CA2242494C - Novel n-substituted 4-((4'-aminobenzoyl)-oxymethyl)-piperidines having gastric prokinetic properties - Google Patents

Abstract

This invention concerns the compounds of formula (I) the N-oxide forms, the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein R1 is C1-6alkyloxy, C2-6alkenyloxy or C2-6alkynyloxy; R2 is hydrogen or C1-6alkyloxy, or when taken together R1 and R2 may form a bivalent radical of formula wherein in said bivalent radicals one or two hydrogen atoms may be substituted with C1-6alkyl, R3 is hydrogen or halo;
L is C3-6cycloalkyl, C5-6cycloalkanone, C2-6alkenyl optionally substituted with aryl, or L is a radical of formula -Alk-R4, -Alk-NR5R6, 1-R6-4-piperidinyl, Alk-X-R7, -Alk-Y-C(=O)-R9 or -Alk-Y-C(=O)-NR11R12, wherein each Alk is C1-12alkanediyl; R4 is hydrogen, C1-6alkylsulfonylamino, C3-6cycloalkyl, C3-6cycloalkanone, Ar-, di(Ar)methyl, Ar-oxy- or Het1; R5 is hydrogen or C1-6alkyl; R6 is Het2;
R7 is hydrogen, C1-6alkyl, hydroxyC1-6alkyl, C3-6cycloalkyl or Ar or Het2; X
is O, S, SO2 or NR8; said R8 being hydrogen, C1-6alkyl or Ar; R9 is hydrogen, C1-6alkyl, C3-6cycloalkyl, Ar, ArC1-6alkyl, di(Ar)methyl, C1-6alkyloxy or hydroxy; Y is NR10 or a direct bond; said R10 being hydrogen, C1-6alkyl or Ar; R11 and R12 each independently are hydrogen, C1-6alkyl, C3-6cycloalkyl, Ar or ArC1-6alkyl, or R11 and R12 combined with the nitrogen atom bearing R11 and R12 may form a pyrrolidinyl or piperidinyl ring both being optionally substituted with C1-6alkyl, amino or mono or di(C1-6alkyl)amino, or said R11 and R12 combined with the nitrogen bearing R11 and R12 may form a piperazinyl or 4-morpholinyl radical both being optionally substituted with C1-6alkyl. Processes for preparing said products, formulations comprising said products and their use as a medicine are disclosed, in particular for treating conditions which are related to impairment of gastric emptying.

Description

NOVEL N-SUBSTITUTED 4-[(4'-AMINOBENZOYL)-OXYMETHYL)-PIPERIDINES HAVING GASTRIC
PROKINETIC PROPERTIES.
The present invention is concerned with novel compounds of formula (I} having superior gastrokinetic properties. The invention further relates to methods for preparing such novel compounds, pharmaceutical compositions comprising said novel compounds as well as the use as a medicine of said compounds.
Compounds structurally related to the present novel compounds are disclosed in the i0 prior art. WO 93/05038, published on March 18, 1993, discloses (1-butyl-4-piperidinyi)methyl 8-amino-7-chloro-1,4-benzodioxan-5-carboxylate having 5 receptor antagonistic activity. WO 93116072, published on August 19, 1993 discloses (1-butyl-4-piperidinyl) methyl-5-amino-6-chloro-3,4-dihydro-2H-I-benzopyran-8-carboxylate hydrochloride having 5 HT4 receptor antagonistic activity.
Recently, Fancelli D. et al., Bioorganic & Medicinal Chem. Lett., 6:263-266, 1996, and WO-96/33186, published on October 24, 1996, disclose (I-butyl-4-piperidinyl)methyl-4-amino-5-chioro-2,3-dihydrobenzo[b]furan-7-carboxylate hydrochloride having 5 HTq receptor agonistic activity.
WO 94/29298, published on December 22, 1994 discloses 8-amino-7-chloro-I,4-benzodioxan-5-( 1-butyl-4-piperidinyl)carboxylate having 5 HT4 receptor antagonistic activity. WO 94/10174, published on May I 1, 1994 discloses 5-(1-(3-pyridylmethyl)-4-piperidinyl)methyl-8-amino-7-chloro-I,4-benzo-dioxancarboxylate, [1-(2-carbo-ethoxyethyl}-4-piperidinyl]methyl-8-amino-7-chloro-1,4-benzodioxan-5-carboxylate, [1-(3-hydroxybutyl)-4-piperidinyl]methyl-8-amino-7-chloro-1,4-benzodioxan-5-carboxylate having 5 HTq. receptor antagonistic activity. Also, WO-96/28424, published on September 19, 1996, discloses disubstituted 1,4-piperidine esters and amides having 5 HTq. receptor antagonistic activity.
The cited prior art documents disclose compounds having 5 HTq. receptor antagonistic activity and may generally be used in the treatment or prophylaxis of gastrointestinal disorders, cardiovascuiar disorders and CNS disorders. In particular, these compounds are thought to be useful in the treatment of irritable bowel syndrome (IBS), especially the diarrhoea aspects of IBS by blocking the ability of 5-HT to stimulate gut motility.
The problem which this invention sets out to solve is to provide gastric prokinetic compounds, i.e. the actual stimulation of gastric motility.

It is generally believed that gastric prokinetic activity is correlated with 5 HT4 receptor agonist activity, i.e. the opposite of 5 HTq. antagonist activity, (King F.D.
et aL, J. Med.
Chem_, 36:683-689, 1993 and Langlois M. et al., Bioorganic 8z Medicinal Chem.
LeZt., 4:1433-1436, 1994).
Hence it was surprising to find that the present compounds of formula (I) show gastric prokinetic activity.
In one embodiment, this invention concerns the use of compounds of formula Ri Ra O _ L-N~CHZ O-C ~ ~ NHZ (1), the N oxide forms, the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein R1 is Cl_6alkyloxy, C2_6alkenyloxy or C2_6alkynyloxy;
R2 is hydrogen or C1_6alkyloxy, or when taken together R1 and R2 may form a bivalent radical of formula -O-CH2-O- (a-1 )~

-O-CH2-CH2- (a-2), -~-CH2-CH2-W (a-3)~

-O-CH2-CH2-CH2' (a-q.), -~-CH2-CHZ-CH2-~- (a-S)~

-O-CHI-CH2-CH2-CH2- (a-6), wherein in said bivalent radicals one or two hydrogen atoms may be substituted with Cl_balkyl;

R3 is hydrogen or halo;

L is C3_6cycloalkyl, Cg_6cycloalkanone, C~_6alkenyI optionally substituted with Ar, or L is a radical of formula Alk-R4 (b-1 ) -Alk-NRSR6 (b-2), ~N_'R6 (b-3)~

