WO1999062892A1 - Aminoazole compounds - Google Patents

Abstract

The invention relates to a compound of formula (I), wherein the variables have the meanings indicated, or a salt thereof; methods for their preparation, pharmaceutical compositions, and the use of compounds of formula (I) and salts thereof.

Description

Aminoazole Compounds

The invention relates to a compound of formula (I),

(I), wherein

(i) al^ and alk₂ are independently a bond or Cι-C₄alkylene;

X is the C atom and Y the S, O or NH atom; or

X is the N atom and Y is the N atom;

Ar is phenylene;

Ri is hydrogen, d-C₇alkyl, Cι-C₇alkoxy-C C₇alkyl, C₃-C₈cycloalkyl-Cι-C₇alkyl, Cι-C₇alkoxy,

Cι-C₇alkoxy-Cι-C₇alkoxy, CF₃, halogen, nitro or cyano, or R, is phenyl, pyridyl, pyrrolyl, furyl or thienyl;

R₂ has the same meanings as Ri if X is C, or is hydrogen, C C₇alkyl or C₃-C₈cycloalkyl-C

C₇alkyl if X is N;

R₃ and R₄ are independently hydrogen, Ci-Cyalkyl, C C alkoxy-Cι-C₇alkyl, C₃-C₈cycloalkyl-

CrC₇alkyl, halogeno-d-dalkyl, aminocarbonyl-Cι-C₇-alkyl, wherein the amino group is unsubstituted or is monosubstituted or disubstituted independently by CrC₇alkyl or phenyl-

C C₇alkyl, or they are phenyl or phenyl-C C₇alkyl; whereas R₃ and R₄ are not simultaneously hydrogen; or

R₃ and R₄ together are C₃-C alkylene; wherein an (hetero)aromatic radical phenylene, phenyl, pyridyl, pyrrolyl, thienyl, furyl is independently unsubstituted or substituted once or several times by a substituent selected from the group comprising Cι-C₇alkyl, Cι-C alkoxy-Cι-C₇alkyl, hydroxy, CrC₇alkoxy, d-

C₇alkoxy-CrC₇alkoxy, CF₃, halogen, nitro and cyano;

(ii) also to a corresponding compound of formula (I), wherein R₁ is phenyl disubstituted by oxy-CrC₂alkylene-oxy, which is furthermore unsubstituted or substituted once or several times by a substituent selected from the group consisting of C_rC₇alkyl, d-Cyalkoxy-Cr

C₇alkyl, hydroxy, d-C₇alkoxy, Ci-C₇alkoxy-C C₇alkoxy, CF₃, halogen, nitro and cyano; (iii) also to a corresponding compound of formula (I), wherein R₃ and R₄ are independently furanyl or pyranyl; or a salt, especially a pharmaceutically acceptable salt, thereof; methods for their preparation, pharmaceutical compositions, and the use of compounds of formula (I) and salts thereof.

The compounds of formula (I) may be present in the form of salts, in particular pharmaceutically acceptable salts. In each case, acid addition salts may be formed with the basic amino group. Suitable acid components are for example strongly inorganic acids, such as mineral acids, for example halogen halides, e.g. hydrochloric acid, or strongly organic carboxylic acids, for example acetic acid or trifluoroacetic acid, or organic sulfonic acids, e.g. methanesulfonic acid or p-toluenesulfonic acid. In a broader sense, the invention relates also to salts which are not suitable for therapeutic purposes and may be used for example in the isolation or purification of free compounds of formula (I) or pharmaceutically acceptable salts thereof. Only salts that are pharmaceutically acceptable and non-toxic are used therapeutically and those salts are therefore preferred.

If compounds of the invention have at least two optically active carbon atoms, they may be present in the form of stereoisomers, stereoisomeric mixtures, and (essentially) pure diastereomers. Corresponding compounds with an optically active C atom are present in the form of racemates, especially in the form of (essentially) pure enantiomers. Corresponding stereoisomers are likewise a subject of the present invention.

The general terms used hereinbefore and hereinafter have the following meanings, unless defined otherwise.

d-dalkylene is especially methylene, ethylene, n-propylene, n-butylene, 1 ,2- or 2,3- propylene or 1 ,2-, 1 ,3- or 2,3-butylene. Methylene is preferred.

Phenylene is 1 ,2- 1 ,3- or 1 ,4-phenylene.

d-dalkyl is for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- butyl or a corresponding pentyl, hexyl or heptyl radical. d-C₄alkyl, especially methyl, is preferred. d-dalkoxy is for example methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyl- oxy, sec-butyloxy, tert-butyloxy or a corresponding pentyloxy, hexyloxy, or heptyloxy radical. Cι-C₄alkoxy is preferred. Methoxy is especially preferred.

d-C₇alkoxy-Cι-C₇alkyl is in particular Cι-C₄alkoxy-Cι-C alkyl, such as methoxyethyl, 2- ethoxyethyl, 2-n-propyloxyethyl or ethoxymethyl.

d-dalkoxy-d-dalkoxy is in particular Cι-C₄alkoxy-Cι-C alkoxy, such as methoxyethoxy, 2-ethoxyethoxy, 2-n-propyloxyethoxy or ethoxymethoxy.

Pyridyl is 2-, 3-, or 4-pyridyl.

Pyrrolyl is 2- or 3- pyrroyl, furyl 2- or 3- furyl, thienyl 2- or 3- thienyl.

Halogen is in particular halogen with an atomic number up to and including 35, i.e. fluorine, chlorine or bromine, and in a broader sense includes iodine. Fluorine or chlorine is preferred.

C₃-C₇cycloalkyl-Cι-C₇alkyl is in particular C₃-C₆cycloalkyl-d-C alkyl, for example cyclopropylmethyl or -ethyl, cyclobutylmethyl or -ethyl, cyclopentylmethyl or -ethyl, or cyclohexylmethyl or -ethyl. Cyclopropylmethyl is especially preferred.

Halogeno-d-dalkyl is in particular halogeno-C C₄alkyl, for example chloromethyl, trifluoromethyl, 2-trifluoroethyl, 2-chloroethyl or 2,2,2-trifluoroethyl.

Phenyl-d-C₇alkyl is in particular phenyl-d-C₄alkyl, such as benzyl or 1 - or 2-phenethyl.

