HK1095327B

HK1095327B - 4-(aminomethyl)-piperidine benzamides as 5ht4-antagonists

Info

Publication number: HK1095327B
Application number: HK07100899.5A
Authority: HK
Inventors: Jean-Paul René Marie André BOSMANS; Henricus Jacobus Maria Gijsen; Laurence Anne Mevellec
Original assignee: Janssen Pharmaceutica N.V.
Priority date: 2003-06-19
Filing date: 2004-06-10
Publication date: 2010-04-16

Description

As 5HT4-4- (aminomethyl) -piperidine benzamides as antagonists

The invention relates to a polymer having 5HT₄Novel compounds of formula (I) having antagonistic properties. The invention further relates to processes for the preparation of such novel compounds, pharmaceutical compositions comprising said novel compounds and the use of said compounds as medicaments.

WO-00/37461 discloses compounds having 5HT₄Bicyclic benzamides of 3-or 4-substituted 4- (aminomethyl) -piperidine derivatives having antagonistic properties.

The compounds of the present invention differ structurally from the compounds known in the cited art by the presence of a functional group other than hydrogen or halogen at the 4-position of the benzamide moiety.

Unexpectedly, the compounds of formula (I) of the present invention have improved metabolic stability compared to the compounds disclosed in WO-00/37461.

The present invention relates to compounds of formula (I):

a stereochemically isomeric form thereof, an N-oxide form thereof, or a pharmaceutically acceptable acid or base addition salt thereof,

wherein

-R¹-R²-is a divalent 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)，

wherein in the divalent radical, one or two hydrogen atoms, optionally on the same or different carbon atoms, may be replaced by C_1-6Alkyl or hydroxyl is substituted, and the alkyl or the hydroxyl is substituted,

R³is hydrogen, halogen, C_1-4An alkyl group;

R⁴is C_1-6An alkyl group; by cyano or C_1-6Alkoxy-substituted C_1-6An alkyl group; c_1-6An alkoxy group; a cyano group; amino or mono-or di (C)_1-6Alkyl) amino;

R⁵is hydrogen or C_1-6Alkyl, and-OR⁵The group is located at the 3-or 4-position of the piperidine moiety;

l is hydrogen, or L is a group of the formula

-Alk-R⁶ (b-1)，

-Alk-X-R⁷ (b-2)，

-Alk-Y-C(＝O)-R⁹(b-3), or

-Alk-Z-C(＝O)-NR¹¹R¹² (b-4)，

Wherein each Alk is C_1-12An alkanediyl group; and is

R⁶Is hydrogen; a hydroxyl group; a cyano group; c_3-6A cycloalkyl group; c_1-6An alkylsulfonylamino group; aryl or Het;

R⁷is C_1-6An alkyl group; hydroxy-substituted C_1-6An alkyl group; c_3-6A cycloalkyl group; aryl or Het;

x is O, S, SO₂Or NR⁸(ii) a The R is⁸Is hydrogen or C_1-6An alkyl group;

R⁹is hydrogen, C_1-6Alkyl radical, C_3-6Cycloalkyl, hydroxy or aryl;

y is a direct bond, or NR¹⁰Wherein R is¹⁰Is hydrogen or C_1-6An alkyl group;

z is a direct bond, O, S or NR¹⁰Wherein R is¹⁰Is hydrogen or C_1-6An alkyl group;

R¹¹and R¹²Each independently of the other being hydrogen, C_1-6Alkyl radical, C_3-6Cycloalkyl, or R¹¹And R¹²And with R¹¹And R¹²May form a pyrrolidinyl, piperidinyl, piperazinyl or 4-morpholinyl ring, both of which may optionally be substituted by C_1-6Alkyl substitution;

aryl represents unsubstituted phenyl or is substituted by 1, 2 or 3 substituents independently chosen from halogen, hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Phenyl substituted with substituents for alkylcarbonyl, nitro, trifluoromethyl, amino, aminocarbonyl and aminosulfonyl; and

het is furyl; quilt C_1-6Alkyl or halo substituted furyl;

a tetrahydrofuranyl group; quilt C_1-6Alkyl-substituted tetrahydrofuranyl;

dioxolanyl; quilt C_1-6An alkyl-substituted dioxolanyl group;

a dioxanyl group; quilt C_1-6Alkyl-substituted dioxanyl;

a tetrahydropyranyl group; quilt C_1-6Alkyl-substituted tetrahydropyranyl;

2, 3-dihydro-2-oxo-1H-imidazolyl; is one or two are independently selected from halogen or C_1-62, 3-dihydro-2-oxo-1H-imidazolyl substituted with a substituent of alkyl;

a pyrrolidinyl group; is one or two of each independently selected from halogen, hydroxy or C_1-6Pyrrolidinyl substituted with a substituent for alkyl;

a pyridyl group; is one or two of each independently selected from halogen, hydroxy or C_1-6Pyridyl substituted with a substituent for alkyl;

a pyrimidinyl group; is one or two of each independently selected from halogen, hydroxy or C_1-6Pyrimidinyl substituted with alkyl substituents;

a pyridazinyl group; is one or two of each independently selected from hydroxyl and C_1-6Alkoxy radical, C_1-6A pyridazinyl group substituted with a substituent of an alkyl group or a halogen;

a pyrazinyl group; is one or two of each independently selected from hydroxyl and C_1-6Alkoxy radical, C_1-6A pyrazinyl group substituted with an alkyl or halogen substituent.

Halogen as used in the above definitions broadly refers to fluorine, chlorine, bromine and iodine; c_1-4Alkyl is defined as straight and branched chain saturated hydrocarbon groups having from 1 to 4 carbon atoms, e.g., methyl, ethyl, propyl, butyl, 1-methyl-ethyl, 2-methylpropyl, and the like; c_1-6Alkyl is intended to include C_1- ₄Alkyl and its higher homologues having 5 or 6 carbon atoms, for example, 2-methyl-butyl, pentyl, hexyl and the like; c_3-6Cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; c_1-12Alkanediyl is defined as containing from 1 to 12 carbon atomsDivalent straight-chain or branched-chain hydrocarbon groups of the subgroups, 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-nonanediyl, 1, 10-decanediyl, 1, 11-undecanediyl, 1, 12-dodecanediyl and branched-chain isomers thereof. C_1-4Alkanediyl is defined as a divalent straight or branched chain hydrocarbon radical containing from 1 to 4 carbon atoms, for example, methanediyl, 1, 2-ethanediyl, 1, 3-propanediyl, and 1, 4-butanediyl.

The term "stereochemically isomeric forms" as used hereinbefore defines all the possible isomeric forms which the compounds of formula (I) may possess. Unless otherwise indicated or indicated, the chemical designation of a compound denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More specifically, the stereocenter may have the R-or S-configuration; the substituents on the divalent cyclic (partially) saturated groups may have either the cis-or trans-configuration. Compounds containing a double bond may have E or Z-stereochemistry at the double bond. The stereochemically isomeric forms of the compounds of formula (I) are expressly intended to be embraced within the scope of the present invention.

The pharmaceutically acceptable acid and base addition salts mentioned above are intended to include the therapeutically active non-toxic acid and base addition salt forms which the compounds of formula (I) are able to form. Pharmaceutically acceptable acid addition salts are conveniently obtained by treating the base form with a suitable acid. Suitable acids include, for example, inorganic acids such as hydrohalic acids, e.g., hydrochloric or hydrobromic acids, sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids such as acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid (i.e., oxalic acid), malonic acid, succinic acid (i.e., succinic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, and the like.

Conversely, the salt form may be converted to the free base form by treatment with a suitable base.

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

The term addition salt as used above also comprises the solvates which the compounds of formula (I) and salts thereof are able to form. Such solvates are for example hydrates, alcoholates and the like.

Some compounds of formula (I) may also exist in their tautomeric forms. Such forms, although not explicitly indicated in the above formula, are also included within the scope of the present invention. For example, when an aromatic heterocycle is substituted with a hydroxyl group, the keto form may be the predominant tautomer.

The N-oxide forms of the compounds of formula (I), which may be prepared in a manner known in the art, are intended to include those compounds of formula (I) in which one or more nitrogen atoms are oxidized to the N-oxide. Particular N-oxides include those in which the piperidine-nitrogen is N-oxidized.

A group of valuable compounds includes those compounds of formula (I) wherein one or more of the following limitations apply:

a)-R¹-R²-is a group of formula (a-3); and/or

b)-R¹-R²-is a group of formula (a-5); and/or

c)R³Is hydrogen or halogen; and/or

d)R⁴Is methyl, methoxy, methoxymethyl, cyano, cyanomethylamino, amino or C_1-6An alkylamino group; and/or

e)R⁵Is hydrogen OR methyl, and-OR⁵The radicals being located on the piperidine ring3-or 4-position; and/or

f)R⁵Is hydrogen, and-OR⁵The group is located at the 3-position of the piperidine ring; and/or

g)R⁵Is hydrogen, and-OR⁵The group is located at the 4-position of the piperidine ring; and/or

h)-OR⁵The group is located at the 3-position of the piperidine ring and is in the trans position to the methylene group at the 4-position of the piperidine moiety; and/or

i)-OR⁵The group is located at the 3-position of the piperidine ring and is in the trans position to the methylene group at the 4-position of the piperidine moiety, the absolute configuration of the piperidine moiety being (3S, 4S); and/or

j) L is hydrogen;

k) l is a group of formula (b-1), (b-2), (b-3) or (b-4); or

L) L is a radical of formula (b-1) wherein Alk is C_1-4Alkanediyl, and R⁶Is hydrogen, hydroxy, cyano, C_3-6Cycloalkyl radical, C_1-6Alkylsulfonylamino, which represents an aryl group of a phenyl group substituted by halogen or hydroxyl; or Het represents tetrahydrofuryl, dioxolanyl, or C_1-4An alkyl-substituted dioxolanyl group, or a pyridyl group; or

L is a group (b-2) wherein Alk is C_1-4Alkanediyl, X represents O, R⁷Is C_3-6Cycloalkyl radical, C_1-6Alkyl, C substituted by hydroxy_1-6Alkyl, or aryl representing phenyl substituted by aminosulfonyl; or

L is a group (b-2) wherein Alk is C_1-4Alkanediyl, X represents NR⁸Wherein R is⁸Is hydrogen and R⁷Is C_1-6Alkyl, or Het represents C_1-6An alkyl-substituted pyrimidinyl or pyrazinyl group; or

L is a group (b-2) wherein Alk is C_1-4Alkanediyl, X represents SO₂，R⁷Is C_1-6An alkyl group; or

L is a group (b-3) wherein Alk is C_1-4Alkanediyl, Y is a direct bond and R⁹Is C_1-6Alkyl or hydroxy; or

L is a group of the formula (b-4) wherein Alk is C_1-4Alkanediyl, Z is a direct bond, R¹¹And R¹²Represents hydrogen, or R¹¹And R¹²And with R¹¹And R¹²Is combined with nitrogen atom to form a quilt C_1-6Alkyl-substituted pyrrolidinyl or piperazinyl; or

L is a group of the formula (b-4) wherein Alk is C_1-4Alkanediyl, Z is O, R¹¹And R¹²And with R¹¹And R¹²The nitrogen atoms of (a) combine to form a pyrrolidinyl group.

Other valuable compounds are those of the formula (I) in which

-R¹-R²Is a divalent radical of the formula

-O-CH₂-CH₂-O- (a-3)，

-O-CH₂-CH₂-CH₂-O- (a-5)，

R³Is hydrogen, halogen, C_1-4An alkyl group;

l is hydrogen, or L is a group of the formula

-Alk-R⁶ (b-1)，

-Alk-X-R⁷ (b-2)，

-Alk-Y-C(＝O)-R⁹(b-3), or

-Alk-Z-C(＝O)-NR¹¹R¹² (b-4)，

Wherein each Alk is C_1-12An alkanediyl group; r⁶Is hydrogen; a hydroxyl group; a cyano group; c_3-6A cycloalkyl group; c_1-6An alkylsulfonylamino group; aryl or Het;

x is O, S, SO₂Or NR⁸(ii) a The R is⁸Is hydrogen or C_1-6An alkyl group;

R⁹is C_1-6Alkyl or hydroxy;

y is a direct bond;

z is a direct bond or O;

R¹¹and R¹²Each independently is hydrogen, or C_1-6Alkyl, or R¹¹And R¹²And with R¹¹And R¹²May be combined to form a quilt with C_1-6Alkyl-substituted pyrrolidinyl or piperazinyl;

aryl represents unsubstituted phenyl or is substituted by 1, 2 or 3 substituents independently chosen from halogen, hydroxy, C_1-6Alkyl radical, C_1-6Phenyl substituted with substituents for alkoxy and aminosulfonyl; and

het is tetrahydrofuryl; quilt C_1-6Alkyl-substituted tetrahydrofuranyl;

dioxolanyl; quilt C_1-6An alkyl-substituted dioxolanyl group;

a pyridyl group; is one or two of each independently selected from halogen, hydroxy, C_1-6Pyridyl substituted with a substituent for alkyl;

a pyrimidinyl group; is one or two of each independently selected from halogen, hydroxy, or C_1-6Pyrimidinyl substituted with alkyl substituents;

Particular compounds are those of formula (I) wherein-OR⁵The radical preferably represents a hydroxyl OR methoxy group, in the 3-position of the piperidine moiety having the trans configuration, i.e. -OR⁵The group is in the trans position relative to the methylene group on the piperidine moiety.