-Alk-X-R~ (b-4), -Alk-Y-C(=O)-R9 (b-S), or -Alk-Y-C(=O)-NR11R12 (b-6), wherein AIk is C1_l2alkanediyl;
R4 is hydrogen, C1_6alkylsuifonylamino, Cg_6cycloaikyl, Cg_6cycloalkanone, Ar-, di(Ar)methyl, Ar-oxy- or Hett;
R$ is hydrogen or C1_6alkyI;
R6 is Het2;
R~ is hydrogen, Ci_6alkyl, hydroxyCl_6alkyi, C3_6cycloalkyl, Ar or Het2;
X is O, S, S02 or NR8; said R8 being hydrogen, C1_6alkyl or Ar;
R9 is hydrogen, C1_6alkyl, C3_6cycloalkyl, Ar, ArCi_6alkyl, di(Ar)methyl, C1_6alkyloxy or hydroxy;
Y is NRIa or a direct bond; said Rl~ being hydrogen, Ct_6alkyl or Ar;
R1 l and R12 each independently are hydrogen, Ci_6aIkyl, C3_6cycloalkyl, Ar or IS ArCZ_6alkyl, or Rl1 and R12 combined with the nitrogen atom bearing R11 and may form a pyrrolsdinyl or piperidinyl ring both being optionally substituted with C1_6alkyi, amino or mono or di(C1_6alkyi)amino, or said R11 and R12 combined with the nitrogen bearing R11 and R12 may form a piperazinyl or 4-morpholinyI
radical both being optionally substituted with CI_6alkyl;
each Ar being unsubstituted phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, hydroxy, C1_6alkyi, Ct_6alkyloxy, amino-sulfonyl, C1_6alkylcarbonyl, nitro, trifluorornethyi, amino or aminocarbonyl;
and Hetl and Het2 each independently are selected from furan; furan substituted with C1_6alkyl or halo; tetrahydrofuran; a tetrahydrofuran substituted with C1_6alkyl; a dioxolane; a dioxolane substituted with CZ_6alkyl, a dioxane; a dioxane substituted with C1_~alkyI; tetrahydropyran; a tetrahydropyran substituted with CZ_6alkyl;
pyrrolsdinyl; pyrrolsdinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, or C1-6aIkyl; pyridinyl;
pyridinyl substituted with one or two substituents each independently selected from 3U halo, hydroxy, cyano, C1_6alkyl; pyrimidinyl; pyrimidinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, C1_~alkyl, C1_6alkyloxy, amino and mono and di(C1_6aikyl)amino; pyridazinyl; pyridazinyl substituted with one or two substituents each independently selected from hydroxy, C1_6alkyloxy, Cl_salkyl or halo; pyrazinyl; pyrazinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, C1_6alkyi, C1_6alkyloxy, amino, mono- and di(C1_6alkyl)amino and CI_6aikyloxycarbonyl;

._ Hetl can also be a radical of formula O O O O
13 ~
R -N N- R13-NI 'N- R13-N~N- ~ N-~ ~ ~ ~ ( ~ it (c-1) {c-2) (c-3) (c Hetl and Het2 each independently can also be selected from the radicals of formula O O O
~R13 / N

S N Rla S N R N
(d-1) (d-2) (d_3) (due) R13 and R14 each independently are hydrogen or Ct~alkyl;
with the proviso that L is other than n-hutyl when Rl and R2 are taken together to form a bivalent radical of formula (a-2);
for the manufacture of a medicine for treating conditions involving a decreased motility of the stomach.
In another embodiment, this invention concerns novel compounds of formula (I') Ri R2 O _ L-N~~CHz O-C ~ ~ ~~ (I,)~

the N-oxide forms, the pharmaceutically acceptable acid addition salts and the ~0 stereochemically isomeric forms thereof, wherein Rl is C1_6alkyloxy, C2_6alkenyloxy or C2_6alkynyloxy;
R2 is hydrogen or Ci_6alkyloxy, or when taken together R1 and R2 may form a bivalent radical of formula -O-CH2-O- {a-1)~
-O-CH2-CH2- (a-2), -O-CH2-CH2-O- (a-3), -O-CH2-CH2-CH2- (a-4), -O-CH2-CH2-CH2-O- (a-5), -O-CH2-CH2-CH2-CH2- (a-6), wherein in said bivalent radicals one or two hydrogen atoms may be substituted with C1_6alkyl;
R3 is hydrogen or halo;
L is C3_6cycloalkyl, CS_6cycloalkanone, C2_6alkenyl optionally substituted with Ar, or L is a radical of formula -AIk-R4 (b-1 ), -Alk-NRSRb {b-2), ---( _N-R6 (b-3), -Alk-X-R7 (b-4), -Alk-Y-C(=O)-R9 (b-5), or -AIk-Y-C(=O)-NR11R12 (b-6), wherein Alk is CI_12a1kanediyl;
R4 is hydrogen, C1_6alkylsulfonylamino, C3_6cycloalkyl, C5_6cycloalkanone, Ar-, di(Ar)methyl, Ar-oxy- or Hetl;
R$ is hydrogen or C1_galkyl;
R6 is Het2;
R~ is hydrogen, C1_6alkyl, hydroxyCl_~alkyl, C3_6cycloalkyl, Ar or Het2;
X is O, S, S02 or NR8; said R8 being hydrogen, C1_6alkyl or Ar;
R~ is hydrogen, Cl_6alkyl, Cg_6cycloalkyl, Ar, ArCl_6alkyi, di{Ar)methyl, C1_6alkyloxy or hydroxy;
Y is NRlo or a direct bond; said Rid being hydrogen, Ci_6alkyl or Ar;
Rl1 and R12 each independently are hydrogen, C1_6alkyl, C3_6cycloalkyl, Ar or ArCt_6alkyl, or R11 and R12 combined with the nitrogen atom bearing R11 and may form a pyrrolsdinyl or piperidinyl ring both being optionally substituted with C1_6alkyl, amino or mono or di(Cl_~alkyl)amino, or said Ri 1 and R 12 cnmhinP~_ with the nitrogen bearing R11 and R12 may form a piperazinyl or 4-morpholinyl radical both being optionally substituted with C1_6alkyl;
each Ar being unsubstituted phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, hydroxy, CI_6alkyl, C1_6alkyloxy, amino-sulfonyl, C1_6alkylcarbonyl, nitro, trifluoromethyl, amino or aminocarbonyl;
and Hetl and Het2 each independently are selected from furan; furan substituted with C1_6alkyl or halo; tetrahydrofuran; a tetrahydrofuran substituted with C1_6alkyl; a dioxolane; a dioxolane substituted with C1_6alkyl, a dioxane; a dioxane substituted with C1_6alkyI; tetrahydropyran; a tetrahydropyran substituted with C1_6alkyl;
pyrrolidinyl; pyrrolidinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, or Ct_6alkyl; pyridinyl;
pyridinyl substituted With one or two substituents each independently selected from halo, hydroxy, cyano, C1_6allcyl; pyrimidinyl; pyrimidinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, CI_6alkyl, CI_6alkyloxy, amino and mono and di(Cl_6alkyl)amino; pyridazinyl; pyridazinyl substituted with one or two substituents each independently selected from hydroxy, C1_dalkyloxy, Ct_6alkyI or halo; pyrazinyl; pyrazinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, Ct_6alkyl, Cr_6alkyloxy, amino, mono- and di(C1_6alkyl)amino and C1_6alkyloxycarbonyl;
Hetl can also be a radical of formula O O O O
13_ ~ ~
R N N- R13-NI 'N- Ri3-N' \N- / N-/ \ V ~ w ~
(c-1 ) (c-2) (c-3) (c-4) Hetl and Het2 each independently can also be selected from the radicals of formula O O O
/ S ,Rls / N

S N Rla S N R N
(d_1) (d_2) (d_3) Cd_4) R13 and R14 each independently are hydrogen or Cl~alkyl;
with the proviso that R4 is other than hydrogen, phenyl, 4-fluorophenyl, 4-methylphenyl or 4-methoxyphenyl when R1 and R2 are taken together to form a bivalent radical of formula -O-CH2-CH2-O-; or L is other than n-butyl when R1 and R2 are taken together to form a bivalent radical of formula (a-2) or (a-4.).
The proviso is intended to exclude compounds EI, E2, E22 - E25, E27, E28, E30, E39 - E42 which are disclosed in WO-93/05038, compound E6 disclosed in WO-93/16072 and compound FCE 29029A disclosed in WO-96/33186.

