCl and the mixture was extracted with DCM. The organic layer was separated. The aqueous layer was alkalized with a

30% NaOH solution and extracted with DCM. The organic layer was separated, dried and filtered, and the solvent was evaporated to obtain 8 g of intermediate (57). Intermediates (58) and (59) were prepared analogously.

Example A.22

a) Preparation of

A mixture of intermediate (2) (0.336 mol) and triethylamine (0.4 mol) in DCM (1000 ml) was stirred at 5 ° C, then ethyl chloroformate (0.35 mol) was added dropwise and the reaction mixture was stirred for 30 minutes. To this mixture was added a solution of intermediate (48) (83 g) in DCM (1000 ml) at 5 ° C, then the reaction mixture was allowed to reach room temperature and washed with water. The organic layer was separated, dried and filtered, and the solvent was evaporated to obtain 150 g of intermediate (60).

10 b) Preparation of

A mixture of intermediate (60) (0.336 mol) in 2-propanol saturated with HCl (160 ml) and 2-propanol (1400 ml) was stirred and refluxed for 1 hour. The solvent was evaporated and the residue was dissolved in a mixture of DCM and a small amount of methanol. The mixture was washed with aqueous ammonia solution, and the organic layer was separated, dried and filtered. The solvent was evaporated to obtain 71 g of intermediate (61).

Table I-1: Intermediates (62) - (88) were prepared according to the same procedure of Example A.20

Intm.

Structure Physical data

62

trans; .HCl (1: 2)

63

trans;

64

trans;

65

trans; .HCl (1: 1)

66

trans;

67

trans;

Intm.

Structure Physical data

68

trans;

69

3S-trans;

70

trans;

71

trans;

72

73

3S-trans;

74

3S-trans;

75

trans;

76

trans; .HCl (1: 1)

78

trans; .HCl (1: 1)

79

trans; .HCl (1: 1)

Intm.

Structure Physical data

80

3S-trans;

81

3S-trans;

82

trans;

83

3S-trans;

84

3S-trans;

85

trans;

86

trans;

87

3S-trans;

88

trans;

B. Preparation of the final compounds

Example B.1

A mixture of intermediate (62) (0.008 mol), 3-chloro-1-propanesulfonamide (0.012 mol) and Na2CO3 (0.03 mol) in 2

5 butanol (100 ml) was stirred and heated at reflux for 40 hours. More 3-chloro-1-propanesulfonamide (0.02 mol) was added and the mixture was stirred and heated at reflux for 24 hours; then it cooled. The sticky product precipitated. The solids were filtered. The remaining sticky solid was dissolved in CH3OH / CH2Cl2 and filtered. The filtrate was concentrated. Methanol was added to the filtrate. The residue was recrystallized from methanol. The solid was filtered, washed with methanol and dried. The residue was washed with H2O / CH2Cl2, filtered, washed with water and dried to obtain 2.02 g of the

10 compound (1) (p.150 ° C).

Example B.2

a) Preparation of

A mixture of intermediate (63) (0.01 mol), 3-chloro-1-propanesulfonamide (0.015 mol) and Na2CO3 (0.02 mol) in isobutanol (100 ml) was stirred and heated at reflux for 70 hours. The solvent was evaporated. The residue was dissolved in DCM and methanol, then washed with water, dried and filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: 90/10 of CH2Cl2 / (CH3OH / NH3)). The desired fractions were collected and the solvent was evaporated to obtain 0.9 g of intermediate (89).

b) A mixture of intermediate (89) (0.002 mol) in methanol (150 ml) was hydrogenated with 10% palladium on carbon

(0.5 g) as a catalyst in the presence of a thiophene solution (0.5 ml). After incorporation of hydrogen (3 equivalents), the catalyst was filtered and the filtrate was evaporated. The residue was purified by silica gel column chromatography (eluent: 95/5 of CH2Cl2 / (CH3OH / NH3)). Fractions containing product were collected and the solvent was evaporated. The residue was dissolved in 2-propanol and a small amount of DIPE, converted to the salt of (E) -2-butenedioic acid (1: 1), filtered, washed and dried to obtain 0.72 g of the compound

(8) (mp 186 ° C).