More specific compounds are of formula (I): wherein the divalent radical-R¹-R²Is a radical of formula (a-3) OR (a-5), -OR⁵The group represents a hydroxyl group and is located at the 3-position of the piperidine moiety having the (3S-trans) configuration, which corresponds to the absolute (3S, 4S) configuration of the piperidine moiety.

Preferred compounds are more specific compounds: wherein-R¹-R²-is a group of formula (a-5); r³Is hydrogen; r⁴Is methyl; r⁵Is hydrogen.

More preferred compounds are the following preferred compounds: wherein L is a group of the formula (b-2) wherein X is O and Alk is C_1-4Alkanediyl and R⁷Is C_1-6Alkyl, preferably methyl.

The most preferred compounds are the following: (87) (125), (158), (159), (162), (163), (165), (168), (177), (183), (184), (185), (186), (187), (200), (202), (211), (225), (228), (229), (246), and (247).

The compounds of formula (I) may be prepared by reacting an intermediate of formula (II) with a derivative of formula (III) or optionally a reactive functional derivative thereof, for example a carbonylimidazole derivative, an acid halide or a mixed anhydride. The amide bond may be formed by stirring the reactants in a suitable solvent, optionally in the presence of a base such as triethylamine.

Compounds of formula (I-b), defined as compounds of formula (I) wherein L is other than hydrogen, may generally be prepared by: n-alkylating an intermediate of formula (I-a) with an intermediate of formula (IV), wherein W is a suitable leaving group such as a halogen, e.g., fluorine, chlorine, bromine, iodine, or in some cases, W may also be a sulfonyloxy group, e.g., a reactive leaving group such as methanesulfonyloxy, benzenesulfonyloxy, trifluoromethanesulfonyloxy, and the like. The compound of formula (I-a) is defined as a compound of formula (I) wherein L represents hydrogen. The reaction can be carried out in a reaction-inert solvent such as acetonitrile, 2-pentanol, isobutanol, dimethylacetamide or DMF, optionally in the presence of a suitable base such as sodium carbonate, potassium carbonate, N-methylpyrrolidone or triethylamine. Stirring may increase the reaction rate. The reaction can be conveniently carried out at a temperature in the range between room temperature and the reflux temperature of the reaction mixture.

Alternatively, compounds of formula (I-b) may also be prepared by reductive N-alkylation of compounds of formula (I-a) using intermediates of formula L '═ O (v), where L' ═ O represents a derivative of formula L-H in which two geminal hydrogen atoms are substituted by oxygen, by reductive N-alkylation procedures known in the art.

The reductive N-alkylation may be carried out in a reaction inert solvent such as dichloromethane, ethanol, toluene or mixtures thereof, and in the presence of a reducing agent such as a borohydride, e.g. sodium borohydride, sodium cyanoborohydride or triacetoxyborohydride. It may also be convenient to use hydrogen as a reducing agent in combination with a suitable catalyst such as palladium on carbon or platinum on carbon. If hydrogen is used as reducing agent, it is appropriate to add a dehydrating agent, for example aluminum tert-butoxide, to the reaction mixture. In order to prevent undesired further hydrogenation of certain functional groups in the reactants and reaction products, it may also be advantageous to add suitable catalyst poisons such as thiophene or quinoline-sulphur to the reaction mixture. To increase the reaction rate, the temperature may be increased between room temperature and the reflux temperature of the reaction mixture, and optionally the hydrogen pressure may be increased.

The compound of formula (I-a) may be prepared by: intermediates of formula (VI) wherein PG represents a suitable protecting group known in the art, such as t-butoxycarbonyl or benzyl or a photo-removable group, are reacted with an acid of formula (III) or a suitable reactive functional derivative thereof, such as a carbonylimidazole derivative, followed by deprotection of the thus formed intermediate, i.e. removal of PG by methods known in the art.

A compound of formula (I-c) defined wherein R³Is hydrogen and R⁴Compounds of formula (I) which are amino groups may generally be prepared by N-alkylating intermediates of formula (II) with carboxylic acid derivatives of formula (III-a). The N-alkylation reaction may be carried out by stirring the reactants in a suitable solvent, optionally in the presence of a base such as potassium carbonate or triethylamine. The N-alkylation reaction is followed by a hydrogenation step using a suitable catalyst such as palladium on carbon.

A compound of formula (I-d) defined wherein R⁴Compounds of formula (I) which are methylamino groups may generally be prepared by N-alkylating intermediates of formula (II) with carboxylic acid derivatives of formula (III-b) wherein the PG group is a protecting group which can be removed under acidic conditions, e.g. tert-butoxy-carbonyl. The N-alkylation reaction may be carried out by stirring the reactants in a suitable solvent, optionally in the presence of a base such as potassium carbonate or triethylamine. The N-alkylation reaction is followed by hydrolysis under acidic conditions to remove the protecting group PG.

The compounds of formula (I) can be prepared by converting the compounds of formula (I) into each other further according to group conversion reactions known in the art.

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

Intermediates of formula (VI) may be prepared according to the general procedures described for intermediates of formula (VIII) as described in WO-99/02156 or WO-00/37461.

The compounds of formula (I), prepared according to the processes described above, can be synthesized in the form of racemic mixtures of enantiomers, which can be separated from each other according to 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. The diastereomeric salt forms are subsequently separated, for example by selective or fractional crystallization, and the enantiomers are freed therefrom by base. An alternative to separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. The pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction proceeds stereospecifically. Preferably, if a particular stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These processes preferably employ enantiomerically pure starting materials.

A compound of formula (I), the N-oxide forms, the pharmaceutically acceptable acid or base addition salts and the stereoisomeric forms thereof, having 5HT as described in example C.1₄-antagonistic properties.

Furthermore, as described in example c.2, the compounds of formula (I) show improved metabolic stability relative to the structurally related compounds of WO-00/37461. The favourable metabolic stability properties result in a reduced risk of drug-drug interactions at the level of cytochrome P450 enzymes such as CYP1a2, CYP3a4, CYP2D6, CYP2C9 and CYP2C 19, and thus the compounds of the present invention have improved drug safety profiles. Moreover, these advantageous metabolic stability properties may allow for the once daily administration of the compounds of formula (I) instead of the usual dosing regimen with between two or four active ingredient intakes per day, thereby allowing for higher patient compliance.

In view of the 5HT of the compounds of the invention₄Antagonistic properties, which compounds can be used in general for the treatment or prevention of gastrointestinal disorders such as hypermotility, Irritable Bowel Syndrome (IBS), constipation-or diarrhea-predominant IBS, pain-and non-pain-predominant IBS, intestinal hypersensitivity, and reduction of pain associated with gastrointestinal hypersensitivity and/or hyperactivity.

It is also believed that the compounds of formula (I) are effective for preventing or preventing dysregulated, obstructed or impaired gastric regulation such as dyspepsia. Dyspepsia symptoms are e.g. abdominal pressure, lack of appetite, feeling of fullness, early satiety, nausea, vomiting, bloating and hiccups.

The compounds of formula (I) are likewise useful for the treatment of other disorders of the 5HT type₄Associated disorders such as bulimia and bulimia.

In view of the utility of the compounds of formula (I), the present invention also provides a method of treatment of warm-blooded animals including humans (generally referred to herein as patients) suffering from gastrointestinal disorders such as Irritable Bowel Syndrome (IBS). Thus, a method of treatment is provided for relieving conditions in a patient suffering from conditions such as hyper-motility, Irritable Bowel Syndrome (IBS), constipation-or diarrhea-predominant IBS, pain-and non-pain-predominant IBS, bowel hypersensitivity, and the like, and for reducing pain associated with gastrointestinal hypersensitivity and/or hyperactivity.

The compounds of formula (I) may also have potential use in other gastrointestinal disorders, for example those associated with upper intestinal motility. In particular, they have potential use in the treatment of gastric symptoms of gastro-esophageal reflux disease, such as heartburn (including episodic heartburn, nocturnal heartburn, and diet-induced heartburn).

Furthermore, 5HT of the formula (I)₄Antagonistic compounds also have potential use for the treatment or prevention of bladder hypersensitivity, overactive bladder, lower urinary tract symptoms, Benign Prostatic Hypertrophy (BPH), prostatitis, detrusor hyperreflexia, outlet obstruction, urinary frequency, nocturia, urgency, pelvic hypersensitivity, urge incontinence, urethritis, prostatodynia, cystitis, idiopathic bladder hypersensitivity, urinary incontinence or urinary incontinence associated with irritable bowel syndrome. In this respect, 5HT of formula (I)₄-antagonistic compounds are combined with alpha-adrenergic receptor antagonists such as aldoses, indoramins, tamsulosin, doxazosin, terazosin, amonoquine, or prazosin to obtain a composition comprising such alpha-adrenergic receptor antagonists and 5-HT of formula (I)₄Pharmaceutical compositions of receptor antagonists may be advantageous.

The present invention therefore provides the use of a compound of formula (I) as a medicament, and in particular the use of a compound of formula (I) for the preparation of a medicament for the treatment of gastrointestinal disorders such as hyper-motility, IBS, constipation-or diarrhea-predominant IBS, pain-and non-pain-predominant IBS, irritable bowel syndrome, and reduction of pain associated with gastrointestinal hypersensitivity and/or hyperactivity. Including prophylactic and therapeutic medical treatment.

In view of the compounds of the invention5HT₄Antagonistic Properties, the Compounds of the invention may also be used in humans for the treatment or prevention of 5HT₄-related CNS disorders. In particular, the compounds of formula (I) are useful for treating various CNS disorders including, but not limited to, substance abuse, cognitive disorders such as Alzheimer's disease, senile dementia; behavioral disorders such as schizophrenia, mania, obsessive-compulsive disorder and disorders caused by the use of psychoactive substances; mood disorders such as depression, bipolar disorder, anxiety and panic disorder; disorders that can be controlled from the host such as hypertension and sleep disorders; obsessive/compulsive disorders include anorexia and bulimia, and neuropsychiatric disorders, such as the facio-vocal cord tic syndrome (Gilles de la tourette's syndrome), and Huntington's disease.

To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. It is desirable that these pharmaceutical compositions are present in unit dosage forms, preferably suitable for administration orally, rectally or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, e.g., 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, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most convenient oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will typically comprise sterile water, at least in large part, although other components may be included, for example, to aid solubility. For example, injection solutions can be prepared in which the carrier comprises saline, dextrose solution, or a mixture of saline and dextrose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In compositions suitable for transdermal administration, the carrier optionally includes agents that enhance penetration and/or suitable wetting agents, optionally in combination with minor proportions of suitable additives of any nature that do not result in a significant deleterious effect on the skin. The additives may facilitate administration to the skin and/or may aid in the preparation of the desired composition. These compositions can be administered in a variety of ways, for example, as transdermal patches, as spot doses, as ointments. (I) The acid addition salts of (a) are significantly more suitable for use in the preparation of aqueous compositions due to their increased water solubility over the corresponding base forms.

It is particularly advantageous to formulate the above pharmaceutical compositions in unit dosage form for ease of administration and to have uniform dosages. As used herein the specification and claims, unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, packets of wafer, injectable solutions or suspensions, teaspoonful dosage forms, tablespoonful dosage forms and the like, and segregated multiples thereof.

For oral administration, the pharmaceutical compositions may take the form of solid dosage forms such as tablets (both swallowable and chewable), capsules or gelcaps, prepared by mixing with a pharmaceutically acceptable excipient such as a binder (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate) are prepared in a conventional manner. Tablets may 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 for constitution with water or other suitable vehicle before use. Such liquid medicaments may optionally be combined with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methyl cellulose, hydroxy-propyl methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g. methyl or propyl paraben or sorbic acid) are prepared by conventional methods.

Pharmaceutically acceptable sweeteners include preferably at least one intense sweetener such as saccharin, sodium or calcium saccharin, aspartame, acesulfame potassium, sodium cyclamate, alitame, dihydrochalcone sweeteners, monellin, stevioside or sucralose (4, 1 ', 6' -trichloro-4, 1 ', 6' -trideoxygalactosucrose), preferably saccharin, sodium saccharin or calcium saccharin, and bulk sweeteners such as sorbitol, mannitol, fructose, sucrose, maltose, isomalt, glucose, hydrogenated glucose syrup, xylitol, caramel or honey.

Intense sweeteners may conveniently be used at low concentrations. For example, in the case of sodium saccharin, the concentration may range from 0.04% to 0.1% (w/v) based on the total volume of the final formulation, preferably about 0.06% in low-dose formulations and about 0.08% in high-dose formulations. Bulk sweeteners can be effectively used in large amounts ranging from about 10% to about 35%, preferably from about 10% to about 15% (w/v).

Pharmaceutically acceptable flavoring agents that can mask the bitter taste component in low dosage formulations are preferably fruit flavors such as cherry, raspberry, blackcurrant, or strawberry flavors. The combination of two flavors gives good results. Stronger flavors may be desired in high-dose formulations, such as caramel chocolate flavors, spearmint flavors, fantasy flavors, and the like, as pharmaceutically acceptable accent flavors. Each flavoring agent may be present in the final composition at a concentration ranging from 0.05% to 1% (w/v). Preferably, a combination of said strong odorants is used. It is preferred to use a flavoring agent that does not undergo any change or loss in taste and color under acidic conditions of the formulation.

The formulations of the present invention may optionally include antiflatulent agents, such as dimethicone, alpha-D-galactosidase, and the like.

The compounds of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt.

The compounds of the invention may be formulated for parenteral administration by injection, conveniently by intravenous, intramuscular or subcutaneous injection, for example by bolus injection or continuous intravenous infusion. Formulations for injection may be presented in unit dosage form, for example, in ampoules with added preservative and in one or more dosage form containers. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as isotonic, suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

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

For intranasal administration, it is possible to use the compounds of the invention, for example, as a liquid spray, as a powder or as drops.