_7_ As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; Ct~alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl and the like; C~_6alkyl is meant to include b C1_q.alkyl and the higher homologues thereof having 5 or 6 carbon atoms, such as, for example, 2-methylbutyl, pentyl, beryl and the like; C2_6alkenyl defines straight and branched chain unsaturated hydrocarbon radicals having from 2 to 6 carbon atoms, such as ethenyl, propenyl, butenyl, pentenyl or hexenyl; C2_6alkynyl defines straight and branched chain hydrocarbon radicals having from 2 to 6 atoms containing a triple bond, such as ethynyl, propynyl, butynyl, pentynyl or hexynyl; CI_Salkanediyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 1 to 5 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl and the Like; and C1_6alkanediyl is meant to include C~_Salkanediyl and the higher homologues thereof having 6 carbon atoms, such as, for example, 1,6-hexanediyl and the like.
The term "stereochemically isomeric forms" as used hereinbefore defines all the possible isomeric forms which the compounds of formula (I) or (I') may possess.
Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing alI diastereomers and enantiomers of the basic molecular structure.
More iri particular, stereogenic centers may have the R- or S-configuration.
Stereochemically isomeric forms of the compounds of formula (I) or (I') are obviously intended to be embraced within the scope of this invention.
Some of the compounds of formula (I) or (I') may also exist in their tautomeric form.
Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention. For instance, compounds of formula (1) or (I') wherein Hetl or Het2 is pyrimidinyl substituted with hydroxy, may exist in their corresponding tautomeric form.
The pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) or (I') are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohaiic acids, e.g.
hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such _g_ as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic succinic (i.e, butanedioic acid), malefic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toIuenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the Like acids.
Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.
The term addition salt as used hereinabove also comprises the solvates which the compounds of formula {I) or (I') as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like.
The N-oxide forms of the compounds of formula {I) or {I') are meant to comprise those compounds of formula {I) or (I~ wherein one or several nitrogen atoms are oxidized to the so-called N oxide, particularly those N oxides wherein the piperidine-nitrogen is N oxidized.
Whenever used hereinafter, the term "compounds of formula (I) or (I')" is meant to also include their N oxide forms, their pharmaceutically acceptable addition salts, and their ~0 stereochemically isomeric forms.
A first interesting group of compounds consists of compounds of formula (I') wherein RI and R2 are taken together to form a radical of formula {a-2) or {a-3), wherein optionally one or two hydrogen atoms are substituted with methyl; and R3 is halo.
~5 A second group of interesting compounds are those compounds of formula (I') wherein R1 is methoxy, R2 is hydrogen and R3 is chloro.
A particular group of compounds are those compounds of formula (I') wherein L
is a 30 radical of formula {b-1) and R4 is Hetl or substituted phenyloxy.
Another particular group of compounds are those compounds formula {I') wherein L is a radical of formula (b-2) or (b-3} and R6 is Het2.
35 Preferred compounds are those wherein R1 and R2 are taken together to form a radical of formula {a-2) or (a-3), wherein optionally one or two hydrogen atoms are substituted with methyl; R3 is chloro; L is a radical of formula {b-I), (b-2) or (b-3) wherein R4 is substituted phenyloxy, RS is hydrogen and R6 is Het2; in particular R4 is phenyloxy _g_ substituted with halo and R6 is pyrazinyl or imidazolyl optionally substituted with hydroxy or CI-6alkyl.
Most preferred are [1-[2-[(3-methyl-2-pyrazinyl)amino]ethyl]-4-piperidinyl]methyl4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate; or [ 1-["2-[2,3-dihydro-3-( 1-methylethyl)-2-oxo-1H-imidazol-1-yl]ethyl]-4-piperidinyl]-methyl 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate; or [ 1-[2-[(3-methyl-2-pyrazinyl)amino]ethyl]-4-piperidinyl]methyl 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-carboxylate; or [ 1-[ 1-(3-methyl-2-pyrazinyl)-4-piperidinyl]-4-piperidinyl]methyl 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-carboxylate; and the pharmaceutically acceptable acid addition salts and the stereo isomeric forms thereof.
The compounds of formula (I') may generally be prepared by reacting an intermediate of formula (II) with a carboxylic acid derivative of formula (III) or a reactive functional derivative thereof, such as, for example, an acid chloride or a carbonyl imidazole derivative. Said esterbond formation may be performed by stirring the reactants in an appropriate solvent in the presence of a base, such as sodium imidazolide.
Rt R2 O
L-N t-CH2 OH + HO-C ~ ~ NHz ~ (I') (II) (IIn Another way of preparing compounds of formula (I') is by N alkylating an intermediate of formula (V) with an intermediate of formula (IV), wherein W is an appropriate leaving group such as, for example, a halogen, e.g. chloro or bromo, or a sulfonyloxy leaving group, e.g. methanesulfonyloxy or benzenesulfonyloxy.
Ri Rz /~ O
L-W + HN t--CHZ O-C ~ ~ NHz ~ (I') (V) Rs Said N alkylation reaction can be performed in a reaction-inert solvent such as, for example, a dipolar aprotic solvent, e.g. N,N-dimethylformamide, or a ketone, e.g.
AMENDED SHAT

WO 97/31897 PC~'/EP97/OOS85 sodium carbonate, sodium hydrogen carbonate or triethylamine. Stirring may enhance the rate of the reaction. The reaction rnay conveniently be carried out at a temperature ranging between room temperature and reflux temperature.
Alternatively, an intermediate of formula (V) is reductively N alkylated with an intermediate of formula L'=O (IV-a), wherein L'=O represents a derivative of formula L-H wherein two geminal hydrogen atoms are replaced by oxygen, following "art-known reductive N alkylation grocedures".
Ri R2 O _ L'=O + HN\~CH2 O-C ~ ~ NHa -~-~- (I') ~ a) (V) Rs Said reductive N alkylation may be performed in a reaction-inert solvent such as, for example, dichloromethane, ethanol, toluene or a mixture thereof, and in the presence of a reducing agent such as, for example, a borohydride, e.g. sodium borohydride, sodium cyanoborohydride or triacetoxy borohydride. It may also be convenient to use hydrogen as a reducing agent in combination with a suitable catalyst such as, for example, palladium-on-charcoal or platinum-on-charcoal. In case hydrogen is used as reducing agent, it may be advantageous to add a dehydrating agent to the reaction mixture such as, for example, aluminium tert-butoxide. In order to prevent the undesired further hydrogenation of certain functional groups in the reactants and the reaction products, it may also be advantageous to add an appropriate catalyst-poison to the reaction mixture, e.g., thiophene or quinoline-sulphur. To enhance the rate of the reaction, the temperature may be elevaxed in a range between room temperature and the reflux temperature of the reaction mixture and optionally the pressure of the hydrogen gas may be raised.
Further, compounds of formula (r) wherein L is Alk'-NHR6 and Alk' is C2-6alkanediyl, said compounds being represented by formula (I'-a), can be prepared by treating intermediates (VII) with intermediates (VI), wherein W ~ is a suitable leaving group 3D such as, a halo, e.g. chloro, bromo or iodo, or an alkylthio, e.g.
methylthio, in an appropriate solvent e.g. acetonitrile or dimethylacetamide.
.~i lEti~~~~~~ M. ~~3~~,~9i~V~~'~~A.~