Example B.3 (Reference example)

a) Preparation of

A mixture of intermediate (69) (0.05 mol), methyl 4-bromobutanoate (0.06 mol) and triethylamine (0.06 mol) in DMF (300 ml) was stirred for 20 hours at 70 ° C. The reaction mixture was cooled, water was added and extracted with toluene. The separated organic layer was dried, filtered and the solvent evaporated. The residue was dissolved in DCM, washed with water, dried and filtered, and the solvent was evaporated. The residue was purified on silica gel on a glass filter (eluent: 95/5 of CH2Cl2 / (CH3OH / NH3)). The desired fractions were collected and the solvent was evaporated to obtain 17.1 g of intermediate (90).

Intermediate (90) (0.036 mol) was dissolved in THF (35 ml). 1 N NaOH (0.036 mol) was added dropwise in 2 hours at 18-20 ° C (ice bath). The mixture was stirred for 90 minutes at room temperature. 1N NaOH (5 ml) was added and the mixture was stirred for another hour. 1N HCl (0.036 mol) was added dropwise in one hour at 18-20 ° C (ice bath). The mixture was stirred for 2 hours at room temperature. The solvent was evaporated to obtain

17.5 g of intermediate (91).

c) Triethylamine (0.01 mol) was added at 5 ° C to a mixture of intermediate (91) (0.005 mol) in DCM (100 ml), then ethyl chloroformate (0.005 mol) was added dropwise at 5 ° C and the reaction mixture was stirred at 5 ° C for 1 hour. Methanesulfonamide (0.01 mol) was added at 5 ° C, the mixture was allowed to reach room temperature and stirred at room temperature for 24 hours. The resulting precipitate was filtered, washed and dried to obtain

1.05 g of compound (15) (mp 110 ° C; [α] D20 = - 14.96 ° (c = 22.06 mg / 5 ml in CH3OH)).

Example B.4

a) Preparation of 26

A mixture of intermediate (70) (0.01 mol), 3-chloro-1-propanesulfonamide (0.02 mol) and Na2CO3 (0.02 mol) in 2-methyl1-propanol (100ml) was stirred and refluxed for 48 hours, then It was filtered hot. The solvent of the filtrate was evaporated. The residue was purified on silica gel on a glass filter (eluent: 95/5 of CH2Cl2 / (CH3OH / NH3)) to obtain 2 g of intermediate (92).

b) Intermediate (92) (0.0037 mol) in HCl / 2-propanol (5 ml) and 2-propanol (60 ml) was stirred and refluxed for 1 hour, then cooled to room temperature. The precipitate was filtered, washed and dried to obtain 1.08 g of compound (3) (mp 130 ° C).

Example B.5

A mixture of intermediate (69) (0.0117 mol) and ethenesulfonamide (0.0141 mol) in copper (small quantity) was stirred at 125 ° C for 2 hours, then cooled to room temperature. CH2Cl2 / CH3OH (small amount) / H2O were added. The mixture was basified with K2CO3. The organic layer was separated, dried and filtered, and the solvent was evaporated to dryness. The residue was purified by silica gel column chromatography (eluent: 90/10/1 of CH2Cl2 / CH3OH / NH4OH). The pure fractions were collected and the solvent evaporated. The residue was crystallized from DIPE. The precipitate was filtered and dried to obtain 2,506 g of compound (22) (m.p. 162 ° C; [α] D20 = - 8.81 (c =

14.75 mg / 2 ml in CH3OH)).

Example B.6 (Reference example)

a) Preparation of

A mixture of intermediate (73) (0.036 mol), methyl 4-bromobutanoate (0.047 mol) and triethylamine (0.09 mol) in DMF (200 ml) was stirred at 75 ° C for 16 hours. The reaction mixture was cooled, poured into water and extracted with toluene. The organic layer was dried, filtered and the solvent evaporated. The residue was purified on silica gel on a glass filter (eluent: 97/3 of CH2Cl2 / (CH3OH / NH3)). Fractions containing product were collected and the solvent was evaporated to obtain 12.4 g of intermediate (93).

b) Preparation of

A mixture of intermediate (93) (0.0295 mol) in water (50 ml) was stirred at 95 ° C over the weekend. The reaction mixture was cooled and the solvent evaporated to obtain 8.5 g of intermediate (94).

c) Ethyl chloroformate (0.007 mol) was added dropwise to a mixture of intermediate (94) (0.007 mol), triethylamine

(0.014 mol) in DCM (50 ml) at a temperature of 5 ° C. The reaction mixture was stirred at 5 ° C for 1 hour. Methanesulfonyl chloride (0.014 mol) was added to the solution. The reaction mixture was stirred at room temperature for 24 hours and washed with water. The organic layer was dried and filtered, and the solvent was evaporated. The residue was purified by flash column chromatography on Biotage (eluent: 99/1, 97/3, 96/4, 94/6 of CH2Cl2 / CH3OH). Fractions containing product were collected and the solvent was evaporated. The residue was crystallized from DIPE to obtain 0.7 g (21%) of compound (27) (mp 142 ° C; [α] D20 = - 14.24 ° (c = 9.83 mg / 5 ml in CH3OH)).