It is generally recognized that a therapeutically effective amount will range from about 0.0001 mg/kg to about 1 mg/kg body weight, preferably from about 0.001 mg/kg to about 0.5 mg/kg body weight.

Experimental part

The following abbreviations are used in the procedures described hereinafter: "ACN" represents acetonitrile; "THF", which stands for tetrahydrofuran; "DCM" represents dichloromethane; "DIPE" represents diisopropyl ether; "EtOAc" represents ethyl acetate; "NH"₄OAc "represents ammonium acetate; "HOAc" represents acetic acid; "MIK" represents methyl isobutyl ketone, "DMF" represents dimethylformamide and "DMA" represents dimethylacetamide.

For some chemicals, chemical formulae are used, e.g. NaOH is sodium hydroxide, Na₂CO₃Is sodium carbonate, K₂CO₃Is potassium carbonate, H₂Is hydrogen, N₂Is nitrogen gas, CH₂Cl₂Is dichloromethane, CH₃OH is methanol, NH₃Is ammonia, HCl is hydrochloric acid, NaH is sodium hydride, CaCO₃Is calcium carbonate and KOH is potassium hydroxide.

A. Preparation of intermediates

Example A.1

a) Preparation of intermediate (1)

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 left at room temperature overnight. The mixture was then concentrated and the residue partitioned between DCM and water. The separated aqueous layer was washed with DCM and the organic layer was collected, dried, filtered and concentrated. The product was dried to yield 120 g of intermediate (1).

b) Preparation of intermediate (2)

Intermediate (1) (0.35 mol), K₂CO₃A mixture of (0.77 mol) and tetrabutylammonium bromide (5 g) was stirred in 1, 2-dibromoethane (42ml), DMA (680ml) and acetone (1000ml) and refluxed (70 ℃ C.) for 20 hours. Additional DMA (250ml), tetrabutylammonium bromide (5 g) and 1-bromo-2-chloroethane (29 ml) were added. The reaction mixture was stirred and refluxed for 44 hours. The reaction mixture was then 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 yield 26 g of intermediate (2) (mp 140 ℃).

c) Preparation of intermediate (3)

A mixture of intermediate (2) (0.063 moles) in NaOH1N (100ml) was stirred and refluxed for 4 hours. The reaction mixture was cooled in an ice bath. A 1N HCl solution (100m l) was added to the formed precipitate. The reaction mixture was allowed to warm to room temperature and the precipitate formed was filtered and dried to yield 14.5 g of intermediate (3) (mp 234 ℃).

Example A.2

a) Preparation of intermediate (4)

A mixture of intermediate (2) (0.089mol) in methanol (500ml) was hydrogenated at 50 ℃ with palladium on carbon (10%; 3g) as catalyst in the presence of thiophene solution (1 ml). After absorption of hydrogen (3 equivalents), the catalyst was filtered off with dicalite and the filtrate was evaporated, yielding 20.9 g of intermediate (4).

b) Preparation of intermediate (5)

To a mixture of intermediate (4) (0.1mol) in chloroform (130 ml) was added trifluoroacetic anhydride (0.11 mol). The reaction mixture was stirred for 1 hour and the mixture was concentrated. The residue is purified on a glass filter by means of silica gel (eluent: CH)₂Cl₂/CH₃OH 90/10). The product fractions were collected and the filtrate was concentrated. The residue was purified by column chromatography over silica gel (eluent: CH)₂Cl₂/CH₃OH 98/2). The pure fractions were collected and the solvent was evaporated, yielding 11.0 g of intermediate (5).

c) Preparation of intermediate (6)

Intermediate (5) (0.036mol) was stirred in DMF (100ml) at room temperature under a stream of nitrogen. Under a stream of nitrogen, 60% sodium hydride in paraffin (0.0432mol) was added in portions. The reaction mixture was warmed to 50 ℃. Methyl iodide (0.0432mol) was then added dropwise at 50 ℃ under a stream of nitrogen. The reaction mixture was stirred at 50 ℃ overnight, then the mixture was cooled to room temperature and poured into water (680ml) and then extracted with toluene. The separated organic layer was dried, filtered and concentrated to give 10.8g of intermediate (6).

d) Preparation of intermediate (7)

A mixture of intermediate (6) (0.0338 mol) in 1N NaOH (0.07mol) and water (60ml) was stirred and refluxed for 1 hour. The reaction mixture was cooled to room temperature, then tert-butyl dicarbonate (0.041 mol) was added, and the reaction mixture was stirred at room temperature overnight. Then 1n hcl (0.07mol) was added and the residue was extracted with DCM. The separated organic layer was dried, filtered and concentrated to give 10.0g of intermediate (7).

Example A.3

a) Preparation of intermediate (8)

Methyl 8-chloro-2, 3-dihydro-1, 4-benzodioxane-5-carboxylate (0.44 mol) was dissolved in sulfuric acid (850 ml). The solution was cooled to below 0 ℃. Nitric acid (fuming, 0.44mol) in sulfuric acid (200ml) was added dropwise over 2 hours. The reaction mixture was stirred at-10 ℃ for 45 minutes and then poured into ice-water. Extraction with DCM gave intermediate (8).

b) Preparation of intermediate (9)

A mixture of intermediate (8) (0.20 mol) in THF (1000ml) and NaOH (2N, 1000ml) was stirred at room temperature for 5 hours. THF (700ml) was evaporated at 35 ℃. The aqueous layer was extracted with ethyl acetate (2 × 750 ml). The separated aqueous layer was cooled on an ice bath and acidified with concentrated HCl. The precipitate was filtered off, washed with water and dried to yield 52g of intermediate (9).

Example A.4

a) Preparation of intermediate (10)

A mixture of intermediate (8) (0.095mol) in THF (250ml) was hydrogenated at 50 ℃ with 5% platinum on carbon (3g) as catalyst in the presence of thiophene solution (2 ml). After uptake of hydrogen (3 equivalents), the reaction mixture was filtered over celite and the filtrate was evaporated to give intermediate (10).

b) Preparation of intermediate (11)

A solution of intermediate (10) (0.095mol) in chloroform (200ml) was cooled in a water bath, and trifluoroacetic anhydride (0.125mol) was added dropwise over 20 to 30 minutes, and the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated, toluene (150ml) was added and the mixture was concentrated to about 100ml, followed by DIPE (300 ml). The resulting precipitate was filtered off, washed with DIPE and dried to yield 28.8g of intermediate (11).

c) Preparation of intermediate (12)

To a solution of intermediate (11) (0.084mol) in N, N-dimethylformamide (150ml) was added NaH (0.09mol) in portions at a temperature below 25 ℃ and the reaction mixture was stirred at room temperature for 90 minutes. Methyl iodide (0.09mol) was added dropwise and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was poured into HCl (400ml, 5% aqueous, cold) and the mixture was extracted with DCM (2 times 350 ml). The organic layer was separated, washed with water, dried, and the solvent was evaporated. The residue was dissolved in NaOH (200ml, 2N) and THF (150ml) and the reaction mixture was stirred and refluxed for 90 minutes. The organic solvent was evaporated and the aqueous alkaline concentrate was cooled on ice and acidified with concentrated HCl. The precipitate was filtered off and dried to yield 19.75g of intermediate (12).

Example A.5

a) Preparation of intermediate (13)

A mixture of methyl 8-amino-2, 3-dihydro-1, 4-benzodioxan-5-carboxylate (0.1mol) in water (100ml) was stirred at room temperature. Sulfuric acid (96%) (11ml) was added dropwise at room temperature. At room temperature, NaNO is added dropwise₂(0.1mol) in water (100 ml). The mixture was stirred at room temperature for 30 minutes to obtain a mixture 1. A mixture of Cu (I) Br 0.15mol in aqueous HBr (48%) (100ml) and water (300ml) was stirred at room temperature. Mixture 1 was added dropwise at room temperature. The mixture was stirred at room temperature for 30 minutes and then diluted with water (300 ml). The precipitate is filtered off, washed with water and washed with CH₂Cl₂/CH₃OH/water (300 ml/100 ml/300 ml) dilution. The solution was filtered over dicalite. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was suspended in DIPE/petroleum ether. The precipitate was filtered off and dried to give 23.2g 8-bromo-2, 3-dihydro-1, 4-benzodioxan-5-carboxylic acid methyl ester (intermediate 13).

b) Preparation of intermediate (14)

A solution of intermediate (13) (0.12mol) in sulfuric acid (175ml) was cooled to 0 ℃. A solution of nitric acid (0.12mol) in sulfuric acid (175ml) was added dropwise. The mixture was stirred at-10 ℃ for 10 minutes and poured into ice water. The precipitate was filtered, washed with water and dissolved in DCM. Water was added. The mixture was extracted with DCM. The organic layer was washed with water, dried, filtered and the solvent was evaporated to give 36g of intermediate (14).

c) Preparation of intermediate (15)

A mixture of intermediate (14) (0.055 moles) in NaOH (300ml) and THF (300ml) was stirred at room temperature overnight. The NaOH was evaporated. Ethyl acetate was added. The mixture was extracted with ethyl acetate. The mixture was acidified with HCl. The precipitate was stirred, then filtered, washed with water (minimum amount) and dried to yield 14.3g of intermediate (15).

Example A.6

a) Preparation of intermediate (16)

Methyl 2, 3-dihydroxy-5-methylbenzoate (0.27 mol) and K₂CO₃A mixture of (0.6mol) in 1, 2-dibromoethane (0.4 mol) and acetone (1000ml) was stirred and refluxed for 24 hours. The reaction mixture was cooled, filtered and the solvent was evaporated. The residue was dissolved in DCM and washed with water and 2N aqueous NaOH. The organic layer was dried, filtered and the solvent was evaporated to give 30.5g of intermediate (16).

b) Preparation of intermediate (17)

A solution of intermediate (16) (0.146mol) in NaOH (2N) (400ml) and THF (400ml) was stirred and refluxed for 18 hours. The reaction mixture was cooled and the THF was removed by evaporation. The residue was acidified with concentrated HCI. The resulting solid was filtered off, washed and dried to yield 26.5g of intermediate (17).

Example A.7

a) Preparation of intermediate (18)

At 0 deg.C, adding NaNO₂A solution of (0.1314 mol) in water (29.3ml) was added dropwise to a mixture of intermediate (4) (0.1195 mol) in 1.5N HCl (190 ml). The mixture was stirred at 10 ℃ for 15 minutes and added dropwise to a mixture of CuCN (0.1673mol) and KCN (0.2749mol) in water (293ml) at 5 ℃. The mixture was stirred at 5 ℃ for 1 hour, then at 60 ℃ for 1 hour 30 minutes, then cooled and filtered. The filtrate was extracted with diethyl ether. The organic layer was separated, dried, filtered and the solvent was evaporated to dryness. The residue is treated with CH₂Cl₂/CH₃OH washes, drying, filtration and evaporation of the solvent to dryness. The residue was purified by column chromatography over silica gel (eluent: CH)₂Cl₂Ethyl acetate 98/2). The pure fractions were collected and the solvent was evaporated to dryness to yield 10.4 g of intermediate (18).

b) Preparation of intermediate (19)

A mixture of intermediate (18) (0.0446 mol) and lithium hydroxide monohydrate (0.0891 mol) in THF (300ml) and water (300ml) was stirred at room temperature for 20 hours. The THF was partially evaporated. The mixture was acidified with 3N HCl and extracted with ethyl acetate. The organic layer was separated, dried, filtered and the solvent was evaporated to dryness to give 9.4g of intermediate (19).

Example A.8

Preparation of intermediate (21)

A mixture of intermediate (22) (0.12mol) in 1N NaOH (200ml) was stirred and refluxed for 4 hours. The reaction mixture was left at room temperature overnight, then cooled on an ice bath and 1n hcl solution (200ml) was added. The mixture was warmed to room temperature, and the formed precipitate was filtered to obtain 26.7g of intermediate (21).

Example A.9

a) Preparation of intermediate (22)

A mixture of methyl 5-nitro-2, 3-dihydroxybenzoate (0.3 mol), potassium carbonate (0.66 mol), 1, 3-dibromopropane (0.42 mol) and tetra-n-butylammonium bromide (4.5 g) in acetone (900 ml) and DMA (600ml) was stirred and refluxed for 30 hours. The reaction mixture was stirred at room temperature for two days and then filtered. The solvent was evaporated and the residue 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 column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH 98/2) to yield 33.5g of intermediate (22).

b) Preparation of intermediate (23)

A mixture of intermediate (22) (0.11mol) in THF (250ml) was hydrogenated in the presence of a thiophene solution (1ml) using 10% palladium on carbon (3g) as the catalyst. After uptake of hydrogen (3 equivalents), the catalyst was filtered off with dicalite and the filtrate was concentrated to yield 24.7 g of intermediate (23).

c) Preparation of intermediate (24)

Intermediate (23) (0.11mol) was dissolved in chloroform (500ml) and the mixture was cooled on an ice bath to a temperature below 10 ℃. Trifluoroacetic anhydride (0.14mol) was added dropwise at the same temperature, and then the reaction mixture was stirred at room temperature for 1 hour, followed by concentration. The residue was crystallized from DIPE at room temperature overnight to yield 5.8g of intermediate (24).

d) Preparation of intermediate (25)

60% NaH (0.046mol) was added portionwise to a mixture of intermediate (24) (0.131 mol) in DMF (140 ml) at room temperature under a stream of nitrogen. The mixture was stirred at room temperature for 1 hour. Methyl iodide (0.046mol) was added dropwise. The mixture was stirred at 50 ℃ overnight, then cooled to room temperature, poured into ice water, and extracted with toluene. The organic layer was washed with water, dried, filtered and the solvent was evaporated. Petroleum ether was added and decanted, and the residue was warmed in petroleum ether and decanted again. The residue was concentrated to give 12.8 g of intermediate (25).

e) Preparation of intermediate (26)

A mixture of intermediate (25) (0.0294 mol) in NaOH (1M, 0.059mol) and water (60ml) was stirred and refluxed for 1 hour. The reaction mixture was cooled to room temperature in an ice bath. Tert-butyl dicarbonate (0.036mol) is then added and the reaction mixture is stirred at room temperature overnight. HCl (1N, 0059mol) was added and the product was extracted with DCM. The separated organic layer was dried, filtered and concentrated to give 10.8g of intermediate (26).