WO 97131897 ~. PCT/EP97N00585 Rt R2 O
R6-W~ + H2N-Alk'-N~CHZ O-C ~ ~ NH2 (~) (~ R3 Rt . R2 O
R6-HN-Alk'-N~CH2 O-C ~ ~ NH2 ~~ ) Rs Also, compounds of formula (I~ may be prepared by carbonylation of an intermediate of formula (X>T), wherein X is bromo or iodo, in the presence of an intermediate of formula (>n.
R~ R2 CO
L N~CHi OH + X ~ ~ NHy --~ (T) catalyst ~ .~ R
Said carbonylation reaction is carried out in a reaction-inert solvent such as, e.g.
acetonitrile or tetrahydrofttratt, in the presence of a suitable catalyst and a tertiary amine such as, e.g. triethylamine, and at a temperature ranging between room temperature and the reflux temperature of the reaction.mixture. Suitable catalysts are, for instance, palladium-on-carbon,. palladium(triphenylphosphine) complexes or Raney nickel.
Carbon monoxide is administered at atmospheric pressure or at an increased pressure.
Analogous carbonylation reactions are described in Chapter 8 of "Palladium reagents in organic syntheses", Academic Press Ltd., 8enehtop Edition 1990, by Richard F.
Heck;
and the references cited therein.
The compounds of forW ula (n may further be prepared by converting compounds of formula (~ into each other according to art-known group transformation reactions.
The compounds of formula (n may also-be converted to the corresponding N-oude forms following art-known procedures for converting a trivalent nitrogen, into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide.
Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides; e.g. sodium peroxide, potassium peroxide;
appropriate organic peroxides may comprise peroxy acids such as, for example, * Trade-mark WO 97/3189'7 PC~'/EP97/00585 benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g.
3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. tert-butyl hydroperoxide. Suitable soivents are, for example, water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g.
2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
The starting materials and some of the intermediates are known compounds and are connmercially available or may be prepared according to conventional reaction procedures generally known in the art. For instance, some intermediates of formula (III) have been described in EP-0,389,037.
An intermediate of formula (V) may be prepared by reacting an intermediate of formula (VIII), wherein PG represents an appropriate protective group, such as, for example, a tert-butoxycarbonyl, a benzyl group or a photoremovable group, with an acid of formula (III) or an appropriate reactive functional derivative thereof, and subsequent deprotection of the thus formed intermediate, i.e. removal of PG by art-known methods.
R1 R~
O
PG-N~CHZ OH + HO-C ~ / NHZ --a. -~ (V) (V~ (III) An intermediate of formula (II) may be prepared by reacting an intermediate of formula (IX), which may be prepared by deprotecting an intermediate of formula (VIII), with an intermediate of formula (IV).
L-W + H-N~CH~ OH --(n') (I
In some cases, it may be appropriate to protect the primary alcohol functionality during the reactionsequence starting from intermediate ((IX) to intermediate (II).
Protecting groups for primary alcohol functionalities are art-known. These protecting groups may then be removed at the appropriate time during the further synthesis.
Intermediates of formula (VII) can be prepared by treating an intermediate (V) with an intermediate of formula (X), wherein W2 is an appropriate leaving group such as, for example, a halogen, e.g. chloro or bromo, or a sulfonyloxy leaving group, e.g, methane----a .. ;WO 97/31897 : _ PCT/EP97100585 sulfonyloxy or benzenesulfonyloxy, and Alk" is C1_Salkanediyl, according to the . previously described N alkylation method, and subsequent reduction of intermediate (Xl] with an appiropriate reducing agent such as, e.g. Raney nickel, in a reaction-inert solvent e.g. THF and in the presence of hydrogen.
R~ R2 O
NC~Alk'~-W2 + (~ ---~- NC-Alk"-N~CH2-O-C ~ ~ NH2 --~ (VIn (X) (XI) R3 Ester derivatives of intermediates of formula (I>n can generally be prepared by carbonylating an intermediate of formula (X>n, wherein X is bromo or iodo in the presence of an alcohol of formula ~, wherein R is Cl_6alkyl.
Rt R2 ~ R1 R2 CO
X ~ ~ NHZ + ROH ~-----~ ROOC ~ ~ NH2 R3 ~) (~-a) R3 Said earbonylation reaction is carried out in a reaction-inert solvent such as, e:g.
acetonitrile or tetrahydrofuran, in the presence of a suitable catalyst and potassium acetate or a tertiary amine such as, e.g. triethylamine, and at a temperature ranging between room temperature and the reflux temperature of the reaction mixture.
Suitable catalysts are, for instance, palladium-on-carbon or Raney nickel. Carbon monoxide~is administered at atmospheric pressure or at an increased pressure. Analogous carbonylation reactions are described in Chapter 8 of "Palladium reagents in organic syntheses", Academic Press Ltd., Benchtop Edition 1990, by Richard F. Heck;
and the references cited therein.
The compounds o~ formula (>) as prepared in the hereinabove described processes may be 'synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (17 may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for exatuple,~by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali: An alternative manner of separating the enantiomeric forms of the compounds of formula. (>] involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric.forms of the appropriate starting * Trade-mark materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
The compounds of formula (I) or (I'), the N oxide forms, the pharmaceutically acceptable salts and stereoisomeric forms thereof possess favourable intestinal motility stimulating properties. In particular the present compounds show significant gastric emptying activity as is evidenced in example C.1, the "Gastric emptying of an acaloric IO liquid meal delayed by administration of lidamidine in conscious dogs"-test.
In view of the capability of the compounds of the present invention to enhance the gastrointestinal motility, and in particular to activate gastric emptying, the subject compounds are useful to treat conditions related to a hampered or impaired gastric emptying and more generally to treat conditions related to a hampered or impaired gastrointestinal transit.
The compounds of formula (I) also are believed to have a beneficial effect on the pressure of the LES (Lower Esophagus Sphincter).
Some of the compounds of the present invention also have colon motility stimulating properties.
In view of the utility of the compounds of formula (I), it follows that the present invention also provides a method of treating warm-blooded animals, including humans, (generally called herein patients} suffering from conditions related to a hampered or impaired gastric emptying or more generally suffering from conditions related to a hampered or impaired gastrointestinal transit. Consequently a method of treatment is grovided for relieving patients suffering from conditions, such as, for example, gastro-oesophageal reflux, dyspepsia, gastroparesis, constipation, post-operative ileus, and intestinal pseudo-obstruction. Gastroparesis can be brought about by an abnormality in the stomach or as a complication of diseases such as diabetes, progressive systemic sclerosis, anorexia nervosa and myotonic dystrophy. Constipation can result form conditions such as lack of intestinal muscle tone or intestinal spasticity.
Post-operative ileus is an obstruction or a kinetic impairment in the intestine due to a disruption in muscle tone following surgery. Intestinal pseudo-obstruction is a condition characterized by constipation, colicky pain, and vomiting, but without evidence of physical obstruction. The compounds of the present invention can thus be used either to take away the actual cause of the condition or to relief the patients from symptoms of the conditions. Dyspepsia is an impairment of the function of digestion, that can arise as a symptom of a primary gastrointestinal dysfunction, especially a gastrointestinal dysfunction related to an increased muscle tone or as a complication due to other S disorders such as appendicitis, galbladder disturbances, or malnutrition.
The symptoms of dyspepsia may also arise due to the intake of chemical substances, e.g. SSRI's.
Hence, the use of a compound of formula (I') as medicine is provided, and in particular the use of a compound of formula (n for the manufacture of a medicine for treating conditions involving a decreased motility of the stomach. Both prophylactic and therapeutic treatment are envisaged.
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. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectaIly or by parenteral injection.
For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent andlor a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause a significant deleterious effect to the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.