(Hetero)aromatic radicals, unless otherwise defined, are unsubstituted or substituted once or several times, for example disubstituted or trisubstituted, by a substituent selected from the group comprising d-C alkyl, d-C₄alkoxy, halogen, CF₃, cyano and nitro. Phenyl disubstituted by oxy-Cι-C₂alkylene-oxy is in particular phenyl 1 ,2-disubstituted by oxy- methylene-oxy. Obesity is a widespread phenomenon, which is responsible for a wide range of disease symptoms and has a negative influence on health as a whole. In addition, obesity is associated with substantial socioeconomic costs and represents a major financial burden on the healthcare system. To solve this problem, an approach must be found by which obesity and the associated diseases and disorders can be systematically treated. It has been found that eating behaviour can be regulated by modulating the Y5 receptor subtype of neuropeptide Y (NPY).

Extensive pharmacological studies have shown that compounds of formula (I) and pharmaceutically acceptable salts thereof are suitable as antagonists of the neuropeptide Y5 receptor subtype.

The compounds of the present invention and pharmaceutically acceptable salts thereof have been demonstrated to have a marked and selective affinity for the Y5 receptor (demonstrated in Y5-receptor binding studies) and to show anatagonistic properties both in vitro and in vivo. These properties manifest themselves in vitro through their ability to inhibit the NPY-induced elevation of calcium in stably transfected cells which express the Y5 receptor. In vivo, the antagonistic effect manifests itself in the ability to inhibit the feeding induced in conscious rats either by intraventricular administration of NPY or 24-hour food deprivation.

Binding assays

The selective affinity of the compounds (according to the present invention) for the Y5 receptor was demonstrated in a Y5-binding assay using both LM(tk-)-hY5-7 cells, which normally express NPY5 receptor in humans, and HEK-293 cells, which normally express the NPY5 receptor in rats.

The following buffers were used for preparing the membranes and for the binding assay: a) Buffer 1 (homogenization buffer, pH 7.7 at 4 °C) comprises Tris-HCI [FLUKA, Buchs, Switzerland] (20 mM) and ethylenediaminetetraacetic acid (EDTA) [FLUKA, Buchs, Switzerland] (5 mM); b) Buffer 2 (suspension buffer, pH 7.4 at room temperature) comprises N-2-hydroxyethyipiperazin-N'-2-ethanesulfonic acid (HEPES) [Boehringer Mannheim, Germany] (20 mM), NaCl (10 mM), CaCI₂ (1.26 mM), MgSO₄ (0.81 mM) and KH₂PO₄ (0.22 mM); c) Buffer 3 (bindung buffer, pH 7.4 at room temperature) comprises HEPES (20 mM), NaCl (10 mM), CaCI₂ (1 ,26 mM), MgSO₄ (0.81 mM) and KH₂PO₄ (0.22 mM) and 1 mg/ml bovine serum albumin [FLUKA].

The cells are washed in phosphate-buffered physiological saline and collected with the help of a rubber policeman. The cells are homogenized in ice-cooled hypotonic buffer solution (buffer 1 , pH 7.7, at 4°C) using a Polytron homogenizer (3 impulses of 8 seconds) The homogenate is centrifuged for 20 minutes at 32.000 g and 4°C. The sediment is resuspended in the same buffer and centrifuged again. The resulting sediment is suspended in buffer 2. The protein concentration is determined using the Coomassie blue method [Pierce, Socochim, Lausanne, CH]. Bovine serum albumin is used as reference standard. The raw membrane suspension is divided into aliquots, frozen in liquid nitrogen, and stored at -80°C. Before it is used, 0.1 % (1 mg/ml) bovine serum albumin is added. ¹²⁵l- [Pro^JhPYY (60 pM final concentration, Anawa, Wangen, Switzerland], dissolved in buffer 3, is used as radioligand.

All compounds to be tested are dissolved in 10^"2 M dimethyl sulfoxide (DMSO) and diluted with buffer 3 to 10^'3 M. Further dilutions are prepared with buffer 3 plus 10% DMSO. The incubations are carried out in Millipore Multiscreen FB filter plates [Millipore, Bedford, USA]. The filter wells aligned to each of the sample wells are pretreated with 2% polyethyleneimine for 30 minutes and rinsed once before use with 300 μl buffer 3. The following substances are pipetted into each sample well. 60 μl buffer 3, 20 μl ¹²⁵l- [Pro^hPYY (600 pM), 20 μl of the compound to be tested (or binding buffer plus 10% DMSO for the controls), 100 μl raw membrane suspension (approximately 10 μg protein). Incubation is carried out at room temperature over a period of 2 hours. Non-specific binding is defined as binding which still takes place in the presence of 1 μM [Pro^hPYY [BACHEM, Bubendorf, Switzerland]. The incubation is terminated by rapid filtration and fourfold washing with 300 μl phosphate-buffered saline. The filters are removed from the wells of the plate, placed in plastic tubes, and measured for radioactivity in a gamma counter [Gammamaster, WALLAC, Finland]. The IC50 values of the compounds (of the present invention) in the human Y5 receptor lie in most cases between about 0.1 nM and about 10 μM. Illustrative of the invention, the following IC₅₀ values have been determined in the human Y₅ receptor assay:

To determine the antagonistic properties of the compounds (according to the submitted invention) in vitro stably transfected LM(tk-)-hY5-7 cells were used in which an NPY-induced increase in calcium was measured as follows. The cells are collected in a medium comprising EDTA (0.5 mM) and phosphate-buffered saline (PBS). The cells are then washed in phosphate-buffered saline and incubated for 90 minutes at room temperature and pH 7.4 with 10 μM FLUO-AM (fluo-3 acetoxymethyl ester, supplemented with Pluronic as suggested by the manufacturer, Molecular Probes Inc., Eugene, Oregon, USA) in a cell culture buffer of the following composition (NaCl 120 mM, MgCI₂ 1 mM, KCI 5.4 mM, NaH PO 0.33 mM, glucose 11 mM, taurine 5 mM, pyruvate 2 mM, glutamine 1.5 mM, HEPES 10 mM, insulin 10 E/l, BSA 0.1 %). After centrifugation, the cells are resuspended in the cell culture buffer in a concentration of 3-4 million cells/ml, to which 200 μM sulfinpyrazone is added.