Example A.10

a) Preparation of intermediate (27)

60% NaH (0.171mol) was added portionwise to a mixture of intermediate (24) (0.131 mol) in DMF (450 ml) at room temperature under a stream of nitrogen. The mixture was stirred at room temperature for 1 hour. Iodothane (0.171mol) was added dropwise. The mixture was stirred at a temperature between 50 and 60 ℃ 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 was evaporated. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate 90/10) to give 26.5g of intermediate (27).

b) Preparation of intermediate (28)

Lithium hydroxide monohydrate (0.264mol) was added portionwise to a mixture of intermediate (27) (0.063mol) in water (150ml) at room temperature. The mixture was stirred at room temperature for 18 hours. Water (150ml) was evaporated. The mixture was acidified with 3N HCl to give pH 4 and then extracted with ethyl acetate. The organic layer was separated, dried, filtered and the solvent was evaporated to give 14g of intermediate (28).

Example A.11

Preparation of intermediate (29)

Intermediate (24) (0.0565 mol) was dissolved in DMF (110 ml). 60% NaH (0.061mol) was added in portions. The mixture was stirred at room temperature for 90 minutes. 1-iodo-propane (0.061mol) was added and the reaction mixture was stirred at 50-60 ℃ for 45 hours; and then cooled. The mixture was poured into cold HCl (1N, 300ml) and extracted with DCM (2 × 200 ml). The combined organic layers were washed with water, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: hexane/EtOAc 70/30). The desired fractions were collected and the solvent was evaporated. The residue was dissolved in THF (100 ml). Aqueous NaOH (2N, 125ml) was added. The mixture was stirred overnight. The organic solvent was evaporated. The aqueous layer was washed with DCM, saturated with sodium chloride, cooled on an ice bath, and acidified to pH 3 to 4 with concentrated HCl solution. The mixture was then extracted with diethyl ether (4 × 100 ml). The combined organic layers were dried, filtered and the solvent was evaporated to give 6.5g of intermediate (29).

Example A.12

a) Preparation of intermediate (30)

A mixture of intermediate (24) (0.166mol) in DMF (350ml) was stirred at room temperature. NaH (60%) (0.2mol) was added portionwise. The mixture was stirred at room temperature for 1.5 hours and then heated to 50 ℃. 1-iodobutane (0.2mol) was added. The reaction mixture was stirred at 50 ℃ over the weekend; and then cooled. Water was added and the mixture was extracted with toluene. The separated organic layer was dried, filtered and the solvent was evaporated. The residue is purified on a glass filter by means of silica gel (eluent: CH)₂Cl₂/CH₃OH 99/1). The desired fractions were collected and the solvent was evaporated to yield 34 g of intermediate (30).

b) Preparation of intermediate (31)

Intermediate (30) (0.09mol) was stirred in NaH (10%) (400ml) and THF (100ml) at room temperature for 28 h. The organic solvent was evaporated. The aqueous mixture was washed with DCM; it was then acidified (pH 3 to 4) with concentrated HCl solution and extracted with DCM. The combined organic layers were dried, filtered and the solvent was evaporated to give 22g of intermediate (31).

Example A.13

a) Preparation of intermediate (32)

A mixture of intermediate (23) (0.2688 mol), 2-bromo-propane (0.537 mol) and triethylamine (0.403 mol) in DMF (600ml) was stirred at 130 ℃ overnight and then brought to room temperature. The DMF was evaporated. The residue was dissolved in ethyl acetate, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 80/20). The pure fractions were collected and the solvent was evaporated, yielding 25g of intermediate (32) (m.p. 145 ℃).

b) Preparation of intermediate (33)

A mixture of intermediate (32) (0.0942 mol) in NaOH (200ml, 2N) and THF (200ml) was stirred at room temperature for 72 hours. The solvent was removed by evaporation. Ethyl acetate was added. The mixture was extracted with ethyl acetate. The aqueous layer was acidified with HCl to give a pH of 2. The mixture was stirred. The precipitate was filtered, washed with a minimum amount of water and dried to yield 22g of intermediate (33) (mp 203 ℃).

Example A.14

a) Preparation of intermediate (34)

97% sulfuric acid (80ml) was carefully added to 9- (acetylamino) -3,4-dihydro-2H-1, 5-benzodioxepan-6-carboxylic acid methyl ester (0.51 mol) in a mixture of methanol (1000 ml). The mixture was stirred at 60 ℃ for 1 hour and then cooled. The solvent was removed by evaporation. The residue was dissolved in DCM. With KHCO₃The solution washes the mixture. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was suspended in DIPE and a small amount of ACN. The precipitate was filtered off, washed and dried to yield 105g of intermediate (34).

b) Preparation of intermediate (35)

A mixture of intermediate (34) (0.24 mol) in water (240 ml) was stirred at 0 ℃. HCl (120mL) was added dropwise at 0 ℃. The mixture was stirred for 15 minutes. A mixture of sodium nitrite (0.24 mol) in water (120ml) was added dropwise at 0 ℃. The mixture was stirred at 0 ℃ for 30 minutes to obtain a mixture (A). A mixture of copper chloride (0.24 mol) in HCl (120ml) was stirred at room temperature. The mixture (A) is added dropwise. The reaction mixture was stirred at room temperature for 1 hour. The precipitate was filtered off, washed and dried, yielding 55.8g of intermediate (35).

c) Preparation of intermediate (36)

A mixture of intermediate (35) (0.22 mol) and KOH (2.2 mol) in water (1000ml) was stirred and refluxed for 30 minutes, then cooled. The mixture was acidified with concentrated HCl solution. The precipitate was filtered off, washed and dried to yield 48g of intermediate (36).

d) Preparation of intermediate (37)

A mixture of intermediate (36) (0.01 mol) in sulphuric acid (20ml) was cooled to-30 ℃ and then a mixture of nitric acid (0.01 mol) in sulphuric acid (20ml) was added dropwise at-30 ℃ and the reaction mixture was stirred for 5 minutes. The mixture was poured into ice-water and the resulting precipitate was filtered off and washed with water to give intermediate (37).

Example A.15

a) Preparation of intermediate (38)

A mixture of intermediate (34) (0.27 mol) in water (270ml) was stirred at room temperature. Sulfuric acid (97%) (30ml) was added dropwise at room temperature. The mixture was stirred for 15 minutes. A mixture of sodium nitrite (0.27 mol) in water (270ml) was added dropwise at room temperature. The mixture was stirred at room temperature for 30 minutes to obtain a mixture (A). A mixture of copper (I) bromide (0.4 mol) in water (540 ml) and hydrobromic acid (270ml) was stirred at room temperature. At room temperature, the mixture (A) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. The precipitate was filtered off, washed with dilute sulfuric acid solution and water and dried under reduced pressure overnight. The residue was dissolved in DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The solid was dried under reduced pressure to give 71.5g of intermediate (38).

b) Preparation of intermediate (39)

To a mixture of intermediate (38) (0.123mol) in sulfuric acid (280ml) was added dropwise a solution of nitric acid (0.135mol) in sulfuric acid (70ml) at a temperature between 0 and 5 ℃. The reaction mixture was stirred at 0 ℃ for 10 min, poured into ice water and extracted with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated to give intermediate (39).

c) Preparation of intermediate (40)

2N NaOH (700ml) was added to a mixture of intermediate (39) (0.1205 mol) in THF (700ml) at room temperature. The mixture was stirred at room temperature for 2 hours. The NaOH was evaporated. Ethyl acetate was added. The aqueous layer was acidified with concentrated HCl. The precipitate was filtered, washed with a minimum amount of water and dried to yield 36.5g of intermediate (40).

Example A.16

a) Preparation of intermediate (41)

Methyl 2, 3-dihydroxy-5-methylbenzoate (0.198 mol), 1, 3-dibromopropane (0.198 mol) and K₂CO₃A mixture of (0.396 mol) in acetone (360 ml) was stirred and refluxed for 6 hours, then cooled and the solvent was evaporated. The mixture was poured into ice water and filtered. The filtrate was extracted with ethyl acetate. The organic layer was separated, dried, filtered, the solvent was evaporated and purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 80/20 to 70/30) to give intermediate (41).

b) Preparation of intermediate (42)

A mixture of intermediate (41) (0.1129 mol) in a mixture of 2N NaOH solution (370ml) and THF (370ml) was stirred at room temperature for 15 hours. THF was evaporated and the mixture was acidified with 12 NHCl. The precipitate was filtered, washed with water and dried to yield 21.9g of intermediate (42) (mp 74 ℃ C.).

Example A.17

a) Preparation of intermediate (45)

Methyl 5-bromo-2, 3-dihydroxybenzoate (0.397 mol) and K₂CO₃A mixture (0.87 mol) of 1, 3-dibromopropane (49 ml) and acetone (1000ml) was stirred and refluxed for 22 hours, then the reaction mixture was cooled, filtered over dicalite and the solvent was evaporated. The residue is washed with NaHCO₃Partition between (5%, aq) and DCM. The organic layer was separated, dried, filtered over dicalite and the solvent was evaporated to give 112g of intermediate (45).

b) Preparation of intermediate (46)

A mixture of intermediate (45) (0.14mol) in THF (200ml) and 2n naoh solution (300ml) was stirred at 30-60 ℃ for 4 h, then the organic solvent was evaporated and the aqueous concentrate was cooled on ice and extracted with DCM. The aqueous layer was further cooled on ice, acidified to pH 1, filtered off the solid residue and dried to yield 33g of intermediate (46).

c) Preparation of intermediate (47)

A mixture of intermediate (46) (0.33 mol) and copper (I) cyanide (2.7 mol) in DMA (800 ml) was stirred at 140 ℃ for 20 hours, then the reaction mixture was cooled and FeCl was added₃.6H₂O (130g), HCl (33ml) and water (2)00 ml). The mixture was stirred at 60 ℃ for 20 hours, cooled and poured into water. Ethyl acetate was added and the liquid layer was filtered to remove insoluble salts. The organic layer was separated, washed with water, dried, filtered and the solvent was evaporated. The residue was dissolved in water, 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, dried and the solvent was evaporated. The residue was purified by short column chromatography (eluent: CH)₂Cl₂/CH₃OH 95/5+2ml acetic acid) to yield 7g of intermediate (47).

Example A.18

a) Preparation of intermediate (48)

Intermediate (16) (0.126mol), NBS (0.151 mol) and [1, 1' -biphenyl]A mixture of (E) -2, 2' -dicarboxylic acid (0.0126 mol) in tetrachloromethane (500ml) was stirred and refluxed for 5 hours, poured at 10% K₂CO₃Neutralized and extracted with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated to dryness. The residue was purified by column chromatography over silica gel (eluent: CH)₂Cl₂Cyclohexane 80/20 to 100/0) to give 16.5g of intermediate (48).

b) Preparation of intermediate (49)

A mixture of intermediate (48) (0.048 mol) and NaCN (0.1096 mol) in DMSO (330ml) was stirred at room temperature for 15 hours. Adding K₂CO₃(10%). The mixture was extracted with ethyl acetate. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: cyclohexane/ethyl acetate 70/30) to give 10.8g of intermediate (49).

c) Preparation of intermediate (50)

A mixture of intermediate (49) (0.0419 mol) and lithium hydroxide monohydrate (0.0837 mol) in THF (100ml) and water (100ml) was stirred at room temperature for 5 hours. The THF was evaporated. The mixture was acidified with concentrated HCl solution and extracted with ethyl acetate. The organic layer was separated, dried, filtered and the solvent was evaporated to dryness to give 9.8g of intermediate (50).

Example A.19

a) Preparation of intermediate (51)

Intermediate (23) (0.0895 mol) was added portionwise to a mixture of concentrated sulfuric acid (28ml) in water (42ml) at room temperature. Ice (70 g) was added. The mixture was vigorously stirred and then cooled to 0 ℃. Adding NaNO at a temperature between 0 deg.C and 7 deg.C₂(0.0967mol) in water (15 ml). The mixture was stirred for 15 minutes and then added to CuSO under a stream of nitrogen at a temperature between 5 ℃ and 7 ℃₄.5H₂O (0.358mol) in a hot solution (85 ℃ C.) in water (250 ml). The mixture was stirred and refluxed for 30 minutes, then cooled, poured into ice water, and extracted with ethyl acetate. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: toluene/ethyl acetate 80/20). The two fractions were collected and the solvent was evaporated, yielding 2.7g of intermediate (51).

b) Preparation of intermediate (52)

Intermediate (51) (0.012mol), (CH)₃)₂SO₄(0.012 moles) and K₂CO₃A mixture of (0.0144 mol) in acetone (30ml) was stirred and refluxed for 4 hours, then cooled to room temperature and the solvent was evaporated to dryness. The residue was dissolved in a mixture of DCM and water. The organic layer was separated, dried, filtered and the solvent was evaporated to give 2.7g of intermediate (52).

c) Preparation of intermediate (53)

2N NaOH (20ml) was added to a mixture of intermediate (52) (0.0113 mol) in THF (20ml) at room temperature. The mixture was stirred at room temperature for 18 hours. THF was evaporated at 30 ℃. The aqueous layer was extracted twice with ethyl acetate, acidified with 6N HCl, and extracted with ethyl acetate. The organic layer was separated, dried, filtered and the solvent was evaporated to give 2.5g of intermediate (53).