These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment. Acid addition salts of (I) due to their increased water solubility over the corresponding base form, are obviously more suitable in the preparation of aqueous compositions.
S
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of adnunistration and uniformity of dosage.
Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity I0 of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical Garner. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
IS
In general it is contemplated that a therapeutically effective amount would be from about 0.001 mg/kg to about 10 mg/kg body weight, preferably from about 0.02 mg/kg to about 5 mg/kg body weight. A method of treatment may also include administering the active ingredient on a regimen of between one to four intakes per day.
The following examples are provided for purposes of illustration, not limitation.
Experimental part.
Hereinafter "THF" means tetrahydrofuran, "DIPE" means diisopropylether, "DCM"
means dichloromethane, "DMF" means N,N-dimethylformamide and "ACN" means acetonitriIe.
A. Preparation of the intermediates Example A.I
A mixture of 1-(2-amino-ethyl)-4-piperidinemethanol (5.2 g), 2-chloro-3-methyl-pyrazine (5.0 g) and Ca0 {4.5 g) was stirred for 20 hours at I20°C. The reaction mixture was cooled and purified by column chromatography over silica gel {eluent CH2C12/(CH30HlNH3} 92/8). The pure fractions were collected and the solvent was evaporated, yielding 2.3 g (29%) 1-[2-[(3-methyl-2-pyrazinyl)amino]-ethyl]-4-piperidinemethanol (intermediate I }.

Example A.2 A mixture of 1-(2-chioroethyl)-1,3-dihydro-3-(1-methylethyl)-ZH-imidazol-2-one (12 g), 4-piperidinemethanol hydrochloride (9.1 g), N,N diethylethanamine (21 ml) and KI (catalytic amount) in DMF {200 ml) was stirred fax 20 hours at 70°C.
The reaction mixture was cooled and the solvent was evaporated. The residue was purified by column chromatography over silica gel {eluent : CH2C12/(CH30H/NH3) 95/5). The pure fractions were collected and the solvent was evaporated, yielding 6.9 g (43%) 1,3-dihydro-1-[2-[4-(hydroxymethyl)-1-piperidinyl]ethyl]-3-( 1-methylethyl)-2H
imidazol-2-one (intermediate 3).
Table 1 L-N~CHZ OH
Intm. Ex. No. L Ph sical data No.

H
1 A.1 ~ N~N~~CH2)~ -2 A.1 N N~ mp.126.7C
C

N"CH

CH3\ 'N~N~
3 A. ~' 4 A.2 3-(4-fluorophenoxy)propyl-S H

5 A.2 ~ >--N-~CHZ)z -N

Et I
N

6 A.2 ~ -~
~O

/
N

tCH2)3 O

7 A.2 / N~(CH2)2' _ / N

' H
N N
\

8 A.2 ~CH2)g -~ \
~

CN

_18_ Intm. Ex. No. L . Ph sical data No.