The calcium increase is measured at room temperature in a Millititer plate with CytoFluor 2350 (Millipore) at wavelengths of 485 nm (excitation) and 530 nm (emission). 180 μl of the cell suspension is incubated for 5 minutes in the presence of various quantities of compound which are dissolved in 2 μl DMSO (three replicates in each case) (or in 2 μl DMSO for the controls). Finally, NPY is added in a final concentration of 100 nM. The concentrations of the compounds which lead to a 50% inhibition of the maximum calcium increase are calculated. ln this cell system, NPY induces a calcium increase at an EC50 of 50 nM. The data were analysed using Microsoft Excel software. The concentrations which led to a 50% inhibition of the initial values in the controls are given as IC50 values. The IC50 values were determined for the compounds of the present invention and the pharmaceutically acceptable salts thereof.

The ability of the compounds and their pharmaceutically acceptable salts to inhibit the NPY- induced rise in intracellular calcium confirms their antagonistic properties. The IC50 values in most cases lie between about 0.1 nM and about 10 μM.

Measurement of NPY-induced feeding in conscious rats

This antagonism of the Y5 receptor subtype is also observed in vivo using conscious rats in which NPY-induced feeding can be inhibited. For these studies, the food intake was measured in sated rats after cerebroventricular (i.c.v.) adminstration of neuropeptide Y [BACHEM, Feinchemikalien, Bubendorf, Switzerland] both with and without additional administration of compounds (as described in the present invention). All studies were carried out using male Sprague-Dawley rats weighing between 180 and 220 g. The animals were kept in individual Makrolon cages with a photoperiod comprising 1 1 hours of light and 13 hours of dark (the latter from 18.00) under controlled temperatures (21-23°C). Water and feed (NAFAG lab feed pellets) [NAFAG, Gossau, Switzerland] were available ad libitum. A stainless-steel guiding cannula was implanted in the direction of the right cerebral ventricle in each rat under Vetanarcol anaesthesia (50 mg/kg, intraperitoneal) [VETERINARIA AB, Zurich, Switzerland]. The stereotactic coordinates were as follows: - 0.8 mm anterior and +1.3 mm lateral to the bregma, the elevation being -2.0 mm below the interaural line. The guiding cannula was placed on the dura. The injection cannulas jutted out from the guiding cannulas -3.8 mm in a ventral direction (in relation to the cranial surface). The animals were allowed a postoperative recovery phase of at least five days before they were used for the studies.

The fit of the cannulas was checked postoperatively two days before the actual experiments by evaluating the feeding behaviour of all rats following a cerebroventricular (i.c.v.) injection of 300 pmol NPY. For the measurements of NPY-induced feeding, only rats were used which consumed at least 2 g of feed within 2 hours of NPY injection. The injections were carried out in the morning two afters after the start of the light phase. The peptides were administered in 5-10 μl artificial cerebrospinal fluid (ACSF) [FLUKA, Buchs, Switzerland]. ACSF comprises NaCl 124mM, KCI 3.75mM, CaCI₂ 2.5mM, MgSO₄ 2.0mM, KH₄PO₄ 0.22mM, NaHCO₃ 26mM and glucose 10mM. NPY (300 pmol) was given by cerebroventricular injection 10 to 60 minutes after administration of the compounds or the respective vehicle DMSO/water (10% V/V), Cremophor/water (20% V/V) [SIGMA, Buchs, Switzerland] or Tween 80/water (10% V/V) [FLUKA, Buchs, Switzerland].

The food intake was determined by reference to a previously weighed amount of feed pellets placed in the cages at the time of injection with NPY. At each of the times indicated in the figures, the pellets were removed from the cages and replaced by new, previously weighed pellets.

All results are given as mean values ± SEM. Statistical analysis was carried out by analysis of variance. Post hoc comparisons were carried out using the Student-Newman-Keuls test. Statistical significance was assumed at p < 0.05.

The compounds of the present invention led to an inhibition of NPY-induced feeding in rats following oral, intraperitoneal, subcutaneous, intravenous and transdermal administration, mostly at doses between about 0.01 and about 100 mg/kg.

Measurement of feeding in rats after 24 hours' food deprivation

On the basis of the observation that food deprivation leads to an increase in the concentration of NPY in the hypothalamus, it is assumed that NPY is responsible for the feeding induced by hunger. The compounds (of the submitted invention) were therefore also studied in rats after 24 hours' food deprivation. These studies were carried out using male Sprague-Dawley rats weighing between 180 and 250g. The animals were kept for the duration of the study in separate cages and, except for the 24-hour period of fasting, received food and mains water ad libitum. The animals were kept at 22 ± 2°C with controlled air humidity and a photoperiod comprising 12 hours of light (from 6.00 to 18.00) and 12 hours of dark. After the rats had been admitted to their cages, they were allowed two weeks to become accustomed to their new environment and to the powdered feed or feed pellets [NAFAG, Gossau, Switzerland] (acclimatization phase). At the end of this phase, the animals were given no food for a period of 24 hours (starting at 8.00 in the morning) At the end of this fasting phase, the compounds of the present invention or an equivalent volume of the respective vehicle DMSO/water (10%, V/V), Cremophor/water (20%, V/V) or Tween 80/water (10%, V/V) were given to the animals by intraperitoneal, intravenous or oral adminstration. Ten to 60 minutes later, the animals were given food again. During the 24 hours that followed, feeding was measured at various times. The inhibition of feeding by the compounds of the present invention was expressed as a percentage of the food intake of the control animals treated with the vehicle.

In this model of rats deprived of food, the compounds of the present invention led to an inhibition of feeding after oral, intraperitoneal, subcutaneous or intravenous administration; the ED50 was between 0.01 and about 100 mg/kg. Illustrative of the invention, the following inhibition values have been determined in this model of food-deprived rats:

Measurement of food intake in obese Zucker rats

The anti-obesity efficacy of the compounds of the present invention has also been demonstrated in obese Zucker rats, a known animal model for obesity. The studies were carried out using male, obese Zucker rats (fa/fa) [HARLAN CPB, Austerlitz, NL] weighing between 480 and 500 g. The animals were kept for the duration of the study in separate metabolic cages and received feed in powder form and mains water ad libitum. They were kept in a room with a photoperiod comprising 12 hours of light and 12 hours of dark (the latter from 8.00 to 20.00) a temperature of 24°C, and controlled air humidity. After they had been admitted to their metabolic cages, the rats were allowed six days to become accustomed to their new environment and to the powdered feed (acclimatization phase). At the end of this phase, the food consumption during the periods of light and dark was measured. After a three-day control phase, the animals were treated with the compounds of the present invention or the DMSO/water (10% V/V), Cremophor/water (20% V/V) [SIGMA, Buchs, Switzerland] or Tween 80/water (10% V/V) [FLUKA, Buchs, Switzerland].