Example A.20

a) Preparation of intermediate (54)

Intermediate (48) (0.11mol) and 30% CH₃ONa/CH₃A mixture of OH (0.44 mol) in methanol (330ml) was stirred at 60 ℃ for 2 hours, then brought to room temperature and the solvent was evaporated to dryness. The residue was dissolved in a mixture of DCM and water. The mixture was extracted with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated to give 24g of intermediate (54).

b) Preparation of intermediate (55)

Lithium hydroxide dihydrate (0.182 mol) was added dropwise to a mixture of intermediate (54) (0.091 mol) in THF (20ml) and water (200ml) at room temperature. The mixture was stirred at room temperature overnight. The THF was evaporated. Ethyl acetate was added. The mixture was extracted with ethyl acetate. The aqueous layer was acidified with concentrated HCl. DCM was added. The mixture was extracted with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated to give 21.5g of intermediate (55).

Example A.21

Preparation of intermediate (56)

1, 1-Dimethylethyl (trans) -3-hydroxy-4- [ [ (phenylmethyl) amino ] methyl ] -1-piperidinecarboxylate [ described in WO-00/37461 as intermediate (1-d) ] (0.023 mol) was hydrogenated in a mixture of methanol (100ml) using palladium on carbon (10%, 1g) as catalyst. After absorption of hydrogen (1 eq), the catalyst was filtered off and the filtrate was evaporated. The residue was solidified in DIPE + ACN, filtered and dried to give 4g of 1, 1-dimethylethyl (trans) -4- (aminomethyl) -3-hydroxy-1-piperidinecarboxylate (intermediate 56, mp 178 ℃). In a similar manner, but starting from cis-3-hydroxy-4-piperidinemethanol (described in j.org chem., 34, pp.3674-3676 (1969)), there was prepared (cis) -4- (aminomethyl) -3-hydroxy-1-piperidinecarboxylic acid 1, 1-dimethylethyl ester (intermediate 57).

Intermediate (57)

Example A.22

a) Preparation of intermediate (58)

(trans) -3-hydroxy-4- [ [ (phenylmethyl) amino ] methyl ] -1-piperidinecarboxylic acid 1, 1-dimethylethyl ester [ described in WO-00/37461 as intermediate (1-d) ] (2.73 moles) was isolated and purified on a chiral chromatography column on a Chiralcel AD (eluent: hexane/ethanol 80/20). The desired fractions were collected and the solvent was evaporated. Toluene was added and azeotroped on a rotary evaporator to give 377 g of 1, 1-dimethylethyl (3S-trans) -3-hydroxy-4- [ [ (phenylmethyl) amino ] methyl ] -1-piperidinecarboxylate (intermediate 58).

b) Preparation of intermediate (59)

A mixture of intermediate (58) (0.028mol) in methanol (100ml) was hydrogenated using palladium on carbon (10%; 2g) as catalyst. After uptake of hydrogen (1 eq), the catalyst was filtered off and the filtrate was evaporated, yielding 4.7 g of 1, 1-dimethylethyl (3S-trans) -4- (aminomethyl) -3-hydroxy-1-piperidinecarboxylate (intermediate (59); [ alpha ] -1-dimethylethyl [ alpha ] -ester]^20，DAt CH 4.37 ° (c 24.03mg/5 ml)₃In OH)).

Example A.23

a) Preparation of intermediate (60)

Reacting (3R-trans) -3-hydroxy-4- [ [ (4-methylphenyl) -sulfonyl group]Oxymethyl radical]1-Piperidinecarboxylic acid 1, 1-dimethylethyl ester [ described in WO-00/37461 as intermediate (1-c-I)]A mixture of (0.03mol) and benzylamine (0.1mol) in THF (250ml) was stirred at 125 ℃ (reaction kettle) for 16 hours. The reaction mixture was cooled and the solvent was evaporatedAnd (4) sending. The residue was taken up in DCM and K₂CO₃The aqueous solution was partitioned. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was crystallized from DIPE to give 5.3g of (3R-trans) -3-hydroxy-4- [ [ (phenylmethyl) amino group]Methyl radical]1-Piperidinecarboxylic acid 1, 1-dimethylethyl ester (intermediate 60) ([ alpha ])]^20，D-68.65 ° (c 23.16mg/5ml in CH₃In OH); melting Point 91 ℃ C.).

b) Preparation of intermediate (61)

A mixture of intermediate (60) (0.016mol) in methanol (150ml) was hydrogenated at 50 ℃ with palladium on carbon (10%; 2g) as catalyst. After uptake of hydrogen (1 eq), the catalyst was filtered off and the filtrate was evaporated to give (3R-trans) -4- (aminomethyl) -3-hydroxy-1-piperidinecarboxylic acid 1, 1-dimethylethyl ester (intermediate 61).

Example A.24

a) Preparation of intermediate (62)

The reaction was carried out under a nitrogen atmosphere. Sodium hydride (0.3 mol) was added to a solution of trans-3-hydroxy-4- [ [ [ (4-methylphenyl) sulfonyl ] oxy ] methyl ] -1-piperidinecarboxylic acid 1, 1-dimethylethyl ester [ 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 (0.54mol) was added and the resulting reaction mixture was stirred for 90 minutes. A small amount of water was added. The solvent was evaporated and the residue partitioned between water and DCM. The organic layer was separated, dried, filtered and the solvent was evaporated to give trans-4- [ [ [ (4-methylphenyl) sulfonyl ] oxy ] -methyl ] -3-methoxy-1-piperidinecarboxylic acid 1, 1-dimethylethyl ester (intermediate 62).

b) Preparation of intermediate (63)

A mixture of intermediate (62) (0.065 mol) in THF (250ml) was autoclaved at 125 deg.C with liquid NH₃The treatment was carried out for 16 hours. The reaction mixture was filtered and the filtrate was evaporated. The residue was partitioned between 5% aqueous NaOH and DCM. The organic layer was separated, dried, filtered and the solvent was evaporated to give 16 g of 1, 1-dimethylethyl (trans) -4- (aminomethyl) -3-methoxy-1-piperidinecarboxylate (intermediate (63).

Example A.25

a) Preparation of intermediate (64)

A mixture of tert-butyl 4-oxo-1-piperidinecarboxylate (0.1mol) and nitromethane (0.1mol) in methanol (200ml) was stirred at 10 ℃. Sodium methoxide (0.11mol) was added dropwise at 10 ℃. The reaction mixture was stirred at room temperature for 20 hours. The solvent was removed by evaporation. 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, filtered and the solvent was evaporated. The residue was suspended in DIPE, filtered, washed and dried to yield 17.2g of intermediate (64) (m.p. 160 ℃).

b) Preparation of intermediate (65)

A mixture of intermediate (64) (0.058mol) and acetic acid (12ml) in methanol (250ml) was hydrogenated at 14 ℃ using palladium on carbon (10%, 1g) as catalyst. After uptake of hydrogen (3 equivalents)The catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in ice/water, then basified with potassium hydroxide and made up with K₂CO₃And (4) salting out. The mixture was extracted twice with DCM. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was suspended in DIPE, filtered, washed and dried to yield 7.5g of intermediate (65).

Example A.26

a) Preparation of intermediate (66)

Reacting (trans) -4- [ [ (phenylmethyl) amino group]Methyl radical]-3-piperidinol (prepared as intermediate (6) in WO-00/37461) (0.04mol), 3-bromo-1-propanol (0.04mol) and Na₂CO₃(0.08mol) in isobutyl methyl ketone (400ml) was stirred and refluxed for 18 hours. The solvent was removed by evaporation. The residue was partitioned between water and DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH)₂Cl₂/(CH₃OH/NH₃)93/7). The desired fractions were collected and the solvent was evaporated. Toluene was added and then evaporated again to give 7.2g of intermediate (66).

b) Preparation of intermediate (67)

A mixture of intermediate (66) (0.026mol) in methanol (100ml) was hydrogenated using palladium on carbon (10%; 2g) as catalyst. After absorption of hydrogen (1 eq), the catalyst was filtered off and the filtrate was evaporated, yielding 4.4 g of intermediate (67).

Example A.27

a) Preparation of intermediate (68)

Reacting (trans) -4- [ [ (phenylmethyl) amino group]Methyl radical]-3-piperidinol (prepared as intermediate (6) in WO-00/37461) (0.04mol), 1-chloro-3-methoxypropane (0.04mol) and Na₂CO₃(0.08mol) mixture in isobutyl methyl ketone (300ml) was stirred and refluxed for 20 hours, then cooled and the solvent was evaporated. The residue was dissolved in DCM, then washed with water, dried, filtered and the solvent evaporated. The residue is purified by column chromatography on silica gel (eluent: CH)₂Cl₂/(CH₃OH/NH₃)97/3). The pure fractions were collected and the solvent was evaporated, yielding 5g of intermediate (68).

b) Preparation of intermediate (69)

A mixture of intermediate (68) (0.016mol) in methanol (150ml) was hydrogenated using palladium on carbon (10%; 1g) as catalyst. After absorption of hydrogen (1 eq), the catalyst was filtered off and the filtrate was evaporated, yielding 3.3 g of intermediate (69).

Example A.28

a) Preparation of intermediate (70)

Reacting (trans) -3-hydroxy-4- [ [ (phenylmethyl) amino group]Methyl radical]A mixture of 1, 1-dimethylethyl (1, 1-piperidinecarboxylate (intermediate (1-d) in WO-99/02156) (0.426 mol), benzaldehyde (0.5 mol) and palladium on carbon (10%) (5 g) in a thiophene solution (5ml) and methanol (1000ml) was stirred at 70-80 ℃ overnight. The solvent was removed by evaporation. The residue was taken up in DCM (150ml) and 5%Aqueous NaOH (150ml) was partitioned between. The layers of the mixture were separated. The aqueous layer was extracted with DCM. The combined organic layers were dried, filtered and the solvent was evaporated. The residue is purified by column chromatography on silica gel (eluent: CH)₂Cl₂/(CH₃OH/NH₃)90/10). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE and one drop of ACN. The precipitate was filtered and dried to give 2.35 g of (trans) -4- [ [ bis (phenylmethyl) amino ] amino]Methyl radical]1, 1-Dimethylethyl-3-hydroxy-1-piperidinecarboxylate (intermediate 70), mp 133 ℃ C.

b) Preparation of intermediate (71)

A mixture of intermediate (70) (0.284 mol) in a mixture of 2-propanol (1000ml) and 6N HCl in 2-propanol (250ml) was stirred and refluxed for 15 minutes, then cooled. The solvent was removed by evaporation. 5% aqueous NaOH (750ml) was added. The mixture was extracted three times with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 88.95 g of (trans) -4- [ [ bis (phenylmethyl) amino ] methyl ] -3-piperidinol (intermediate 71).

c) Preparation of intermediate (72)

A mixture of intermediate (71) (0.083mol) and butyraldehyde (7g) in methanol (300ml) was hydrogenated in the presence of a thiophene solution (3ml) using palladium on carbon (10%) (2g) as the catalyst. After absorption of hydrogen (1 equivalent), the catalyst was filtered through celite and the filtrate was evaporated. The residue was dissolved in 2N aqueous HCl (500 ml). The mixture was washed with toluene, and then the layers were separated. The aqueous layer was basified with 50% aqueous NaOH and then extracted three times with toluene. The combined organic layers were dried, filtered and the solvent was evaporated to give 29 g of (trans) -4- [ [ bis (phenylmethyl) amino ] methyl ] -1-butyl-3-piperidinol (intermediate 72).

d) Preparation of intermediate (73)

A mixture of intermediate (72) (0.079mol) in methanol (250ml) was hydrogenated using palladium on carbon (10%) (2g) as catalyst. After absorption of hydrogen (2 eq), the catalyst was filtered through celite and the filtrate was evaporated to give 13.8g (trans) -4- (aminomethyl) -1-butyl-3-piperidinol (intermediate 73).

Example A.29

a) Preparation of intermediate (74)

Intermediate (71) (0.0387 mol) was dissolved in 2-methyl-propanol (200 ml). Tetrahydrofuran methanesulfonate (0.05 mol) and Na were added₂CO₃(0.0774 mol). The reaction mixture was stirred and refluxed for 24 hours; and then cooled. The precipitate was filtered. The solvent was removed by evaporation. The residue is purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH 97/3). The desired fractions were collected and the solvent was evaporated, yielding 11.1 g of intermediate (74).

b) Preparation of intermediate (75)

Intermediate (74) (0.0279mol) was hydrogenated in methanol (150ml) using palladium on carbon (10%; 2g) as catalyst. After uptake of hydrogen (2 equivalents), the catalyst was filtered off with decalite and the solvent was evaporated to yield 5.74 g of intermediate (75).