H

N~
N

9 A.2 ~cH2>z _ ~
~
~

CN

O

I6 A.2 i N~ -,N

Cl O

I7 A.2 I N~ _ ,N

Example A.3 a) Sodium hydride (5.8 g) was added to a solution of 1,1-dimethyiethyl 1-piperidine-4-methanolcarboxylate (25 g) in THF (800 ml). The mixture was stirred and refluxed for 3 hours (H~ gas evolution), then cooled (solution I). 1,1'-Carbonylbis-1H-imidazole {19.5 g) was added to a suspension of 4-amino-5-chloro-2-methoxybenzoic acid (24 g) in ACN (800 ml), stirred at room temperature. This mixture was stirred for 2 hours at room temperature (solution II). At room temperature, solution (II) was poured out into solution (I) and the reaction mixture was stirred for 20 hours at room temperature.
Water (t 10 ml) was added. The organic solvent was evaporated. The residue was partitioned between I~CM and H20. The insoluble solid was filtered off. The organic Layer was separated, dried, filtered and the solvent was evaporated. The residue was crystallized from ACN (0°C). The precipitate was filtered off and dried, filtered and the solvent was evaporated. The residue was crystallized from ACN. The precipitate was filtered off and dried (vacuum; 50°C), yielding 20 g (42%) l, l-dimethylethyl 4-[ [(4-amino-5-chloro-2-methoxy-benzoyl)oxyJ methyl]-1-piperidine-carboxylate (intermediate 10).
b) A mixture of intermediate IO ( 18 g) in HCl (25 ml) and THF (2S0 ml) was stirred for minutes at 70°C. The reaction mixture was cooled, alkalized with aqueous ammonia and the layers were separated. The aqueous layer was extracted twice with THF.
The combined organic layers were dried, filtered and the solvent was evaporated.
The residue was purified by column chromatography over silica gel (eluent 25 CH2C12~(CH30H/NH3) 90/10). The pure fractions were collected and the solvent was evaporated. The residue {10 g) was dissolved in CHCI3, washed with aqueous WO 97131897 PCT/Ep9"1i00585 ammonia, dried, filtered and the solvent was evaporated. The residue was suspended in DIPE, filtered off and dried, yielding 8.5 g (65'0) 4-piperidinylmethyl 4-amino-5-x chloro-2-methoxybenzoate (intermediate 11).
In a similar way, 4-piperidinylmethyl 4-amino-5-chloro-2,3-dihydro-2,2-diniethyl-7-benzofurancarboxylate (intermediate 12) and 4-piperidinylmethyl 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate(intermecliate 13) were synthesized.
Example A.4 a) A mixture, of chloroacetonitrile (2.15 ml) and (4-piperidinyl~methyl 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-S-carboxylate {l l g) in N,N-diethylethanamine (7 ml) and DMF ( 150 ml) was stirred at 60°C until the reaction was complete. Then, the mixture was cooled. The solvent was evaporated. The residue was partitioned between DCM and water. The separated organic Layer was dried, filtered and the solvent was evaporated. The residue was crystallized from ACN and the precipitate was filtered off and dried (vacuum, 50°C), yielding 6.G g (530) [1-{cyanomethyl~4-piperidinyl]-methyl 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-carboxylate (intermediate 14?.
b) A mixture of intermediate 14 (6 g) in THF (250 ml) was hydrogenated with Raney nickel (3 g) as a catalyst. After uptake of hydrogen (2 equivalents), the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent CH2C12/{CH30H/NH3) 90110). The pure fractions were collected and the solvent was evaporated, yielding 4 g (68%) [1-(2-amino-ethyl)-4-piperidinyl]methyl 8-amino-7-chloro-2,3-dihydm-1,4-benzodioxin-carboxylaxe (intermediate 15).
Example A.5 a) CaC03 (3.9 g) was added to a mixture of ~1,3-benzodioxol-4-amine (4.11 g) in DCM
(40 ml) and CH30H (20 ml). This mixture was stirred at room temperature. N,N,N
trimethyl benzenemethanaminium dichloroiodate (11.5-g) was added portionwise at mom temperature. The resulting reaction mixture was stirred for -15 minutes at room temperature. The mixture was diluted with watei. The layers were separated.
The aqueous phase was extracted with DCM. The combined organic layers were washed with water, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gcl (eluent : CH2ClZthexane 80120). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from DIPS. The precipitate was filtered off and dried, yielding 3.5 g (46.996) of 7-iodo-1,3 benzodioxol-4-amine (intermediate 18):
* Trade-mark b) Acetic anhydride (14.25 mI) was added dropwise to a mixture of intermediate {36.6 g) in acetic acid (500 mI), stirred at room temperature. The reaction mixture was stirred for 15 minutes at room temperature. The reaction mixture was poured out into water (500 ml). The precipitaxe was filtered, washed with water, then dried, yielding 39.29 g (92.6%) of N (7-iodo-I,3-benzodioxol-4-yl)acetamide (intermediate I9).
c) A mixture of intermediate 19 (38.8 g), potassium acetae (20 g) and Pd/C (10 %; 2 g) in CH30H (500 ml) was stirred at I50°C under 4.9x 106 Pa (50 kg) pressure of CO, during I6 hours. The reaction mixture was cooled, filtered over dicalite, and the filtrate was evaporated. The residue was diluted with water, then extracted three times with DCM. The combined organic layers were dried, filtered and the solvent evaporated.
The residue was dissolved in acetic acid (250 ml) and acetic anhydride (6 mi) was added dropwise. The mixture was stirred for 30 minutes at room temperature, then diluted with water (250 mI} and the resulting precipitate was filtered off, washed with water, then dried, yielding 19.4 g (64.7%) of methyl 7-(acetylamino)-1,3-benzodioxole-4-carboxylate {intermediate 20}.
d) A mixture of intermediate 20 ( 18.5 g) and NCS ( 11.4 g) in ACN ( 130 ml) was stirred and refluxed for one hour. The reaction mixture was cooled. The precipitate was filtered off, washed with ACN, with DIPE, then dried, yielding 18.2 g (87%) of methyl 7-(acetylamino)-6-chloro-1,3-benzodioxole-4-carboxylate (intermediate 21).
e) Intermediate 21 (18.2 g) was added to a solution of KOH (37.6 g) in water (380 mI).
The resulting reaction mixture was stirred and refluxed for 3 hours. The mixture was cooled, acidified with hydrochloric acid, and the resulting precipitate was filtered off, washed with water, suspended in ACN, filtered off, then dried, yielding 14 g (> 95%) of 7-amino-6-chloro-1,3-benzodioxole-4-carboxylic acid (intermediate 22).
f) A mixture of intermediate 22 (I g) and l,l'-carbonyIbis-1H-imidazole (0.8 g) in ACN
(80 ml) was stirred for 3 hours at room temperature. The solvent was evaporated. The residue was partitioned between water and DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was suspended in DIPE, filtered off, then dried (vacuum), yielding 0.8 g {75%) of 1-[(7-amino-6-chloro-1,3-benzodioxoi-4-yl)carbonyl~-1H imidazole (intermediate 23).
B. Preparation of the final compounds Example B.I
A mixture of I-chloro-(4-fluorophenoxy)propane (2.3 g), intermediate 1 I (3 g) and N,N diethylethanamine (2.8 ml) in DMF (50 ml) was stirred for 48 hours at 70°C. The reaction mixture was cooled and the solvent was evaporated. The residue was partitioned between DCM and water. The organic layer was separated, washed with water, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2C12/CH30H 95/5). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from ACN (0°C). The precipitate was filtered off and dried (vacuum;
50°C), yielding 1.17 g (26%) [1-[3-(4-fluorophenoxy)propyl]-4-piperidinyl]methyl 4-amino-5-chloro-2-methoxybenzoate (compound 1, mp. 140.0°C).
ExamnIe B.2 Sodium hydride (0.4 g} was added to a solution of intermediate I (2.3 g} in THF {65 I O ml). The mixture was stirred and refluxed for 3 hours, then cooled (solution I).
1,1'-Carbonylbis-IH-imidazole (1.65 g) was added to a solution of 4-amino-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofurancarboxylic acid (2.42 g) in ACN (65 ml), stirred at room temperature. This mixture was stirred for 2 hours at room temperature.
The solvent was evaporated. The residue was dissolved in THF (65 ml) (solution II). At room temperature, solution (II) was poured out into solution (I) and the reaction mixture was stirred for 90 minutes at room temperature. The solvent was evaporated.
The residue was partitioned between DCM and water. The organic layer was separated, dried,-filtered~nd-the soiveni -was-evaporated:-The residue was-purified-by column chromatography over silica gel (eluent: CH2C12/(CH30H/NH3) 95/5). The pure fractions were collected and the solvent was evaporated. The residue was solidified in DIPE. The precipitate was filtered off and dried vacuum; 50°C), yielding 1.58 g (33%) [ I-[2-[(3-methyl-2-pyrazinyl)amino]ethyl]-4-piperidinyl]methyl 4-amino-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofurancarboxylate (compound 6}.
Example B.3 A mixture of intermediate I5 (2 g) and 4-hydroxy-2-methylthiopyrimidine (0.86 g) in ACN {50 ml) was stirred and refluxed for 24 hours. 4-Hydroxy-2-methylthiopyrimidine (0.28 g) was added. The mixture was stirred and refluxed for 6 hours, cooled and the solvent was evaporated. The residue was taken up in DCM and water. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent CH2C12/CH30Hl(CH30H/NHg) 88//012). The desired fractions were collected and the solvent was evaporated. The residue was repurified by column chromatography over silica geI (eluent : CH2C12/(CH30H/NH3) 90/10). The pure fractions were collected and the solvent was evaporated. The residue was suspended in DIPS, filtered off and dried (vacuum, 60°C), yielding 0.7 g (27%) [I-[2-[(1,4-dihydro-4-oxo-2-pyrimidinyl)amino]-ethyl]-4-piperidinyl]methyl 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-S-carboxylate {compound iS).
Example B.4 S A mixture of intermediate 1 S (2 g), 2-chloro-4-hydroxyquinazoline ( 1.9 g), N,N dimethylacetamide (0.3 ml) and caiciumoxide (0.4 g) was stirred for 1 hour at I40°C, then cooled and partitioned between water and DCM (+ methanol).
The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent : CH2CI2/(CH30HlNH3) 9S/S). The desired fractions were collected and the solvent was evaporated.
The residue was suspended in DIPE, filtered off, then dried (vacuum, 60°C), yielding 1.4 g (SO°lo) [ I -[2-[( 1,4-dihydro-4-oxo-2-quinazolinyl)amino]ethyl]-4-piperidinyl]methyl 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-S-carboxylate (compound 19).
IS Example B.S
1H-imidazole (2.72 g) was added to a solution of 6-chIoro-2-j3-[4-(hydroxymethyl)-1-piperidinyl]propyI]-3(2H) -pyridazinone (2.62 g} in THF (100 mI). NaH (60%, 0.4 g) was added, under nitrogen atmosphere. The mixture was stirred for 10 minutes.
1-[(4-Amino-S-chloro-2,3-dihydro-7-benzofuranyl)carbonyl]-1H imidazole (2.64 g) was added and the resulting reaction mixture was stirred for IS minutes at room temperature. The solvent was evaporated. 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 : CH2C12/hexane/(CH30H/NH3) SO/4S/S}. The desired fractions were collected 2S and the solvent was evaporated. The residue was crystallized from RIPE with a drop of ACN. The precipitate was filtered off, washed and dried, yielding 1.88 g (39%) of [ I -[3-(3-chloro-6-oxo-1 (6H)-pyridazinyl)propyl]-4-piperidinyl]methyl 4-amino-S-chloro-2,3-dihydro-7-benzofurancarboxylate (compound 21, mp: 137 °C) In a similar way, [1-[3-(3-methyl-6-oxo-I(6H)-pyridazinyl)propyl]-4-piperidinyI]-methyl 7-amino-6-chloro-1,3-benzodioxole-4-carboxylate (compound 22) was also prepared.
Tables 2 to 4 list the compounds that were prepared according to one of the above Examples.

Table 2 O _ L-N~CHZ O-C \ / NH2 Cl Co. No. Ex. No. .,- L Ph sical data 1 B.1 3-(4-fluorophenoxy)propylmp.I40.0C

N~ NH-(CH2)z 2 B.2 ( ~ 103 mp.
.
C

3 B.2 CHs~N~N~ mp.I30.3C

able 3 Co. No. Ex. No. L Ra Ph sicaI data.