Example B.7 (Reference example)

60% sodium hydride in oil (0.0033 mol) at room temperature was added to a mixture of compound (36) (0.0027 mol) in DMF (15 ml). The mixture was stirred at room temperature for 1 hour. Methanesulfonyl chloride (0.0027 mol) was added. The mixture was stirred for 48 hours, poured into ice water, saturated with K2CO3 and extracted with ethyl acetate. The organic layer was separated, dried and filtered, and the solvent was evaporated.

5 The residue was purified by silica gel column chromatography (eluent: 80/20/2 CH2Cl2 / CH3OH / NH4OH). The pure fractions were collected and the solvent evaporated. The residue was dissolved in DCM, washed with H2O / K2CO3 and saturated with K2CO3. The organic layer was separated, dried and filtered, and the solvent was evaporated to obtain 0.21 g of the compound (37).

10 Tables F-1-F-4 list the compounds that were prepared according to one of the previous Examples.

Table F-1

Co. No.

Ex. No. -L R3  R4  R5  Physical data

one

B.1 H2N-SO2 (CH2) 3- Cl  NH2  H trans; hydrate (1: 1), m.p. 150 ° C

2

B.2 H2N-SO2 (CH2) 3- H NH2  H trans; hydrate (1: 1), m.p. 207 ° C

3

B.4b H2N-SO2 (CH2) 3- H NHCH3  H trans; hydrochloride (2: 3) hydrate (1: 2) 2-propanolate (2: 1), m.p. 130 ° C

4

B.1 H2N-SO2 (CH2) 4- CH3O H H 3S-trans, m.p. 190 ° C, [a] D 20 = -10.64 ° (c = 25.38 mg / 5 ml in methanol)

5

B.1 H2N-SO2 (CH2) 4- H CH3  H 3S-trans, [a] D 20 = -11.82 ° (c = 10.66 mg / 2 ml in methanol)

6

B.1 H2N-SO2 (CH2) 4- CH3O H CH3 trans; m.p. > 70 ° C

7

B.1 H2N-SO2 (CH2) 4- H F H 3S-trans; m.p. 164 ° C

Table F-2

Co. No.

 Ex. No.  -L R3  R4  Physical data

8

B.2b H2N-SO2- (CH2) 3- H NH2 trans; E-2-butenodioate (1: 1), m.p. 186 ° C

9

B.1 H2N-SO2- (CH2) 3- Cl NH2 trans, m.p. 158 ° C

10

B.1 C6H5-NH-SO2 (CH2) 3- CH3  H trans, m.p. 58 ° C

eleven

B.1 (CH3) 2CH-NH-SO2 (CH2) 3- H CH3 trans; ethanedioate (1: 1), m.p. 80 ° C

12

B.1 C6H5-NH-SO2 (CH2) 3- H CH3 trans; hydrochloride (1: 1), m.p. 137 ° C

13

B.1 (CH3) 2CH-NH-SO2 (CH2) 3- CH3  H trans; hydrochloride (1: 1), m.p. 171 ° C

14

B.1 (CH3) 2CH-NH-SO2 (CH2) 3- H Cl trans; ethanedioate (1: 1), m.p. 170 ° C

15 (Reference example)

B.3c CH3-SO2-NH-CO (CH2) 3- H Cl 3S-trans, m.p. 110 ° C, [a] D 20 = -14.96 ° (c = 22.06 mg / 5 ml in methanol)

16

B.4 H2N-SO2- (CH2) 3- H CH3NH trans; E-2-butenodioate (2: 1) hydrate (1: 1) ethanolate (2: 1), m.p. 100 ° C

17

B.1 C6H5-NH-SO2 (CH2) 3- H Cl trans, m.p. 90 ° C

18

B.1 H2N-SO2- (CH2) 3- CH3  H trans, m.p. 126 ° C

19

B.1 H2N-SO2- (CH2) 3- H CH3 trans, m.p. 82 ° C

twenty

B.1 H2N-SO2- (CH2) 4- H CH3 trans, m.p. 170 ° C

twenty-one

B.1 H2N-SO2- (CH2) 3- H Cl trans, m.p. 56 ° C

22

B.5 H2N-SO2- (CH2) 2- H Cl 3S-trans, m.p. 162 ° C, [a] D 20 = -8.81 ° (c = 14.75 mg / 2 ml in methanol)