The compounds of the present invention led to an inhibition of feeding in obese Zucker rats following oral, intraperitoneal, subcutaneous, or intravenous administration, mostly at doses between about 0.01 and about 100 mg/kg.

Measurement of food intake in obese mice

The anti-obesity efficacy of the compounds of the present invention has also been demonstrated in genetically obese mice. The studies were carried out using male and/or female mice with an ob/ob mutation (The Jackson Laboratory, Bar Harbor, ME) (C57BL/61 - ob) weighing between 30 and 80 g. The mice were kept in Makrolon or metabolic cages and were given feed in powder form and mains water ad libitum. The mice were kept at 24°C and in a photoperiod comprising 12 hours of light (from 8.00 to 20.00) and 12 hours of dark. After they had been admitted to their cages, the mice were allowed six days to become accustomed to their new environment (acclimatization phase). After a three-day control phase, during which the food intake and bodyweight were monitored, the animals were treated with the compounds of the submitted invention or the DMSO/water (10% V/V), Cremophor/water (20% V/V) [SIGMA, Buchs, Switzerland] or Tween 80/water (10% V/V) [FLUKA, Buchs, Switzerland].

The compounds of the present invention led to an inhibition of feeding in the obese ob/ob mice following oral, intraperitoneal, subcutaneous, or intravenous administration, mostly at doses between about 0.01 and about 100 mg/kg.

The animal experiments described above show clearly that the Y5 receptor subtype is the primary mediator of NPY-induced feeding and that appropriate antagonists can be used to treat obesity and related disorders [Nature, Vol. 382, 168 - 171 (1996)].

The compounds of the present invention can inhibit not only feeding induced either by cerebroventricular administration of NPY or by food deprivation but also spontaneous feeding in obese Zucker rats and ob/ob mice. The compounds (of the submitted invention) thus antagonize the binding of neuropeptide Y (NPY) to the Y5 receptor subtype (NPY antagonism) and could be used in particular for the treatment and prevention of disorders or diseases which are associated with the Y5 receptor, i.e. in which the NPY Y5 receptor is involved. They could preferably be used in the treatment of diseases which are caused by eating disorders, such as obesity, bulimia nervosa, diabetes, dysiipidaemia and hypertension. In addition, they can also be used for the treatment of memory impairment, epileptic seizures, migraine, insomnia and pain, as well as for the treatment of sexual dysfunctions, depression, anxiety states, cerebral haemorrhage, shock, decompensated heart failure, nasal congestion and diarrhoea.

The invention relates to a method of treatment for diseases and disorders associated with the Y5 receptor for NPY, which could be used especially for the prevention and treatment of disorders and diseases involving the Y5 receptor of NPY, preferably for the treatment of diseases caused by eating disorders, such as obesity, bulimia nervosa, diabetes, dysiipidaemia, and hypertension. In addition, they can also be used for the treatment of memory impairment, epileptic seizures, migraine, insomnia and pain, as well as for the treatment of sexual dysfunctions, depression, anxiety states, cerebral haemorrhage, shock, decompensated heart failure, nasal congestion and diarrhoea. The method comprises administering to warm-blooded animals, including humans, that require such treatment a therapeutically effective amount of a compound of formula (I) or of a pharmaceutically acceptable salt thereof.

The invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described hereinbefore and as described also hereinafter for the preparation of a medicament for the prevention and treatment of corresponding diseases or disorders.

The invention relates to a medicament which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described hereinbefore and as described also hereinafter for the treatment of corresponding diseases or disorders

The invention relates in particular to a compound of formula (I), wherein alki is a bond or d- dalkylene and alk₂ is d-C alkylene; or a salt, especially a pharmaceutically acceptable salt, thereof. The invention relates in particular to a compound of formula (I), wherein alk, is a bond or d-C₄alkylene and alk₂ is d-C alkylene;

X is the C atom and Y the S, O or NH atom; or

X is the N atom and Y is the N atom;

Ar is phenylene;

R, is d-C alkyl, C₃-C₆cycloalkyl-d-C₄alkyl, d-C alkoxy, CF₃, halogen, nitro or cyano, or R, is phenyl, pyridyl, pyrrolyl, furyl or thienyl;

R₂, has the same meanings as Ri if X is C, or is hydrogen, d-C alkyl or C₃-C₆cycloalkyl-d- dalkyl if X is N;

R₃ is hydrogen, d-C₄alkyl, Cι-C₄alkoxy-C C₄alkyl, C₃-C₆cycloalkyl-d-C₄alkyl, halogeno-C_r

C₄alkyl, aminocarbonyl-Cι-C₄alkyl, wherein the amino group is unsubstituted or is monosubstituted or disubstituted by d-C₇alkyl or phenyl-d-C₇alkyl independently of one another, or it is phenyl-d-C₇alkyl;

R₄ is hydrogen or C C alkyl; whereas R₃ and R₄ are not simultaneously hydrogen; or

R₃ and R₄ together are C₃-C₄alkylene; wherein an (hetero)aromatic radical phenylene, phenyl, pyridyl, pyrrolyl, thienyl, furyl is independently unsubstituted or substituted once or several times by a substituent selected from the group consisting of d-C alkyl, d-C₄alkoxy-Cι-C alkyl, hydroxy, d-C₄alkoxy, Cι-

C₄alkoxy-Cι-C₄alkoxy, CF₃, halogen, nitro and cyano; or a salt, especially a pharmaceutically acceptable salt, thereof.

The invention relates in particular to a compound of formula (I), wherein alk, is a bond or d-C₄alkylene and alk₂ is d-C alkylene;

X is the C atom and Y the S, O or NH atom; or

X is the N atom and Y is the N atom;

Ar is phenylene;

Ri is phenyl or pyridyl;

R₂, has the same meanings as Ri if X is C, or is hydrogen, C C₄alkyl or C₃-C₆cycloalkyl-d- dalkyl if X is N;

R₃ is d-dalkyl, C C₄alkoxy-CrC₄alkyl, halogeno-Cι-C₄alkyl, aminocarbonyl-Cι-C alkyl, wherein the amino group is unsubstituted or is monosubstituted or disubstituted by d- dalkyl or phenyl-d-C₄alkyl independently of one another, or it is phenyl-d-dalkyl; R is hydrogen or C₁-C₄alkyl; or wherein an (hetero)aromatic radical phenylene, phenyl or pyridyl is independently unsubstituted or substituted once or several times by a substituent selected from the group consisting of d-C alkyl, C,-C alkoxy, halogen, CF₃, cyano and nitro. or a salt, especially a pharmaceutically acceptable salt, thereof.