4 B.1 3-(4-fluorophenoxy)propyICH3 mp.105.6C

B.2 3-(4-fluorophenoxy}gropylH mp.130.8C

H

N N
6 B.2 ~ ~ ~ CH3 mp. 126.4.C

H

I
7 B.2 ~N~N~ H mp.188.3C

8 B.2 CH3~N~ ~ CH3 mp.78.6C
T

C

Co. No. Ex. No. - L R8 Physical data 9 B.2 CH3~N~N~ H mp.I30.6C
~' ~3 O

20 B.I I ~N~ H mp.178C

iN

CI

O

21 B.5 ' N~ H mp.137C

~N

Ie 4 R' R2 O
L-N~CHz-O-C \ / NH2 Co. Ex. L R1 and R2 taken physical data No. No. to ether B.2 3-(4-fluorophenoxy)propyl-O-CH2-CH2-O- mp. I57.1 C ;

.C2H204 H
t I1 B.2 ~N~N~ -O-CH2CH2-O- mp.121.4C

12 B.2 N~ N~~'w -O-CHZCH~-O- mp. I68. I C
~
~

N
CH

13 B.2 '~ ~ ~-N-(CH~2 -O-CHzCH~-O- mp.168.5C

N

Et I
14 B.2 ~N -O-CH2CH2-O- mp.138.2C
~ ~p N
l (CH2)3 Co. Ex.L R ~ and R2 takenphysical data.
No. No. to ether H _.
i B.3N N~ -O-CH2CH2-O-~ ~ (CHa)i mp. I30.4 N~ C

H

O

H
N~

16 B.2(CH2)z -O-CH2CH2-O- -! ~

CN

H
N~

17 B.2(CH~3 -O-CHZCH2-O- _ I ~
~

CN

O

18 B.2/ N~(CHa~a -O-CH2-CH2-O- mp. 200.4C ;

.C2H204 O

19 B.4~ I N~H _p_CH2CH2-O- mp.145 \ N ~ NH-- .

(CH2)a~

O

22 B.5~ N~ -O-CH2-O- mp.I25C

,N

O

~

23 B.5~ -O-CH2CH2CH2-O-mp. 148C ;
N

/

.C2H204 O

I
~

24 B.5~ -O-CH2CH2-O- mp. 184C ;
j ,N

.C2H20q.

C. Pharmacological example Bxamnle C.l :"Gastric emu ing of an a~~lflriC Iiauid test meal delayed by 5 administration of Iidamidine in conscious dogs" test Female beagle dogs, weighing 7-14 kg, were trained to stand quietly in Pavlov frames.
They were implanted with a gastric cannula under general anaesthesia and aseptic WO 97131897 PC'T/EP97/~0585 precautions. After a median laparatomy, an incision was made through the gastric wall in the longitudinal direction between the greater and the lesser curve, 2 cm above the nerves of Latarjet. The cannula was secured to the gastric wail by means of a double purse string suture and brought out via a stab wound at the left quadrant of the hypochondrium. Dogs were allowed a recovery period of at least two weeks.
Experiments were started after a fasting period of 24 hours, during which water was available ad libitum. At the beginning of the experiment, the cannula was opened in order to remove any gastric juice or food remnants.
The stomach was cleansed with 40 to SO ml lukewarm water. The test compound was administered LV. {in a volume 2 3 mI via the vena cephalica), S.C. (in a volume 2 3 ml) or P.O. (in a volume of 1 ml/kg body weight, applied intragastrically via the cannula with a device that filled the Lumen of the cannula; after injection of the test compound, 5 ml NaCl 0.9 % was injected in order to correct for the dead space in the injection system). Immediately after administration of the test compound or its solvent, Iidamidine 0.63 mg/kg was administered subcutaneously. 30 Minutes later, the cannula was opened to determine the amount of fluid present in the stomach, promptly followed by reintroduction of the fluid. Then the test meal was administered via the cannula.
This test meal consisted of 250 ml distilled water containing glucose (5 g!1) as a marker. The cannula remained closed for 30 min, whereafter the gastric contents were drained from the stomach to measure total volume {t = 30 minutes). For later analysis 1 ml of the gastric contents was taken, promptly followed by reintroduction of the rest volume into the stomach. This sequence was repeated 4 times with 30 minutes intervals (t = 60, 90, 120, 150 minutes).
In the 1 ml samples of the gastric contents, the glucose concentrations were measured on a Hitachi 717 automatic analyser by the hexokinase method (Schmidt, 1961).
These data were used to determine the absolute amount of glucose that remained in the stomach after each 30 min period, as a measure for the rest volume of the meal itself, independent of acid secretion.
Curves were fitted to the measurement points (glucose vs time) using weighed non-linear regression analysis. Gastric emptying was quantified as the time needed to empty 70% of the meal (t~p~o). The control emptying time was calculated as the mean t~Og~ of the last 5 solvent experiments of the same dog. Acceleration of delayed gastric emptying (dt) was calculated as the time difference between t7oq6 compound ~d t70~ solvent To correct for variations in emptying rate between dogs, ~t was expressed ' as % of t~Ogb solvent {Schuurkes et a1, 1992).

WO 97!31897 PCTIEP97/00585 T le 5 Acceleration of gastric emptying of a liquid meal delayed by lidamidine in conscious dog with a dose of 0.04 mg/kg of the test compound.
Co. No. Acceleration Co. No. Acceleration ~,dt (~dt ' 4 -0.40 11 -0.54 6 -0.41 I2 -0.4g 2 -0.34 I3 -0.28 7 -0.54 10 -0.30 3 -0.30 14 -0.43 5 -0.51 18 -0.27 9 -0.60 D. Composition examples The following formulations exemplify typical pharmaceutical compositions in dosage unit form suitable for systemic or topical administration to warm-blooded animals in accordance with the present invention.
"Active ingredient" (A.L) as used throughout these examples relates to a compound of formula (I), a N oxide form, a pharmaceutically acceptable acid or base addition salt or a stereochemically isomeric form thereof.
Example D.I : Oral solutions 9 g of methyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxybenzoate are dissolved in 41 of boiling purified water. In 3 1 of this solution are dissolved first 10 g of 2,3-dihydroxybutanedioic acid and thereafter 20 g of the A.I. The latter solution is combined with the remaining part of the former solution and I21 of 1,2,3-propanetriol and 3 1 of sorbitol 70% solution are added thereto. 40 g of sodium saccharin are dissolved in 0.51 of water and 2 ml of raspberry and 2 ml of gooseberry essence are added. The latter solution is combined with the former, water is added q.s. to a volume of 201 providing an oral solution comprising 5 rng of the A.I. per teaspoonful (5 ml).
The resulting solution is filled in suitable containers.
Example D.2 : Capsules 20 g of the A.L, 6 g sodium lauryl sulfate, 56 g starch, 56 g lactose, 0.8 g colloidal silicon dioxide, and I.2 g magnesium stearate are vigorously stirred together.
The resulting mixture is subsequently filled into 1000 suitable hardened gelatin capsules, each comprising 20 mg of the A.L.