2. 3

B.5 H2N-SO2- (CH2) 2- CH3  H 3S-trans, m.p. 200 ° C, [a] D 20 = -12.73 ° (c = 7.70 mg / 2 ml in methanol)

24

B.1 CH3-NH-SO2- (CH2) 3- H CH3 trans, m.p. 150 ° C

25

B.5 H2N-SO2- (CH2) 2- H CH3 3S-trans, m.p. 166 ° C

26

B.1 H2N-SO2- (CH2) 4- H Cl 3S-trans, m.p. 172 ° C, [a] D 20 = -7.89 ° (c = 10.64 mg / 2 ml in methanol)

27 (Reference example)

B.6c CH3-SO2-NH-CO (CH2) 3- CH3  H 3S-trans; hydrochloride (10: 1), m.p. 142 ° C; [a] D 20 = -14.24 ° (c = 9.83 mg / 5 ml in methanol)

28 (Reference example)

B.3 CH3-SO2-NH-CO (CH2) 3- H CH3 3S-trans; hydrate (1: 1), m.p. 124 ° C; [a] D 20 = -14.19 ° (c = 10.22 mg / 5 ml in methanol)

29

B.1 H2N-SO2- (CH2) 4- CH3  H 3S-trans, m.p. 190 ° C; [a] D 20 = -10.50 ° (c = 10.10 mg / 2 ml in methanol)

30

B.1 H2N-SO2- (CH2) 4- Cl Cl trans, m.p. 181 ° C

31

B.1 H2N-SO2- (CH2) 4- Br Cl trans, m.p. 187 ° C

32

B.1 H2N-SO2 (CH2) 4- CH3O H 3S-trans, [a] D 20 = -7.85 ° (c = 12.23 mg / 2 ml in methanol)

33

B.1 CH3-NH-SO2- (CH2) 3- H Cl trans; oxalate (1: 1)

3. 4

B.1 CH3-NH-SO2- (CH2) 3- CH3  H 3S-trans; oxalate (1: 1), [a] D 20 = -10.69 ° (c = 7.86 mg / 2 ml in methanol)

35

B.1 H2N-SO2- (CH2) 4- H F 3S-trans, [a] D 20 = -10.39 ° (c = 10.01 mg / 2 ml in methanol)

36

B.1 H2N-SO2- (CH2) 3- H CH3 3S-trans

37 (Reference example)

B.7 CH3-SO2-NH-SO2 (CH2) 3- H CH3 3S-trans; m.p. 108 ° C

38

B.1 H2N-SO2- (CH2) 4- H CH3 cis; m.p. 122 ° C

39

B.1 H2N-SO2- (CH2) 4- H F cis

40

B.1 H2N-SO2- (CH2) 4- CH3O H cis

Table F-3

Co. No.

 Ex. No.  -L R3  R4  Physical data

41

B.1 H2N-SO2- (CH2) 3- H CN trans; oxalate (1: 1), m.p. 145 ° C

42

B.1 H2N-SO2- (CH2) 4- Cl Cl trans, m.p. 156 ° C

43

B.1 H2N-SO2- (CH2) 4- Br Cl trans, m.p. 120 ° C

44

B.1 H2N-SO2- (CH2) 4- H F trans; oxalate (1: 1)

Four. Five

B.1 H2N-SO2- (CH2) 4- H Cl trans

46

B.1 H2N-SO2- (CH2) 3- H F trans; m.p. 138 ° C

Table F-4

Co. No.

 Ex. No.  -L R3  R4  Physical data

47

B.1 H2N-SO2- (CH2) 4- CH3O H -

48

B.1 H2N-SO2- (CH2) 4- H CH3 m.p. 152 ° C

Pharmacological Examples

Example C.1: "5HT4 antagonism"

10 Clone 9 cells of h5-HT4b-HEK 293 were cultured in 150 mm Petri dishes and washed twice with cold PBS. The cells were then scraped off the plates and suspended in 50 mM Tris-HCl buffer, pH 7.4, and collected by centrifugation at 23,500 rpm for 10 minutes. The pellet was resuspended in 5 mM Tris-HCl, pH 7.4, and homogenized with an Ultra Turrax homogenizer. The membranes were separated by centrifugation at 30,000 rpm for 20 min, resuspended in 50 mM Tris-HCl, pH 7.4, and stored at -80 ° C. For him