The invention alternatively relates in particular to a compound of formula (I), wherein X is C; Y is S; or a salt, especially a pharmaceutically acceptable salt, thereof.

The invention relates in particular to a compound of formula (I), wherein wherein alk, is a bond; alk₂ is C C₂alkylene; X is the C atom and Y is S; Ar is phenylene, especially 1 ,4-phenylene;

Ri is phenyl, phenyl disubstituted by oxy-methylene-oxy, pyridyl or thienyl; R₂ is hydrogen, C C alkyl, d-C₄alkoxy or phenyl;

R₃ is d-dalkyl, Cι-C alkoxy-d-C₄alkyl, C₃-C₆cycloalkyl-d-C₄alkyl, halogeno-d-C alkyl, aminocarbonyl-d-dalkyl, wherein the amino group is unsubstituted or independently monosubstituted or disubstituted by Cι-C alkyl, or it is furanyl-Cι-C₄alkyl; R is hydrogen; wherein an (hetero)aromatic radical phenylene, phenyl, phenyl disubstituted by oxy- methylene-oxy, pyridyl, thienyl is independently unsubstituted or substituted once or several times by a substituent selected from the group consisting of d-C alkyl, d-C alkoxy-d- C₄alkyl, hydroxy, Cι-C₄alkoxy, d-C alkoxy-Cι-C₄alkoxy, CF₃, halogen, nitro and cyano; or a pharmaceutically acceptable salt thereof.

The invention alternatively relates in particular to a compound of formula (I), wherein wherein alk, is a bond; alk₂ is C,-C₂alkylene, such as methylene;

X is the C atom and Y is S;

Ar is 1 ,4-phenylene;

R, is phenyl, phenyl substituted by halogen, typically fluorine, or phenyl disubstituted by oxy-methylene-oxy; R₂ is hydrogen;

R₃ is d-C₄alkyl, such as isopropyl, d-C₄alkoxy-CrC₄alkyl, such as 2-methoxyethoxy, C₃-

C₆-cycloalkyl-C,-C alkyl, such as cyclopropylmethyl, or halogeno-C,-C₄alkyl, such as

2-fluoroethyl or 2,2,2trifluoroethyl;

R₄ is hydrogen; or a pharmaceutically acceptable salt thereof.

The invention relates in particular to a compound of formula (I a)

wherein

R, is phenyl, which is unsubstituted or substituted once or several times by a substituent selected from C,-C₄alkyl and halogen;

R₃ is d-dalkyl, C,-C₄alkoxy-C,-C₄-alkyl, halogeno-d-C₄alkyl or C,-C₄alkyl, which is substituted by C,-C₄alkylaminocarbonyl; or a pharmaceutically acceptable salt thereof.

The invention relates in particular to a compound of formula (I a), wherein R, is phenyl, which is unsubstituted or mono- or polysubstituted by d-C₄alkyl or halogen; R₃ is d-dalkyl; or a pharmaceutically acceptable salt thereof.

The invention relates in particular to a compound of formula (I a), wherein R, is phenyl or fluorophenyl, such as 3-fluorophenyl; and R₃ is C,-C₃alkyl, such as methyl, ethyl or isopropyl; or a pharmaceutically acceptable salt thereof.

The invention alternatively relates to a compound of formula (I a), wherein

R, is fluorophenyl, such as 3-fluorophenyl; and R₃ is C₃-C₆cycloalkyl-C,-C₃alkyl,such as cyclopropylmethyl; or a pharmaceutically acceptable salt thereof.

The compounds of the present invention may be manufactured e.g. in a manner known per se. Th e invention furthermore relates to the preparation of compounds of the invention. A method for preparing a compound of formula (I), wherein X is C and Y is S, comprising for example the reaction of a compound of formula (II a)

H₂N

with a compound of formula R,-CH(R₂)-CO-Hal (II b), wherein Hal is halogen.

The reactions described hereinbefore and hereinafter are carried out in a known manner, e.g. in the absence or usually in the presence of a suitable solvent or diluent or a mixture thereof, proceeding as required under conditions of cooling, of ambient temperature, or of heating, e.g. in a temperature range of about -80°C to the boiling temperature of the reaction medium, preferably about -10° to about +200°C, and where appropriate in a closed vessel, under pressure, in an inert gas atmosphere, and/or under non-aqueous conditions.

Halogen Hal is preferably bromine, furthermore chlorine and iodine.

The reaction is carried out preferably in the presence of an organic base. A suitable base for such purposes is for example tri-C,-C₇alkylamine, such as triethylamine, as is a tri-C,- dalkylamine with voluminous radicals, for example ethyldiisopropylamine, or a heterocyclic base, for example pyridine, 4-dimethylaminopyridine or N-methylmorpholine.

The starting material of formula (II a), wherein X is C and Y is S, can for example be prepared by starting from a compound of formula

O₂N-alk,-Ar-alk₂-Hal (II c), wherein Hal is halogen, especially chlorine, bromine or iodine, preferably bromine, and reacting this with an amine of formula R₃-NH₂ (II d). A compound of formula O₂N-alk,-Ar-alk₂-NH-R₃ (II e) thus obtained is reacted in the next step with a -CO-R₄ acid halogenide or acid anhydride based on the structural element to form a compound of formula O₂N-alk,-Ar-alk₂-N(R₃)-CO-R₄ (llf). For the preparation of a compound of formula (I) wherein R₄ is hydrogen, formylacetic anhydride or trichloroacetic anhydride is used as a formylating agent. In the following reaction step, the nitro group is reduced to the amino group by means of a suitable reducing agent, for example by hydrogenation with hydrogen in the presence of a hydrogenation catalyst, such as palladium on carbon. This amino group is finally treated with an isothiocyanate, such as benzoylisothiocyanate, which results in a corresponding compound of formula (II a).

The starting material of formula (II b) is known or can be prepared in a known manner. For example, a compound of formula (II b) is obtainable by haiogenating a compound of formula R,-CO-CH₂-R₂ (II g), for example by brominating with bromine.