Example D.3 : Film-coated tablets Preparation of tablet core A mixture of 100 g of the A.L, 570 g lactose and 200 g starch is mixed well and thereafter humidified with a solution of 5 g sodium dodecyl sulfate arid 10 g polyvinyl-pyrrolidone in about 200 ml of water. The wet powder mixture is sieved, dried and sieved again. Then there are added I00 g microcrystalline cellulose and 15 g hydrogenated vegetable oil. The whole is mixed well and compressed into tablets, giving 10.000 tablets, each comprising 10 mg of the active ingredient.
Coating IO To a solution of 10 g methyl cellulose in 75 ml of denaturated ethanol there is added a solution of 5 g of ethyl cellulose in I50 ml of dichloromethane. Then there are added 75 ml of dichloromethane and 2.5 ml I,2,3-propanetriol. 10 g of polyethylene glycol is molten and dissolved in 75 ml of dichloromethane. The latter solution is added to the former and then there are added 2.5 g of magnesium octadecanoate, 5 g of I5 polyvinylpyrrolidone and 30 ml of concen-trated colour suspension and the whole is homogenated. The tablet cores are coated with the thus obtained mixture in a coating apparatus.
Example D.4 : Injectable solution 20 1.8 g methyl 4-hydroxybenzoate and 0.2 g propyl 4-hydroxybenzoate were dissolved in about 0.5 1 of boiling water for injection. After cooling to about 50°C
there were added while stirring 4 g lactic acid, 0.05 g propylene glycol and 4 g of the A.I.
The solution was cooled to room temperature and supplemented with water for injection q.s.
ad 1 I
volume, giving a solution of 4 mg/mI of A.I. The solution was sterilized by filtration 25 and filled in sterile containers.
Example D.5 : Suppositories .. 3 Grams A.I. was dissolved in a solution of 3 grams 2,3-dihydroxybutanedioic acid in 25 ml polyethylene glycol 400. 12 Grams surfactant and 300 grams triglycerides were 30 molten together. The latter mixture was mixed well with the former solution. The thus obtained mixture was poured into moulds at a temperature of 37-38°C to form 100 suppositories each containing 30 mg/ml of the A.I.

Claims (19)

Claims

1. A compound of formula an N-oxide form, a pharmaceutically acceptable acid addition salt and a stereochemically isomeric form thereof, wherein R1 is C1-6alkyloxy, C2-6alkenyloxy or C2-6alkynyloxy;
R2 is hydrogen or C1-6alkyloxy, or when taken together R1 and R2 may form a bivalent radical of formula -O-CH2-O- (a-1), -O-CH2-CH2- (a-2), -O-CH2-CH2-O- (a-3), -O-CH2-CH2-CH2- (a-4), -O-CH2-CH2-CH2-O- (a-5), -O-CH2-CH2-CH2-CH2- (a-6), wherein in said bivalent radicals one or two hydrogen atoms may be substituted with C1-6alkyl;
R3 is hydrogen or halo;
L is a radical of formula -Alk-R4 (b-1) -Alk-NR5R6 (b-2), wherein Alk is C1-12alkanediyl;
R4 is Het1 or phenyloxy substituted with 1, 2 or 3 substituents each independently selected from halo, trihalomethyl, C1-6alkyl or C1-6alkyloxy;
R5 is hydrogen or C1-6alkyl;
R6 is Het2;
Het1 and Het2 each independently are selected from furan substituted with C1-6alkyl or halo; tetrahydrofuran substituted with C1-6alkyl; dioxolane substituted with C1-6alkyl, dioxane substituted with C1-6alkyl; tetrahydropyran substituted with C1-6alkyl; pyrrolidinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, or C1-6alkyl; pyridinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, C1-6alkyl; pyrimidinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, C1-6alkyl, C1-6alkyloxy, amino and mono and di(C1-6alkyl)amino; pyridazinyl substituted with one or two substituents each independently selected from hydroxy, C1-6alkyloxy, C1-6alkyl or halo; pyrazinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, C1-6alkyl, C1-6alkyloxy, amino, mono- and di(C1-6alkyl)amino and C1-6alkyloxycarbonyl;
Het1 can also be a radical of formula Het1 and Het2 each independently can also be selected from the radicals of formula wherein R13 and R14 each independently are hydrogen or C1-4alkyl,~
provided that when R4 is Het1, then said Het1 is not a radical of formula (d-3).

2. ~A compound according to claim 1 wherein L is a radical of formula (b-2) or (b-3) and R6 is Het2.

3. ~A compound according to claim 1 wherein L is a radical of formula (b-1), (b-2) or (b-3) wherein R4 is phenyloxy substituted with halo, R5 is hydrogen and R6 is pyrazinyl or imidazolyl optionally substituted with hydroxy or C1-6alkyl.

4. ~A compound according to claim 1 wherein R1 and R2 are taken together to form a radical of formula (a-2) or (a-3), wherein optionally one or two hydrogen atoms are substituted with methyl; and R3 is halo

5. ~A compound according to claim 1 wherein the compounds are [1-[2-[(3-methyl-2-pyrazinyl)amino]ethyl]-4-piperidinyl]methyl 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate; or [1-[2-[2,3-dihydro-3-(1-methylethyl)-2-oxo-1H-imidazol-1-yl]ethyl]-4-piperidinyl]-methyl 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate; or [1-[2-[(3-methyl-2-pyrazinyl)amino]ethyl]-4-piperidinyl]methyl 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-carboxylate; or [1-[1-(3-methyl-2-pyrazinyl)-4-piperidinyl]-4-piperidinyl]methyl 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-carboxylate; the stereochemically isomeric forms,~
pharmaceutically acceptable acid addition salts and the N-oxide forms thereof.

6. ~A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound as claimed in any one of claims 1 to 5.

7. ~A process for preparing a pharmaceutical composition as claimed in claim 6 characterized in that a therapeutically active amount of a compound as claimed in any one of claims 1 to 5 is intimately mixed with a pharmaceutically acceptable carrier.

8.~A compound according to any one of claims 1 to 5 for use as a medicine.

9. ~A compound of formula (V) wherein R1, R2 and R3 are as defined in claim 1.

10. ~A process for preparing a compound of formula (I') as claimed in claim 1 characterized by a) ~reacting an intermediate of formula (II) with a carboxylic acid derivative of formula (II) or a reactive functional derivative thereof;
wherein R1, R2, R3 and L are as defined in claim 1, or b) ~N alkylating an intermediate of formula (IV), wherein W represents an appropriate leaving group, with a reagent of formula (V) wherein R1, R2, R3 and L are as defined in claim 1; or c) reacting an appropriate ketone or aldehyde intermediate of formula L'=O (IV-a), said L=O represents a derivative of formula L-H wherein two geminal hydrogen atoms are replaced by oxygen, with a piperidine of formula (V) wherein R1, R2, R3 and L are as defined in claim 1, or d) carbonylating an intermediate of formula (XII), wherein X is bromo or iodo, in the presence of an intermediate of formula (II) wherein R1, R2, R3 and L are as defined in claim 1, in a reaction-inert solvent in the presence of a suitable catalyst and a tertiary amine and at a temperature ranging between room temperature and the reflux temperature of the reaction mixture.

11. The process according to claim 10, wherein in process a), the reactive functional derivative of the carboxylic acid derivative of formula (III) is an acyl chloride derivative of the carboxylic acid derivative of formula (III).

12. The process according to claim 10, wherein in process b), W is a halide.

13. The process according to claim 10, 11 or 12, wherein the reaction inert solvent is acetonitrile or tetrahydrofuran.

14. The process according to any one of claims 10 to 13, wherein the suitable catalyst is palladium-on-carbon.

15. The process according to any one of claims 10 to 14, wherein the tertiary amine is triethylamine.

16. The process according to any one of claims 10 to 15, further comprising converting the compound of formula (I') into another compound of formula (I').

17. The process according to any one of claims 10 to 16, further comprising converting the compound of formula (I') into a therapeutically active non-toxic acid addition salt by treatment with an acid.

18. The process according to claim 17, further comprising converting the acid addition salt into a free base form by treatment with an alkali.

19. The process according to any one of claims 10 to 18, further comprising preparing a stereochemically isomeric form or an N-oxide form of the compound of formula (I').