Example A.30

a) Preparation of intermediate (76)

1, 1-Dimethylethyl (prepared as intermediate (1-e) in WO-00/37461) (0.06mol) was stirred and refluxed in 2-propanol saturated with HCl (60mL) and 2-propanol (400mL) for 30 minutes, then cooled. The solvent was evaporated and azeotroped with toluene. The residue was dried to give 12g of intermediate (76).

b) Preparation of intermediate (77)

4-bromo-butyronitrile (0.06mol), intermediate (76) (0.06mol) and Na were added₂CO₃(0.24 mol) a mixture in ACN (600ml) was stirred and refluxed for 20 hours; then cooled and filtered. The solvent was removed by evaporation. The residue was purified by column chromatography over silica gel (eluent: CH)₂Cl₂/(CH₃OH/NH₃)85/15). The desired fractions were collected and the solvent was evaporated, yielding 4.5g of intermediate (77).

Example A.31

a) Preparation of intermediate (78)

A mixture of trifluoroacetic acid (1.15mol) in water (2000ml) was stirred at room temperature. 1, 2, 3, 6-tetrahydro-1- (phenylmethyl) -pyridine (1.15mol) was added dropwise to the mixture, and the mixture was stirred at room temperature for 15 minutes. N-bromosuccinimide (1.4 mol) was added in portions and the mixture was warmed to 30-35 ℃ over 1 hour. The reaction mixture was stirred for 30 minutes. N-bromosuccinimide (0.085 mol) was added again in portions and the mixture was warmed to 35 ℃. The reaction mixture was stirred at room temperature overnight, then decanted and added dropwise to a 20% NaOH solution (2000 ml). The mixture was stirred at room temperature overnight. The product (3 ×) was extracted with DCM. The separated organic layer was dried, filtered and concentrated to give 193g of intermediate (78).

b) Preparation of intermediate (79)

A mixture of lithium hydride (0.66 mol) in THF (600ml, p.a.) was reacted at room temperature under nitrogen, then a mixture of 2-hydroxy-2-methyl-propionitrile (0.66 mol) in THF (150ml) was added dropwise, and the reaction mixture was stirred at room temperature for 2 hours to give a mixture (a). A mixture of intermediate (78) (0.6mol) in THF (250ml) was added dropwise to mixture (a), and after completion of the addition, the reaction mixture was stirred and refluxed for 4 hours, and then stirred at room temperature overnight. DCM and water were added and the organic layer was separated, dried, filtered and the solvent was evaporated to give 128 g of intermediate (79).

c) Preparation of intermediate (80)

Intermediate (79) (0.6mol) was reacted in CH at 14 ℃ using Raney Nickel as catalyst₃OH/NH₃(1.5 l). After absorption of hydrogen (2 equivalents), the catalyst is filtered off and the solvent is evaporated. The residue was dissolved in ACN and converted to the oxalate salt (1: 1) with oxalic acid (0.6 ml). The solvent was decanted. The residue was suspended in 2-propanol. The precipitate was filtered and dissolved in methanol, boiled and cooled. The precipitate was filtered, washed and dried to yield 107g of intermediateA body (80).

Example A.32

Preparation of intermediate (81)

Reacting methyl [4- [ (methylsulfonyl) oxy ] methyl]Butyl radical]1, 1-Dimethylethylcarbamate (0.02mol), intermediate (76) (0.02mol) and Na₂CO₃(0.08mol) mixture in ACN (100ml) was stirred and refluxed for 48 hours, cooled, filtered and the filtrate was evaporated. The residue is purified by column chromatography on silica gel (eluent: CH)₂Cl₂/(CH₃OH/NH₃)80/20) to yield 2.4g of intermediate (81).

Example A.33

a) Preparation of intermediate (82)

Intermediate (3) (0.146mol) was stirred in DCM (400 ml). Triethylamine (0.146mol) was added. The reaction mixture was cooled to a temperature below 10 ℃. At this temperature, formic acid (0.146mol) was added dropwise and the reaction mixture was stirred at this temperature for 1 hour (═ mixture a). Intermediate (56) (0.146mol) was stirred in DCM (400ml) at room temperature for 1 hour; then added to the mixture (A). The reaction mixture was stirred at room temperature for 90 minutes. Water was added. The separated organic layer was dried, filtered and the solvent was evaporated to give 81g of intermediate (82).

b) Preparation of intermediate (83)

Intermediate (82) (0.15 mol) was stirred and refluxed in 2-propanol/6N HCl (120ml) and 2-propanol (1200 ml) for 2 hours. The reaction mixture was allowed to cool to room temperature overnight. The precipitate formed was filtered off and dried to yield 54.5g of intermediate (83) (m.p. 150 ℃ C.).

In a similar manner, intermediates (84) and (85) were prepared.

Intermediate (84) intermediate (85)

Example A.34

a) Preparation of intermediate (86)

A mixture of intermediate (7) (0.08mol) in DCM (400ml) and triethylamine (0.1mol) was stirred at 5 ℃. Formic acid (0.08mol) was added dropwise. The mixture was stirred at 5 ℃ for 30 minutes. Intermediate (80) (0.08mol) and triethylamine (0.25 mol) in DCM (400ml) were added at 5 ℃. The reaction mixture was warmed to room temperature and washed with water. The separated organic layer was dried, filtered and the solvent was evaporated and co-evaporated with toluene to give 41g of intermediate (86).

b) Preparation of intermediate (87)

Intermediate (86) (0.08mol) was hydrogenated in methanol (250ml) using palladium on carbon (10%; 2g) as catalyst. After uptake of hydrogen (1 eq), the catalyst was filtered off and the solvent was evaporated, yielding 34 g of intermediate (87).

In a similar manner, intermediate (88) was prepared.

Intermediate (88)

Example A.35

Preparation of intermediate (89)

Intermediate (7) (0.013mol) was stirred in DCM (100 ml). Triethylamine (0.015mol) was added and the mixture was stirred at 5 ℃. Formic acid (0.013mol) was added dropwise at 5 ℃; the reaction mixture was then stirred at 5 ℃ for 30 minutes. Triethylamine (0.03mol) and intermediate (67) (0.013mol) in DCM (100ml) were added at 5 ℃. The reaction mixture was warmed to room temperature and then washed with water. The separated organic layer was dried, filtered and the solvent was evaporated to give 5.3g of intermediate (89).

Example A.36

a) Preparation of intermediate (90)

Intermediate (9) (0.06mol) was added to DCM (250 ml). Triethylamine (8.4ml) was added and the mixture was cooled to-5 ℃. Formic acid (0.06mol) was added dropwise over 5 minutes. The reaction mixture was stirred at a temperature ranging between-5 and-10 ℃ for 40 minutes. Intermediate (56) (0.06mol) in DCM (50ml) and triethylamine (8.4ml) was added immediately. The ice bath was removed and the mixture was stirred at room temperature for 2 hours. DCM (200ml) was added. The mixture was washed with water/NaOH (5% aqueous solution)/water/cold HCl (5% aqueous solution)/water. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was triturated in DIPE/ACN. The precipitate was filtered off and dried to yield 23.2g of intermediate (90).

b) Preparation of intermediate (91)

Intermediate (90) (0.0478mol) was hydrogenated in methanol (250ml) at 50 ℃ in the presence of a thiophene solution (3ml) using platinum on carbon (5%, 3g) as the catalyst. After absorption of hydrogen (3 equivalents), the catalyst was filtered off with dicalite and the solvent was evaporated. The residue was triturated in DIPE. The precipitate was filtered off and dried to yield 19.7g of intermediate (91) (mp 161 ℃ C.).

In a similar manner, intermediates (92), (93) and (94) were prepared.

Example A.37

Preparation of (intermediate 95)

A mixture of intermediate (17) (0.336mol) and triethylamine (0.4 mol) in DCM (1000ml) was stirred at 5 ℃, 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 (59) (83 g) in DCM (1000ml) at 5 ℃ and the reaction mixture was brought to room temperature and washed with water. The organic layer was separated, dried, filtered and the solvent was evaporated to yield 150g of intermediate (95).

Table I-1: following the same procedure as in example A.38, intermediates (96) to (114) were prepared

Example A.38

Preparation of intermediate (115)

4-methoxy-1-butanol (0.9 mol) was stirred in DCM (1500 ml) and triethylamine (1.35 mol) was added, followed by dropwise addition of methanesulfonyl chloride (1.1 mol) (temperature raised to 40 ℃ C.) and stirring of the reaction mixture at room temperature for 2 hours. The mixture was washed with water. The organic layer was separated, dried and the solvent was evaporated, then co-evaporated with toluene to give 167g of intermediate (115).

Example A.39

Preparation of intermediate (116)

Triethylamine (0.11mol) was added to a mixture of 3-cyclohexyloxypropan-1-ol (0.063mol) in DCM (120ml), followed by dropwise addition of methanesulfonyl chloride (0.07mol), and the reaction mixture was stirred at room temperature for 1 hour. With Na₂CO₃The aqueous solution and the water wash the mixture. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue is purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH 99/1). The product fractions were collected and the solvent was evaporated, then co-evaporated with toluene to give 8.6g of intermediate (116).

Example A.40

a) Preparation of intermediate (117)

A mixture of 4-phenoxybutyl chloride (0.135mol) in DCM (50ml) was stirred and cooled to 0 ℃. Chlorosulfonic acid (0.149mol) was added dropwise over 45 minutes. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 hours. Oxalyl dichloride (0.176mol) was then added dropwise followed by DMF (2 ml). The reaction mixture was stirred at room temperature for 20 hours. The mixture was then poured onto ice, extracted with DCM, dried and the solvent evaporated to give intermediate (117).

b) Preparation of intermediate (118)

A solution of intermediate (117) (0.135mol) in THF (500ml) was stirred and cooled to 0 ℃ before ammonia (gas) was bubbled through the solution. The reaction mixture was filtered and the solvent was evaporated. DCM (600ml) was added to the residue and the mixture was washed with HCl (600ml, 1N). The aqueous layer was separated and extracted with DCM (2X, 300 ml). The combined organic layers were washed with brine, dried, and the solvent was evaporated. The residue is treated with CH₃The OH/DIPE crystals were filtered off and dried to yield 18.5g of intermediate (118).

Intermediates (119) and (120) are prepared in a similar manner but starting from 4-phenoxypropyl chloride or 4-phenoxyethyl chloride.

Intermediate (119) intermediate (120)

Example A.41

Preparation of intermediate (121)

1-Pyrrolidinecarbonyl chloride (0.037 mol) was dissolved in tetrachloromethane (12 ml). 3-bromo-1-propanol (0.036mol) was added dropwise and the reaction mixture was stirred at room temperature for 7 days. The mixture was cooled on ice and CH was added₃OH/(NH₃) (2 ml). DCM (100ml) was then added and the mixture washed with water, dried and the solvent evaporated. The residue was purified on a glass filter over silica gel (eluent: DCM). The product fractions were collected and the solvent was evaporated, yielding 4g of intermediate (121).

Example A.42

a) Preparation of intermediate (122)

A mixture of intermediate (87) (0.0154mol), methyl 4-bromo-butyrate (0.02mol) and triethylamine (0.02mol) in DMF (150ml) was stirred at 70 ℃ overnight. The reaction mixture was cooled and the solvent was evaporated. The residue was dissolved in DCM and washed with water. The separated organic layer was dried, filtered and the solvent was evaporated to give 8g of intermediate (122).

b) Preparation of intermediate (123)

Intermediate (122) (0.0154mol) was stirred and refluxed in HCl/2-propanol (6N) (0.09mol) and methanol (100ml) for 1 hour. The reaction mixture was cooled. The solvent was removed by evaporation. The residue was dissolved in DCM and washed with water/NH₃And (6) washing. The separated organic layer was dried, filtered and the solvent was evaporated. The residue is purified by column chromatography on silica gel (eluent: CH)₂Cl₂/(CH₃OH/NH₃)97/3). The desired fractions were collected and the solvent was evaporated, yielding 1.75 g of intermediate (123).

In a similar manner, intermediates (124) to (129) were prepared.

Intermediate (124)

Intermediate (125)

Intermediate (126)

Intermediate (127)

Intermediate (128)

Intermediate (129)

For the preparation of the final compounds, intermediates known from the prior art have also been used, for example 3-cyanopropyl bromide, tetrahydrofurfuryl methanesulfonate, 3-hydroxy-propyl bromide, 2-methoxyethyl bromide, 3-methoxypropyl chloride, (trans) -4- (aminomethyl) -1- [2- (1, 3-dioxolan-2-yl) ethyl ] -3-piperidinol (described as intermediate 8 in WO-00/37461), 1-chloro-3- (1-methylethoxy) -propane, 2- (3-chloropropyl) -2-methyl-1, 3-dioxolane, 2- (2-bromoethyl) -1, 3-dioxolane, 4-bromobutyric acid methyl ester, 2-chloro-acetonitrile, 2- (2-chloroethoxy) -ethanol, N- (2-chloroethyl) -methanesulfonamide, and N- [3- [ (methylsulfonyl) oxy ] propyl ] -methanesulfonamide.

B. Preparation of the Final Compounds

Example B.1

A mixture of intermediate (95) (0.336mol) in HCl/2-propanol (160ml) and 2-propanol (1400ml) 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, filtered and evaporated to give 71g of compound (255).