A method for the preparation of a compound of formula (I), wherein X is C, R₂ is hydrogen, and Y is N, comprising for example the S-alkylation of a compound of formula (II a) as the starting material, for example using methyliodide to form the methylthio derivative, followed by reaction with a compound of formula R,-CO-CH(R₂)-NH₂ (II h) or a salt thereof in the presence of one of the bases stated hereinbefore, for example Hϋnig's base, to form the corresponding imidazole derivative of formula (I).

The starting material of formula (II h) is known or can be prepared in a known manner.

The invention is illustrated in particular by the following examples and relates also to the compounds said in the examples to be new and to the use of said compounds and to methods for the preparation thereof.

Salts of compounds of formula (I) may be prepared in a known manner. Acid addition salts of compounds of formula (I), for example, are obtainable by treatment with an acid or a suitable ion exchange reagent. Acid addition salts can be converted to free compounds in the usual manner, for example by treatment with a suitable basic agent.

Acid addition salts obtained can be converted in known manner to other salts, for example by treating another acid with a suitable metal salt, such as a sodium, barium, or silver salt, in a suitable solvent, in which a resulting inorganic salt is insoluble and thus eliminated from the reaction equilibrium. The compounds of formula I, including their salts, are also obtainable in the form of hydrates, or may include the solvent used for crystallization (solvates).

Because the new compounds in free form and in the form of their salts are closely related, the terms free compounds and their salts refer also where appropriate within the meaning and the purpose of this invention to the corresponding salts and free compounds.

Diastereomeric and racemate mixtures obtained can be separated in known manner, on the basis of the physicochemical differences of the components, into the pure diastereomers and enantiomers, for example by chromatography and/or fractionated crystallization.

The new compounds of formula (I) may be present for example in the form of pharmaceutical preparations which comprise a therapeutically effective amount of active substance, if necessary together with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers, and which are suitable for enteral, for example oral or parenteral, administration. The present pharmaceutical preparations which, if so desired, may contain further pharmacologically active substances are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes, and contain from about 0.1 % to 100%, especially from about 1 % to about 50%, of the lyophilizates to about 100% of the active substance.

The invention relates likewise to the use of compounds of formula (I), preferably for the preparation of pharmaceutical compositions. The dosage may depend on various factors, such as the route of administration, species, age and/or condition of the individual. The daily doses to be administered lie between about 0.25 and about 10 mg/kg in the case of oral adminstration and preferably between about 20 mg and about 500 mg for warmblooded animals with a bodyweight of about 70 kg.

The following Examples serve to illustrate the invention; temperatures are indicated in degrees centigrade.

Example 1 : N-lsopropyl-N-[4-(4-phenylthiazol-2-ylamino)benzyl]formamide

0.38 g N-lsopropyl-N-(4-thiocarbamoylaminobenzyl)formamide is heated to boiling in 0.21 ml triethylamine and 5 ml ethanol and mixed with 0.3 g phenacylbromide. The mixture is kept under reflux for 20 minutes, then cooled down, taken up in dichloromethane and washed with water. The organic phase is dried over sodium sulfate, evaporated, taken up in acetonitrile and mixed with 1.1 equivalent of hydrochloric acid in ethanol. N-lsopropyl-N-[4- (4-phenylthiazol-2-ylamino)benzyl]formamide is obtained as white crystals. Melting point 173°C.

The starting material can be prepared for example as follows:

(a) lsopropyl-(4-nitrobenzyl)amine hydrochloride (CAS Reg. No. 111961 -43-4, Beilstein III, Vol. 12, page 2365)

A solution of 5 g p-nitrobenzylbromide in 20 ml dichloromethane is added drop by drop at room temperature to 7 ml isopropylamine in 50 ml toluene. The mixture is stirred at room temperature for 4 hours. The reaction mixture is taken up in ethyl acetate, washed with water and dried over sodium sulfate. The oily residue is dissolved in isopropanol and 5-6 normal hydrochloric acid solution in isopropanol is added. N-lsopropyl-(4-nitrobenzyl)amine hydrochloride is obtained as white crystals. ¹H-NMR (DMSOd₆): 9.55 ppm (2H, s, wide), 8.3 (2H, d), 7.9 (2H, d), 4.3 (2H, benzyl), 3.3 (1 H, m), 1.3 (6H, d).

(b) N-lsopropyl-N-(4-nitrobenzyl)formamide

A vessel is prepared with 250 mg isopropyl-(4-nitrobenzyl)amine hydrochloride, 10 ml dichloromethane and 0.754 ml diisopropylethylamine. A solution of 191 mg formylacetic anhydride (mixed anhydride from acetic acid and formic acid, Beilstein E II, Vol. 2, p. 170, H, Vol. 2, p. 165.E IV, Vol. 2, p. 386.E III, Vol. 2, p. 370, CAS Reg. No. 2258-42-6) in 10 ml dichloromethane is added drop by drop over a period of 1 hour. The mixture is stirred at room temperature for 5 hours, extracted with water, dried (sodium sulfate) and evaporated. The residue is dissolved in ethyl acetate and mixed with some ether (turbidity). After standing at room temperature overnight, N-isopropyl-N-(4-nitrobenzyl)formamide precipitates out as a brownish crystallizate. Drying under a high vacuum at 60°C yields the product with a melting point of 136 °C. Rotamers are observed in ¹ H-NMR (DMSOd₆).

(c) N-(4-Aminobenzyl)-N-isopropylformamide

1.37 g N-lsopropyl-N-(4-nitrobenzyl)formamide in 30 ml tetrahydrofuran is hydrogenated in the presence of 0.15 g palladium carbon (10%) at room temperature under normal pressure until saturation. After filtration from the catalyst, the solution was concentrated by evaporation. ¹H-NMR (DMSOd₆), 2 rotamers in each case: 8.28 and 8.15 ppm (1 H, 2s), 6.9 (2H, 2d), 6.5 (2H, 2d), 5.0 (2H, wide), 4.23 und 4.2 (2H, 2s), 4.1 and 3.7 (1 H, 2m), 1.1 and 1.0 (6H, 2d). The raw product thus obtained, N-(4-aminobenzyl)-N-isopropylformamide, is used in this form in the next step.