In the experiment, the test mixtures (0.5 ml) contained 50 μl of the assessed ligand (5-HT4 antagonist [3H] GR113808 0.1 nM) and 0.4 ml of membrane preparation (15 μg protein / ml). 50 µl of 10% DMSO was added to determine total binding. 50 μl of 1 μM of (+) - trans- (1-butyl-3-hydroxy-4-piperidinyl) methyl 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxy-5-carboxylate was added (a 5HT4 agonist patented by Janssen Pharmaceutica) to determine non-specific binding. The assay buffer of [3H] GR113808 was HEPES-NaOH

20 50 mM, pH 7.4. The mixtures were incubated for 30 min at 25 ° C. The incubation was stopped by filtration on a Unifilter 96 GF / B pre-soaked in 0.1% polyethyleneimine, followed by six washing steps with 50 mM HEPES-NaOH, pH 7.4. Isotherms for binding with respect to the concentration of ligands (rectangular hyperbola) were calculated by a non-linear regression analysis and pCI50 values for all the compounds studied are listed below in Table C.1.

Table C.1: 5HT4 antagonism data

Co. No.

 pCI50  Co. No.  pCI50  Co. No.  pCI50

one

7.92 17 8.75 33 8.66

2

8.02 18 8.28 3. 4 8.94

3

7.66 19 8.47 35 9.39

4

8.83 twenty 8.33 37 7.8

5

9.13 twenty-one 8.52 38 7.95

6

7.54 22 8.27 39 7.9

7

8.73 2. 3 8.24 40 6.8

8

7.3 24 8.54 41 7.25

9

7.61 25 8.07 42 8.82

10

8.89 26 9.17 43 8.77

eleven

8.4 27 7.92 44 8.43

12

8.79 28 7.51 Four. Five 8.86

13

8.47 29 8.78 46 8.38

14

8.71 30 8.77 47 7

fifteen

7.45 31 9.05 48 7.68

16

6.56 32 8.44

Example C.2: "Metabolic stability"

Subcellular tissue preparations were prepared according to Gorrod et al. (Xenobiotica 5: 453-462, 1975) by centrifugal separation after mechanical tissue homogenization. The liver tissue was washed in

10 0.1 M Tris-HCl buffer (pH 7.4) ice cream to remove excess blood. The tissue was dried with filter paper, weighed and cut into large pieces using surgical scissors. The pieces of tissue were homogenized in 3 volumes of 0.1 M phosphate buffer (pH 7.4) ice cream.

Tissue homogenates were centrifuged at 9000 x for 20 minutes at 4 ° C. The resulting supernatant was stored at -80 ° C and is called 'S9'.

Fraction S9 can also be centrifuged at 100,000 x g for 60 minutes (4 ° C). The resulting supernatant was carefully aspirated, divided into aliquots and called 'cytosol'. The pellet was resuspended in 0.1 M phosphate buffer (pH 7.4) to a final volume of 1 ml per 0.5 g of original tissue weight and was called 'microsomes'.

20 All subcellular fractions were divided into aliquots, immediately frozen in liquid nitrogen and stored at -80 ° C until use.

For the samples to be studied, the incubation mixture contained PBS (0.1M), compound (5 μM), 25 microsomes (1 mg / ml) and a NADPH generating system (0.8 mM glucose-6-phosphate, chloride of 0.8 mM magnesium and

0.8 glucose-6-phosphate dehydrogenase units). Control samples contained the same material but microsomes were replaced by thermally inactivated microsomes (10 minutes at 95 degrees Celsius). The recovery of the compounds in the control samples was always 100%.

The mixtures were pre-incubated for 5 minutes at 37 degrees Celsius. The reaction started at the zero evaluation point (t = 0) by adding 0.8 mM NADP and the samples were incubated for 60 minutes (t = 60). The reaction was stopped by adding 2 volumes of DMSO. The samples were then centrifuged for 10 minutes at 900 x g and the supernatant was stored at room temperature for a period not exceeding 24 hours before analysis. All incubations were carried out in duplicate. Supernatant analysis was carried out

35 by LC-MS analysis. The elution of the samples was carried out in an Xterra MS C18 (50 x 4.6 mm, 5 μm, Waters, USA). An HPLC Alliance 2790 system (provider: Waters, USA) was used. It was eluted with buffer A (25 mM ammonium acetate (pH 5.2) in H2O / acetonitrile (95/5)), solvent B being acetonitrile and solvent C methanol with a flow rate of 2.4 ml / min. The gradient used was increasing the concentration of the organic phase from 0% to 50% of B and 50% of C in 5 min up to 100% of B in 1 minute in a linear fashion and a concentration of the organic phase was kept stationary for 1.5 more minutes. The total volume of

5 injection of the samples was 25 μl.