Example B.2

a) Preparation of intermediate (20)

A mixture of intermediate (85) (0.01 mol), intermediate (115) (0.014 mol) and sodium carbonate (0.02mol) in isobutanol (100ml) was stirred and refluxed for 40 hours; then cooled and filtered. The solvent of the filtrate was evaporated. The residue is purified by column chromatography on silica gel (eluent: CH)₂Cl₂/(CH₃OH/NH₃)97/3). The desired fractions were collected and the solvent was evaporated, yielding 2.6 g of intermediate (20).

b) The intermediate (20) (0.006mol) was hydrogenated in methanol (100ml) using palladium on carbon (10%, 1g) as a catalyst in the presence of a thiophene solution (0.5 ml). After absorption of hydrogen (3 equivalents), the catalyst is filtered off and the solvent is evaporated. The residue is purified on a glass filter with silica gel (eluent: CH)₂Cl₂/(CH₃OH/NH₃)96/4). The desired fractions were collected, filtered and the solvent was evaporated. The residue was dissolved in 2-propanol and converted with (E) -2-butenedioic acid to (E) -2-butenedioic acid salt (1: 1). The precipitate was filtered, washed and dried to give 1.8g of Compound (1) (m.p. 174 ℃ C.).

Example B.3

a) Preparation of intermediate (43)

Intermediate (26) (0.012mol) was dissolved in DCM (60 ml). Triethylamine (0.012mol) was added and the reaction mixture was cooled to a temperature below 10 ℃. Formic acid (0.012mol) was added carefully and the reaction mixture was stirred at a temperature below 10 ℃ for 45 minutes to give mixture (a). Intermediate (67) (0.011mol) was stirred in DCM (60 ml). Triethylamine (0.029mol) was added, and the reaction mixture was stirred at room temperature for 45 minutes to obtain a mixture (B). The mixture (a) was added to the mixture (B), and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with 5% NaOH, then water. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue is purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH 95/5). The product fractions were collected and the solvent was evaporated, yielding 3.5g of intermediate (43).

b) A mixture of intermediate (43) (0.007mol) in 6N HCl/2-propanol (7ml) and 2-propanol (70ml) was stirred and refluxed for one hour. The solvent was removed by evaporation. The residue was partitioned between water and DCM. Sodium carbonate was added. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was suspended in DIPE, filtered and dried (vacuum, 40 ℃). The residue was dissolved in water and 50% NaOH. The mixture was extracted with DCM. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was dried (vacuum, 40 ℃ C.), then crystallized from DIPE/ACN, filtered and dried to give 1.3 g of compound (2) (m.p. 150 ℃ C.).

Example B.4

a) Preparation of intermediate (44)

A mixture of intermediate (88) (0.0106 mol), 1-bromo-2-methoxy-ethane (0.015mol) and sodium carbonate (0.02mol) in isobutanol (100ml) was stirred and refluxed for 20 hours, then the reaction mixture was cooled, the salt was filtered and the filtrate was evaporated. The residue is purified by column chromatography on silica gel (eluent: CH)₂Cl₂/(CH₃OH/NH₃)97/3). The product fractions were collected and the solvent was evaporated, yielding 3.3 g of intermediate (44).

b) A mixture of intermediate (44) (0.0067 mol) and 6N HCl/2-propanol (0.03mol) in 2-propanol (80ml) was stirred and refluxed for 1 hour, then the reaction mixture was cooled and the solvent was evaporated. The residue was dissolved in DCM and washed with 2% aqueous NaOH. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was suspended in DIPE, the mixture was boiled and cooled. The resulting precipitate was filtered, washed and dried to give 1.78g of compound (33) (m.p. 135 ℃ C.).

Example B.5

A mixture of compound (255) (0.0125mol), 3-methoxypropyl chloride (0.025mol) and potassium carbonate (0.0375mol) in ACN (50ml) was stirred and refluxed for 20 hours. The reaction mixture was cooled, poured into water and extracted with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue is purified by column chromatography on silica gel (eluent: CH)₂Cl₂/(CH₃OH/NH₃)93/7/0.5). The pure fractions were collected and the solvent was evaporated. The precipitate was filtered and recrystallized from a mixture of 2-propanone and DIPE to give 3g of the compound (200) (m.p.; [ alpha.; 108 ℃)]^20，D-10.70 °, (c-10.28 mg/2ml in methanol)).

Example B.6

A mixture of compound (8) (0.0094 mol), butyraldehyde (0.0094 mol) and potassium acetate (0.015mol) in methanol (100ml) was hydrogenated with platinum/carbon (5%, 1g) as a catalyst in the presence of a thiophene solution (2 ml). After absorption of hydrogen (1 equivalent), the catalyst was filtered through celite and the filtrate was evaporated. The residue was partitioned between 2% aqueous NaOH (100ml) and DCM (150 ml). The layers were separated. The aqueous phase was back-extracted with DCM (100 ml). The combined organic layers were dried, filtered and the solvent was evaporated. The residue is purified by column chromatography on silica gel (eluent: CH)₂Cl₂/(CH₃OH/NH₃)97/3). The product fractions were collected and the solvent was evaporated. The residue was dissolved in ACN and converted to the ethanedioic acid salt (1: 2), filtered and dried to give 1.62 g of compound (11) (m.p.)>110℃)。

A similar procedure can be used to prepare compound such as compound (64) using 4-fluoro-benzaldehyde instead of butyraldehyde.

Example B.7

Intermediate (123) (0.004mol) was stirred and refluxed in water (100ml) for 6 hours. The reaction mixture was cooled and washed with DCM. The solvent was removed by evaporation. The residue was suspended in ACN. The precipitate was filtered, washed and dried to give 1.58g of compound (16) (m.p. 240 ℃ C.).

Example B.8

Triethylamine (1.4 ml) was added to a suspension of intermediate (12) (0.01 mol) in DCM (75 ml) and the reaction mixture was cooled to a temperature below 0 ℃. At temperatureFormic acid (0.96) was added dropwise below 0 ℃ and the reaction mixture was stirred for 30 minutes at a temperature below 0 ℃. A suspension of intermediate (69) (0.01 mol) in DCM (25 ml) and triethylamine (2.4 ml) was added and the mixture was stirred at room temperature for 3 hours. DCM (100ml) and water (150ml) were added, the mixture stirred and the layers separated. The organic layer was washed with 5% aqueous NaOH and water, then dried, filtered and the solvent was evaporated. The residue is purified by column chromatography on silica gel (eluent: CH)₂Cl₂/(CH₃OH/NH₃)96/4). The product fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE with a small amount of ACN, and the resulting precipitate was filtered and dried to give 2.2g of compound (26) (m.p. 106 ℃ C. -108 ℃ C.).

Example B.9

A mixture of compound (43) (0.0051mol) in 5% aqueous HCl (50ml) and THF (50ml) was stirred at room temperature overnight; then concentrated in vacuo. The concentrate was basified with aqueous ammonia and extracted with DCM (3 ×). The separated organic layer was dried, filtered and the solvent was evaporated. The residue was crystallized from DIPE/ACN. The precipitate was filtered and dried to give 1.9g of compound (44) (m.p. 130 ℃ C.).

Example B.10

a) Preparation of intermediate (130)

Compound (24) (0.026mol) was added to CH₃OH/NH₃Hydrogenation was carried out in (250ml) with Raney Nickel as catalyst in the presence of thiophene solution (1 ml). After absorption of hydrogen (2 equivalents), the catalyst is filtered off and the solvent is evaporated. The residue was crystallized from ACN (0 ℃). The precipitate was filtered off and dried to yield 8g of intermediate (130).

b) Intermediate (130) (0.008mol) was dissolved in chloroform (100 ml). Triethylamine (0.012mol) was added. Adding dropwise into chloroform (10ml) at a temperature below 5 deg.CMethanesulfonyl chloride (0.008 mol). The reaction mixture was stirred for 30 minutes, washed with water, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH)₂Cl₂/(CH₃OH/NH₃)93/7). The desired fractions were collected and the solvent was evaporated. The residue was suspended in DIPE/ACN (0 ℃). The precipitate was filtered and dried to give 1.1g of compound (63) (m.p. 180 ℃ C.).

Example B.11

A mixture of intermediate (130) (0.016mol), 2-chloro-3-methyl-pyrazine (0.016mol) and calcium oxide (0.02mol) in DMA (5ml) was stirred at 120 ℃ for 48 hours; and then cooled. Adding water and using CH₂Cl₂/CH₃OH extracting the mixture. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH)₂Cl₂/(CH₃OH/NH₃)93/7). The desired fractions were collected and the solvent was evaporated. The residue was suspended in DIPE (0 ℃). The precipitate was filtered and dried to give 1.45g of compound (68) (m.p. 100 ℃ C.).

Example B.12

a) Preparation of intermediate (131)

A mixture of intermediate (88) (0.01 mol) and 1, 1-dimethyl-methyl- (3-oxopropyl) -carbamate (± 0.015mol) in THF (100ml) was hydrogenated with palladium on carbon (10%, 2g) as catalyst in the presence of thiophene solution (2 ml). After absorption of hydrogen (1 eq), the catalyst was filtered off and the filtrate was evaporated. The residue was purified by short column chromatography on silica gel. The product fractions were collected and the solvent was evaporated, yielding 2.9 g of intermediate (131).

b) A mixture of intermediate (131) (0.0048mol) and HCl/2-propanol (6N) (5ml) in 2-propanol (100ml) was stirred and refluxed for 1 hour,the reaction mixture was then cooled and the solvent was evaporated. The residue was dissolved in DCM and washed with 2% aqueous NaOH. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue is purified by column chromatography on silica gel (eluent: CH)₂Cl₂/(CH₃OH/NH₃)90/10). The product fractions were collected and the solvent was evaporated. The residue was dissolved in 2-propanol and converted to (E) -2-butenedioic acid salt (2:3) with fumaric acid (2 eq). The precipitate was filtered and dried to obtain 1.13g of Compound (81) (melting point)>130℃)。

Example B.13

a) Preparation of intermediate (132)

A mixture of intermediate (3) (0.013 moles) in DCM (60ml) was stirred and cooled on an ice bath. Triethylamine (0.013mol) was added carefully and the mixture was stirred at 10 ℃ and formic acid (0.013mol) was added dropwise and the mixture was stirred for 45 minutes. A solution of intermediate (73) (0.012mol) in DCM (30ml) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with 5% aqueous NaOH and water. The separated aqueous layer was extracted with DCM. The separated organic layer was dried, filtered and concentrated. The residue is purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH 90/10). The pure fractions were collected and the solvent was evaporated. The residue was concentrated with toluene and the solvent was evaporated to give 2.75g of intermediate (132).

b) A mixture of intermediate (132) (0.0069mol) in methanol (150ml) was hydrogenated using palladium on carbon (10%, 1g) as catalyst in the presence of a thiophene solution (1 ml). After absorption of hydrogen (3 equivalents), the catalyst was filtered off with dicalite and the filtrate was concentrated. The residue was crystallized from 2-propanol and DIPE and converted to the ethanedioic acid salt (2: 3). The residue was filtered and dried to yield 2.25g of compound (107) (m.p. >160 ℃ C.).

Example B.14

a) Preparation of intermediate (133)

A mixture of intermediate (26) (0.016mol) in DCM (60ml) was stirred, triethylamine (0.016mol) was added and the reaction mixture was cooled on an ice bath (temperature below 10 ℃). Formic acid (0.016mol) is then added dropwise and the reaction mixture is stirred at a temperature below 10 ℃ for 45 minutes (solution A). A solution of intermediate (69) (0.013mol) in DCM (60ml) was stirred at room temperature, triethylamine (0.03mol) was added and the reaction mixture was stirred at room temperature for 45 min. The first solution (a) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water. The separated organic layer was dried, filtered and concentrated. The residue was purified by column chromatography over silica gel (eluent: CH)₂Cl₂/(CH₃OH/NH₃7N) 95/5). The product fractions were collected and the solvent was evaporated, yielding 3.1 g of intermediate (133).

b) A mixture of intermediate (133) (0.006mol) in 2-propanol/HCl (6N) (6ml) and 2-propanol (60ml) was stirred and refluxed for 1 hour. The reaction mixture was left at room temperature overnight and then concentrated. The residue was partitioned between aqueous ammonia and DCM. The separated organic layer was dried, filtered and concentrated. The product was crystallized from ACN and DIPE, filtered off and dried to yield 1.55 g of compound (113) (m.p. 126 ℃).

Example B.15

a) Preparation of intermediate (134)

Compound (226) (0.013mol) in CH₃OH/NH₃(300ml) Raney Nickel (1g) was used as a catalystAnd (4) hydrogenating the agent. After absorption of hydrogen (2 equivalents), the catalyst was filtered off and the filtrate was evaporated, yielding 5.1 g of intermediate (134).

b) Methanesulfonyl chloride (0.54ml) was added dropwise to a mixture of intermediate (134) (0.0064mol) and triethylamine (0.013mol) in DCM (60ml) at room temperature. After 3 hours, methanesulfonyl chloride (0.2ml) was added, and the mixture was stirred for 24 hours. The mixture was washed with water, the organic layer was dried, filtered and the solvent was evaporated. The residue is purified by flash column chromatography on silica gel (eluent: CH)₂Cl₂/(CH₃OH/NH₃)99/1, 98/2, 97/3). The product fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE with a small amount of ACN, filtered, washed and dried to give 0.7g of compound (193) (m.p. [ alpha. [ 134 ℃ C. ]; m.]^20，D-9.83 ° (c 23.40mg/5ml in CH₃In OH)).

Example B.16

A mixture of compound (192) (0.006mol) in pyridine (0.012mol), DCM (50ml) and THF (50ml) was stirred (5 ℃) under an argon atmosphere. Thionyl chloride (0.006mol) (5 ℃) was added dropwise. The reaction mixture was stirred at 5 ℃ for 1 hour and bubbled with ammonia (gaseous) gas bubbles at 5 ℃ for 10 minutes. After reaching room temperature, the mixture was stirred for 2 hours, dissolved in DCM and washed with water. The organic layer was dried, filtered and the solvent was evaporated. The residue is purified on a glass filter with silica gel (eluent: CH)₂Cl₂/(CH₃OH/NH₃)93/7). The product fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE, filtered, washed and dried to obtain 0.4g of compound (197) (m.p.; [ alpha.;) having a melting point of 136 ℃]^20，DIn CH (11.52 ° (c 10.42mg/5 ml)₃In OH)).