(d) N-lsopropyl-N-(4-thiocarbamoylaminobenzyl)formamide

5.4 g N-(4-Aminobenzyl)-N-isopropylformamide in 30 ml tetrahydrofuran is mixed with 2.7 ml benzoylisothiacyanate. The mixture is stirred for 2 hours at room temperature and then concentrated by evaporation in a vacuum. 150 ml methanol and a solution of 2.8 g potassium carbonate in 50 ml water are added and the mixture stirred for 4 hours at room temperature (until dissolved). The reaction mixture is concentrated by evaporation and the remaining aqueous phase is extracted with dichloromethane and dried over sodium sulfate. After evaporation, crystallization from ether is carried out and N-isopropyl-N-(4- thiocarbamoylaminobenzyl)formamide obtained as white crystals. Rf value 0.1 (petroleum ether / ethyl acetate 1 :1 ).

The following compounds of formula (I a) can be prepared in analogous manner, for example as described in Example 1 :

^*) = in the form of hydrochloride.

Example 18:

N-[4-(4-Phenylthiazol-2-ylamino)benzyl]-N-(tetrahydrofuran-2-ylmethyl)formamide

A mixture of 0.78mmol N-(tetrahydrofuran-2-ylmethyl)-N-(4-thioureabenzyl)formamide, 0.78 mmol triethylamine and 0.78 mmol phenacylbromide in 10 ml ethanol is heated to reflux for 20 minutes. After removal of the solvent in the rotary evaporator, the mixture is taken up in dichloromethane and extracted with water. The organic phase is dried over sodium sulfate and then concentrated by evaporation. The raw product is taken up in 5 ml acetonitrile and converted to the hydrochloride with 1.1 equivalents of an 8.5 N hydrochloric acid solution in ethanol. Crystallization is initiated by addition of diethylether until turbidity is attained. Filtration takes place after 1 hour and drying is carried out at 50° in a high vacuum. N-[4-(4-Phenylthiazol-2-ylamino)benzyl]-N-(tetrahydrofuran-2-ylmethyl)formamide is obtained in the form of slightly greenish crystals. Melting point 144°. Rf value 0.2 (ethyl acetate / petroleum ether 1 :1 ).

The starting material can be prepared for example as follows:

23 mmol 4-nitrobenzylbromide is added in portions to a solution of 92 mmol tetrahydrofurfurylamine in dichloromethane (temperature rises to about 30°C). The mixture is stirred overnight at room temperature, washed twice with water, dried over sodium sulfate and evaporated and dried under a high vacuum to remove surplus amine. The raw product is converted to the hydrochloride by treatment with 5-6N hydrochloric acid in isopropanol with the addition of some ether. N-4-Nitrobenzyl-N-(tetrahydrofuran-2-ylmethyl)amine hydrochloride is obtained. Rf value 0.1 (ethyl acetate / petroleum ether 1 :1 ).

A solution of 3.6 mmol N-4-nitrobenzyl-N-(tetrahydrofuran-2-ylmethyl)amine (racemate) and 3.96 mmol Hϋnig's base in 50 ml dichloromethane are cooled to 10°C, and 3.6 mmol trichloroacetic aldehyde is slowly added. The mixture is stirred for 5 hours at 10-15°, the reaction mixture washed with 2N aqueous hydrochloric acid, the organic phase dried over sodium sulfate and evaporated in a vacuum, resulting in N-4-nitrobenzyl-N-(tetrahydrofuran- 2-ylmethyl)formamide. Rf value 0.18 (ethyl acetate / petroleum ether 1 :1 ).

The raw product N-4-nitrobenzyl-N-(tetrahydrofuran-2-ylmethyl)formamide is hydrogenated in the presence of 0.1 g palladium carbon (10%) in 20 ml tetrahydrofuran at room temperature and under normal pressure until saturation. Filtration via Hyflo Supergel (Fluka) yields a colourless solution of N-(4-aminobenzyl)-N-(tetrahydrofuran-2-ylmethyl)formamide. This solution is used directly in the next step without further purification. Rf value 0.12 (ethyl acetate / petroleum ether 1 :1 ).

To the solution of N-(4-aminobenzyl)-N-(tetrahydrofuran-2-ylmethyl)formamide obtained above, 3.6 mmol benzoylisothiocyanate is added drop by drop. The solution is stirred for 4 hours and concentrated by evaporation under a vacuum. The resulting intermediate product is readily hydrolysed by treatment in a mixture of methanol and 3.6 mmol potassium carbonate in 50 ml water. After methanol has been evaporated off, the product is extracted with dichloromethane, dried and crystallized with ether, resulting in N-(tetrahydrofuran-2- ylmethyl)-N-(4-thioureabenzyl)formamide. Rf value 0.02 (ethyl acetate / petroleum ether 1 :1 ).

Example 19: N-Cyclopropylmethyl-N-{4-[4-(3-fluorophenyl)thiazol-2-ylamino]benzyl}formamide

A mixture of 1.14 mmol N-cyclopropylmethyl-N-(4-thioureabenzyl)formamide (96%), 1 ,14 mmol triethylamine and 1.14 mmol 3-fluorophenacylbromide is heated to reflux for 20 minutes in 10 ml ethanol. After removal of the solvent in the rotary evaporator, the mixture is taken up in dichloromethane and extracted with water. The organic phase is dried over sodium sulfate and then concentrated by evaporation. The raw product is chromatographed on a flash column (silicagel 60, 40-63 micrometer, solvent: petroleum ether / ethyl acetate 1 :1 - 2:3). The purified free base is dissolved in acetone and dry hydrochloric acid gas is introduced until pH 1 is achieved. The mixture is cooled to room temperature and treated carefully with ether. After ca. 1 hour the solvent is removed by filtration and the residue is washed with little acetone and then with ether and dried in vacuo at 55 °C for 20 hours. Melting point 154-156 °C. Rf value 0.23 (ethyl acetate / petroleum ether 1 :1 ).

The starting material can be prepared for example as follows:

46 mmol 4-nitrobenzylbromide is added in portions to a solution of 185 mmol cyclopropylmethylamine in dichloromethane (temperature rises to about 30°C). The mixture is stirred overnight at room temperature, washed twice with water, dried over sodium sulfate and evaporated and dried under a high vacuum to remove surplus amine. The raw product is converted to the hydrochloride by treatment with 5-6N hydrochloric acid in isopropanol with the addition of some ether. (4-Nitrobenzyl)cyclopropylmethylamine hydrochloride is obtained. Rf value 0.13 (ethyl acetate / petroleum ether 1 :1 ).