A Quatro triple quadrupole mass spectrometer with an ESP source was used as a detector. The source and desolvation temperature were set at 120 and 350 ° C respectively and nitrogen was used as a desiccant and nebulizer gas. Data were acquired in positive scan mode (monoionic reaction). Voltage

10 focal was set to 10 V and the residence time was 1 second.

Metabolic stability was expressed as the% metabolism of the compound after 60 minutes (equation presented by way of example) of incubation in the presence of active microsomes (E (act)).

Table C.2:% of metabolized compound after 60 minutes 5

Co. No.

% metabolized Co. No.  % metabolized

4

eleven 27 5

5

13 28 6

6

9 29 17

7

3 30 12

fifteen

36 31 18

18

7 32 0

19

14 35 fifteen

twenty

2 38 3

twenty-one

twenty-one

39 2

22

28.5 40 0

2. 3

8 44 27

24

53 47 0

25

8.5 48 6

26

13

Claims (9)

1. A compound of formula (I) of pharmaceutically acceptable acid or base, where -R1-R2- is a bivalent radical of formula

-O-CH2-O

(a-1),

-O-CH2-CH2

(a-2),

-O-CH2-CH2-O

(a-3),

-O-CH2-CH2-CH2

(a-4),

-O-CH2-CH2-CH2-O

(to 5),

-O-CH2-CH2-CH2-CH2

(a-6),

-O-CH2-CH2-CH2-CH2-O

(a-7),

-O-CH2-CH2-CH2-CH2-CH2

(a-8),

wherein in said bivalent radicals optionally one or two hydrogen atoms of the same carbon atom or of different carbon atoms may be replaced by C1-6 alkyl or hydroxy, R3 is hydrogen, halo, C1-6 alkyl or C1-6 alkyloxy; R4 is hydrogen, halo, C1-6 alkyl; C1-6 alkyl substituted with cyano or C1-6 alkyloxy; C1-6 alkyloxy; cyano, amino or, mono- or di (C1-6 alkyl) amino; R5 is hydrogen or C1-6 alkyl and the radical -OR5 is located at position 3 or 4 of the piperidine moiety; L is a radical of the formula -Alq-R6, wherein Alq is C1-4 alkanediyl; Y R 6 is aminosulfonyl or aminosulfonyl substituted with C 1-4 alkyl or phenyl.

2.

A compound as claimed in claim 1 wherein the radical -OR5 is located at position 3 of the piperidine moiety with trans configuration.

3.

A compound as claimed in claim 2 wherein the absolute configuration of said piperidine moiety is (3S, 4S).

Four.

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound according to any one of claims 1 to 3.

5.

A process for preparing a pharmaceutical composition according to claim 4 wherein a therapeutically active amount of a compound according to any one of claims 1 to 3 is in intimate admixture with a pharmaceutically acceptable carrier.

6.

A compound according to any one of claims 1 to 3 for use as a medicine.

7.

A compound according to any one of claims 1 to 3 for use in the treatment of gastrointestinal disorders.

8.

A compound according to any one of claims 1 to 3 for use in the treatment of hypermotility, irritable bowel syndrome (IBS), IBS with a predominance of constipation or diarrhea, IBS with predominantly pain or no pain, or hypersensitivity intestinal.

9.

A process to prepare a compound of formula (I) where

a) an intermediate of formula (II) is reacted with a carboxylic acid derivative of formula (III) or a reactive functional derivative thereof; b) an intermediate of formula (IV) is subjected to N-alkylation with an intermediate of formula (V) in an inert reaction solvent and optionally in the presence of a suitable base; wherein, in the above reaction schemes, the radicals -R1-R2-, R3, R4, R5 and L are as defined in claim 1 and W is a suitable leaving group; C) or the compounds of formula (I) are interconverted by transformation reactions known in the art; or, if desired, a compound of formula (I) is converted into a pharmaceutically acceptable acid addition salt or, conversely, an acid addition salt of a compound of formula (I) is converted into a free base with alkali; and, if desired, preparing stereochemically isomeric forms thereof.