Example B.17

A mixture of compound (192) (0.005mol) and triethylamine (0.01 mol) in DCM (30ml) was stirred at 5 ℃. Formic acid (0.005mol) was added dropwise at 5 ℃. The mixture was stirred at 5 ℃ for 30 minutes. 1-methyl-piperazine (0.015mol) was then added at 5 ℃. The reaction mixture was brought to room temperature and washed with water. Will haveThe organic layer was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH)₂Cl₂/(CH₃OH/NH₃)95/5). The product fractions were collected and the solvent was evaporated. The residue was dissolved in ethyl acetate and converted to the ethanedioic acid salt (1: 1). The precipitate was filtered and dried to obtain 0.6g of the compound (238) (melting point)>112℃)。

Example B.18

A mixture of compound (241) (0.0033 mol), potassium hydroxide (0.009 mol) and ethanol (50ml) was stirred and refluxed for 5 days. The mixture was cooled and the solvent was evaporated. The residue was partitioned between water and DCM and extracted 2 times with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH)₂Cl₂/(CH₃OH/NH₃)95/5). The product fractions were collected and the solvent was evaporated. The residue was dried to obtain 0.14g of compound (249).

Table F-1 lists compounds prepared according to one of the above examples.

TABLE F-1

Pharmacological examples

Example c.1: "5 HT₄Antagonism "

H5-HT_4bHEK293 clone 9 cells were cultured in 150mm Petri dishes and washed twice with cold PBS. The cells were then scraped from the culture dish and suspended in 50mM Tris-HCl buffer, pH7.4, and collected by centrifugation at 23,500rpm for 10 minutes. The pellets were resuspended in 5mM Tris-HCl pH7.4 and homogenized using an Ultra Turrax homogenizer. The cell membranes were collected by centrifugation at 30,000rpm for 20 minutes, resuspended in 50mM Tris-HCl, pH7.4, and stored at-80 ℃. For the experiments, the test mixture (0.5ml) contained 50. mu.l of tritiated ligand (5-HT)₄Antagonist [2 ]³H]Gr1138080.1nm) and 0.4 ml cell membrane preparation (15 μ g protein/ml). 50 μ l of 10% DMSO was added for total binding. Mu.l of 1. mu.M (+) -trans- (1-butyl-3-hydroxy-4-piperidinyl) methyl 8-amino-7-chloro-2, 3-dihydro-1, 4-benzodioxan-5-carboxylate (5 HT, a specialty for Janssen pharmaceuticals) was added₄Agonist) was used to determine non-specific binding.

The [2 ]³H]GR113808 assay buffer was 50mM HEPES-NaOH, pH 7.4. The mixture was incubated at 25 ℃ for 30 minutes. The culture was terminated by filtration through Unifilter 96 GF/B pre-soaked in 0.1% polyethyleneimine followed by six washes with 50mM HEPES-NaOH pH 7.4.

pIC of all test compounds was calculated using non-linear regression analysis to calculate the ligand concentration binding isotherms (rectangular hyperbolas)₅₀The data are listed in table c.1 below.

Table c.1: 5HT₄Antagonistic data

Example c.2: "Metabolic stability"

The sub-cellular tissue preparation was prepared by centrifugation following mechanical homogenization of the tissue according to the method of good et al (Xenobiotica 5: 453-462, 1975). Liver tissues were washed in ice-cold 0.1M Tris-HCI (pH7.4) buffer to wash away excess blood. The tissue was then blotted dry, weighed and coarsely minced using surgical scissors. The tissue fragments were homogenized in 3 volumes of ice-cold 0.1M phosphate buffer (pH 7.4).

The tissue homogenate was centrifuged at 9000Xg for 20 minutes at 4 ℃. The resulting supernatant was stored at-80 ℃ and designated as 'S9'.

The S9 fraction may be further centrifuged at 100.000Xg for 60 minutes (4 ℃). The resulting supernatant was carefully aspirated, aliquoted and designated as 'cytosol'. In 1ml final volume/0.5 g initial tissue weight, the pellet was resuspended in 0.1M phosphate buffer (pH7.4) and called 'microsome'.

All sub-cellular fractions were aliquoted, immediately frozen in liquid nitrogen, and stored at-80 ℃ until use.

For the sample to be tested, the culture mixture contained PBS (0.1M), compound (5. mu.M), microsomes (1mg/ml) and NADPH-producing system (0.8mM glucose-6-phosphate, 0.8mM magnesium chloride and 0.8 units of glucose-6-phosphate dehydrogenase). The control sample contained the same material, but the microsomes were replaced with heat-inactivated (at 95 degrees celsius, 10 minutes) microsomes. The recovery of compound in the control sample was always 100%.

The mixture was pre-incubated at 37 ℃ for 5 minutes. The reaction was started by adding 0.8mM NADP at time point zero (t ═ 0) 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 at 900Xg for 10 minutes and the supernatants were stored at room temperature and analyzed no more than 24 hours ago. All cultures were performed in duplicate. Analysis of the supernatant was performed by LC-MS analysis. Elution of samples was performed on Xterra MSC18(50 x 4.6mm, 5 μm. waters, US). An Alliance 2790 (supplier: Waters, US) HPLC system was used. Elution was performed with buffer A (25mM ammonium acetate (pH 5.2) in water/acetonitrile (95/5), solvent B acetonitrile and solvent C methanol at a flow rate of 2.4 ml/min. The gradient used was increasing organic phase concentration: in a linear fashion, from 0% to 50% B and 50% C over 5 minutes, from 1 minute to 100% B, and the organic phase concentration was kept constant for an additional 1.5 minutes. The total injection volume of the sample was 25. mu.l.

As detector a Quatro triple quadrupole mass spectrometer equipped with an ESP source was used. The source and dissociation temperatures were set at 120 and 350 c, respectively, and nitrogen was used as the spray and drying gas. Data were obtained in the positive scan mode (single ion reaction). The cone voltage was set at 10V and the dwell time was 1 second.

Metabolic stability is expressed as% metabolism after 60 minutes incubation of a compound in the presence of active microsomes (E (act)) (equations are given as examples)

(metabolism = 100% - ((e (act)) Total Ionic Current (TIC)/e (act) at t ═ 60 TIC) x 100).

Table c.2: metabolism of the inventive compounds (left panel) compared to the analogous structure of WO-00/37461 (right panel)%

Claims

1. A compound of formula (I):

a stereochemically isomeric form thereof, an N-oxide form thereof, or a pharmaceutically acceptable acid or base addition salt thereof, wherein

-R¹-R²Is a divalent radical of the formula

-O-CH₂-CH₂-O- (a-3)，

-O-CH₂-CH₂-CH₂-O- (a-5)，

Wherein in the divalent radical, one or two hydrogen atoms, optionally on the same or different carbon atoms, may be replaced by C_1-6An alkyl group or a hydroxyl group is replaced,

R³is hydrogen, halogen or C_1-4An alkyl group;

l is hydrogen, or L is a group of the formula

-Alk-R⁶ (b-1)，

-Alk-X-R⁷ (b-2)，

-Alk-Y-C(＝O)-R⁹(b-3), or

-Alk-Z-C(＝O)-NR¹¹R¹² (b-4)，

Wherein each Alk is C_1-12An alkanediyl group; and is

x is O, S, SO₂Or NR⁸(ii) a The R is⁸Is hydrogen or C_1-6An alkyl group;

R⁹is hydrogen, C_1-6Alkyl radical, C_3-6Cycloalkyl, hydroxy or aryl;

y being a direct bond or NR¹⁰Wherein R is¹⁰Is hydrogen or C_1-6An alkyl group;

R¹¹and R¹²Each independently of the other being hydrogen, C_1-6Alkyl radical, C_3-6Cycloalkyl, or R¹¹And R¹²And with R¹¹And R¹²Are combined to form a pyrrolidinyl, piperidinyl, piperazinyl or 4-morpholinyl ring, both optionally substituted with C_1-6Alkyl substitution;

het is furyl; quilt C_1-6Alkyl or halo substituted furyl;

a tetrahydrofuranyl group; quilt C_1-6Alkyl-substituted tetrahydrofuranyl;

dioxolanyl; quilt C_1-6An alkyl-substituted dioxolanyl group;

a dioxanyl group; quilt C_1-6Alkyl-substituted dioxanyl;

a tetrahydropyranyl group; quilt C_1-6Alkyl-substituted tetrahydropyranyl;

a pyrazinyl group; is one or two of each independently selected from hydroxyl and C_1-6Alkoxy radicalBase, C_1-6A pyrazinyl group substituted with an alkyl or halogen substituent.

2. A compound as claimed in claim 1, a stereochemically isomeric form thereof, an N-oxide form thereof, or a pharmaceutically acceptable acid or base addition salt thereof, wherein

-R¹-R²Is a divalent radical of the formula

-O-CH₂-CH₂-O- (a-3)，

-O-CH₂-CH₂-CH₂-O- (a-5)，

R³Is hydrogen, halogen or C_1-4An alkyl group;

l is hydrogen, or L is a group of the formula

-Alk-R⁶ (b-1)，

-Alk-X-R⁷ (b-2)，

-Alk-Y-C(＝O)-R⁹(b-3), or

-Alk-Z-C(＝O)-NR¹¹R¹² (b-4)，

Wherein each Alk is C_1-12An alkanediyl group; and is

x is O, S, SO₂Or NR⁸(ii) a The R is⁸Is hydrogen or C_1-6An alkyl group;

R⁹is C_1-6Alkyl radicalOr a hydroxyl group;

y is a direct bond;

z is a direct bond or O;

R¹¹and R¹²Each independently is hydrogen, or C_1-6Alkyl, or R¹¹And R¹²And with R¹¹And R¹²Is combined with the nitrogen atom of (C) to form a quilt_1-6Alkyl-substituted pyrrolidinyl or piperazinyl;

het is tetrahydrofuryl; quilt C_1-6Alkyl-substituted tetrahydrofuranyl;

dioxolanyl; quilt C_1-6An alkyl-substituted dioxolanyl group;

3. A compound as claimed in claim 1 OR claim 2, a stereochemically isomeric form thereof, an N-oxide form thereof, OR a pharmaceutically acceptable acid OR base addition salt thereof, wherein-OR⁵The group is located at the 3-position of the piperidine moiety having the trans configuration.

4. A compound as claimed in claim 3, a stereochemically isomeric form thereof, an N-oxide form thereof, or a pharmaceutically acceptable acid or base addition salt thereof, wherein the absolute configuration of the piperidine moiety is (3S, 4S).

5. A compound as claimed in claim 1 or 2, a stereochemically isomeric form thereof, an N-oxide form thereof, or a pharmaceutically acceptable acid or base addition salt thereof, wherein-R¹-R²-is a group of formula (a-5); r³Is hydrogen; r⁴Is methyl; and R⁵Is hydrogen.

6. A compound as claimed in claim 5, a stereochemically isomeric form thereof, an N-oxide form thereof, or a pharmaceutically acceptable acid or base addition salt thereof, wherein L is a group of formula (b-2), wherein X is O and Alk is C_1-4Alkanediyl and R⁷Is C_1-6An alkyl group.

7. The compound of claim 1, a stereochemically isomeric form thereof, an N-oxide form thereof, or a pharmaceutically acceptable acid or base addition salt thereof, wherein said compound is (3S-trans) -8-methyl-3, 4-dihydro-2H-benzo [ b ] [1, 4] dioxepan-6-carboxylic acid [ 3-hydroxy-1- (3-methoxy-propyl) piperidin-4-ylmethyl ] -amide or a pharmaceutically acceptable acid addition salt thereof.

8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound according to any one of claims 1 to 7.

9. A process for preparing a pharmaceutical composition according to claim 8, wherein a therapeutically active amount of a compound according to any one of claims 1 to 7 is intimately mixed with a pharmaceutically acceptable carrier.

10. Use of a compound according to any one of claims 1 to 7 for the preparation of a medicament for the treatment of 5HT₄-the use of a pharmaceutical aspect of the related disorder.

11. A process for the preparation of a compound of formula (I) according to claim 1, wherein:

a) reacting the intermediate of formula (II) with a carboxylic acid derivative of formula (III) or a reactive functional derivative thereof;

b) n-alkylating the intermediate of formula (IV) with a compound of formula (I-a), defined as a compound of formula (I) wherein L represents hydrogen, in a reaction inert solvent and optionally in the presence of a suitable base, thereby obtaining a compound of formula (I-b), defined as a compound of formula (I) wherein L is not hydrogen;

c) reacting a suitable ketone or aldehyde intermediate of formula L ═ O (v), which is a compound of formula L-H, where at C, with a compound of formula (I-a)_1-12(ii) two geminal hydrogen atoms in the alkanediyl moiety are substituted by ═ O, thereby obtaining a compound of formula (I-b);

wherein in the above reaction scheme, the group-R¹-R²-、R³、R⁴、R⁵And L is as defined in claim 1 and W is a suitable leaving group;

d) or converting the compounds of formula (I) into each other according to conversion reactions known in the art; alternatively, the compound of formula (I) is converted into a pharmaceutically acceptable acid addition salt or, conversely, the acid addition salt of the compound of formula (I) is converted with a base into the free base form; alternatively, stereochemically isomeric forms thereof are prepared.