A solution of 46 mmol (4-nitrobenzyl)cyclopropylmethylamine and 50.6 mmol Hϋnig's base in 50 ml dichloromethane is cooled to 10°C, and 46 mmol trichloroacetic aldehyde is slowly added. The mixture is stirred for 5 hours at 10-15°, the reaction mixture washed with 2N aqueous hydrochloric acid, the organic phase dried over sodium sulfate and evaporated in a vacuum, resulting in N-(4-nitrobenzyl)cyclopropylmethylamine. Rf value 0.33 (ethyl acetate / petroleum ether 1 :1 ).

The raw product N-(4-nitrobenzyl)-N-cyclopropylmethylformamide is hydrogenated in the presence of 1.0 g palladium carbon (10%) in 200 ml tetrahydrofuran at room temperature and under normal pressure until saturation. Filtration via Hyflo Supergel (Fluka) yields a colourless solution of N-(4-aminobenzyl)-N-cyclopropylmethylformamide. This solution is used directly in the next step without further purification. Rf value 0.23 (ethyl acetate / petroleum ether 1 :1 ).

To the solution of N-(4-aminobenzyl)-N-cyclopropylmethylformamide obtained above, 46 mmol benzoylisothiocyanate is added drop by drop. The solution is stirred for 4 hours and concentrated by evaporation under a vacuum. The resulting intermediate product is readily hydrolysed by treatment in a mixture of methanol and 46 mmol potassium carbonate in 100 ml water. After methanol has been evaporated off, the product is extracted with dichloromethane, dried and crystallized with ether, resulting in N-cyclopropylmethyl-N-(4- thioureabenzyl)formamide. Rf value 0.07 (ethyl acetate / petroleum ether 1 :1 ).

In analogous manner, for example as described in Examples 1 , 18 or 19, the following compounds of formula

can be prepared:

The manufacture of the corresponding bromoketone starting material of the following examples is disclosed in

(22): Coppola, Gary M. et al.; Synlett (1995), Issue 11 , 1 143-4.

(23): McKay, William R.; Proctor, George R.; J. Chem. Soc, Perkin Trans. 1 (1981 ), Issue

9, 2435-42.

(24) Klose, Walter; Schwarz, Katica. J; Heterocycl. Chem. (1985), 22(3), 669-71. Formulation example: hard gelatin capsules, comprising 100 mg active substance, for example N-isopropyl-N-[4-(4-phenylthiazol-2-ylamino)benzyl]formamide or a salt, for example the hydrochloride, thereof, can be prepared for example as follows:

Composition (for 1000 capsules)

Active ingredient 100.0 g

Lactose 250.0 g

Microcrystalline cellulose 30.0 g

Sodium lauryl sulfate 2.0 g

Magnesium stearate 8.0 g

The sodium lauryl sulfate is added to the lyophilized active ingredient via a sieve with a mesh size of 0.2 mm. Both components are intimately mixed. Then first the lactose is added via a sieve with a mesh size of 0.6 mm and then the microcrystalline cellulose via a sieve with a mesh size of 0.9 mm. Thereupon these components are intimately mixed for a further 10 minutes. Finally the magnesium stearate is added via a sieve with a mesh size of 0.8 mm. After 3 minutes of further mixing, 390 mg each of the formulation obtained are filled into hard gelatin capsules of size 0.

Claims

What is claimed is

Compound of formula (I)

(i) alk, is a bond or C,-C₄alkylene and alk₂ is C,-C₄alkylene;

X is the C atom and Y the S, O or NH atom; or

X is the N atom and Y is the N atom;

Ar is phenylene;

R, is hydrogen, C,-C₇alkyl, C,-C₇alkoxy-C,-C₇alkyl, C₃-C₈cycloalkyl-C╬╣-C₇alkyl, C,-C₇alkoxy,

C,-C₇alkoxy-C,-C₇alkoxy, CF₃, halogen, nitro or cyano, or Ri is phenyl, pyridyl, pyrrolyl, furyl or thienyl;

R₂, has the same meanings as R, if X is C, or is hydrogen, C,-C₇alkyl or C₃-C₈cycloalkyl-C,- dalkyl if X is N;

R₃ and R₄ are independently hydrogen, C╬╣-C₇alkyl, C,-C₇alkoxy-C,-C₇alkyl, C₃-C₈cycloalkyl-

C,-C₇alkyl, halogeno-C,-C₇alkyl, aminocarbonyl-C,-C₇alkyl, wherein the amino group is unsubstituted or is monosubstituted or disubstituted independently by d-C₇alkyl or phenyl-

C,-C₇alkyl, or they are phenyl or phenyl-C╬╣-C₇alkyl; whereas R₃ and R₄ are not simultaneously hydrogen; or

R₃ and R₄ together are C₃-C₄alkylene;

wherein an (hetero)aromatic radical phenylene, phenyl, pyridyl, pyrrolyl, thienyl, furyl is independently unsubstituted or substituted once or several times by a substituent selected from the group consisting of d-C₇alkyl, C C₇alkoxy-C,-C₇alkyl, hydroxy, C,-C₇alkoxy, C,- C₇alkoxy-C,-C₇alkoxy, CF₃, halogen, nitro and cyano;

(ii) also a corresponding compound of formula (I), wherein Ri is phenyl disubstituted by oxy- C╬╣-C₂alkylene-oxy, which is furthermore unsubstituted or substituted once or several times by a substituent selected from the group consisting of d-C₇alkyl, CrC₇alkoxy-C C₇alkyl, hydroxy, C C₇alkoxy, C C alkoxy-C╬╣-C₇alkoxy, CF₃, halogen, nitro and cyano; (iii) also a corresponding compound of formula (I), wherein R₃ and R₄ are independently furanyl or pyranyl; or a salt thereof.

2. A compound, according to claim 1 , of formula (I), wherein alki is a bond or C╬╣-C₄alkylene and alk₂ is d-C₄alkylene;

X is the C atom and Y the S, O or NH atom; or X is the N atom and Y is the N atom; Ar is phenylene; Ri is phenyl or pyridyl;

R₂, has the same meanings as Ri if X is C, or is hydrogen, C╬╣-C alkyl or C₃-C₆cycloalkyl-d- dalkyl if X is N;

R₃ is d-dalkyl, d-C₄alkoxy-d-C alkyl, halogeno-d-C alkyl, aminocarbonyl-C C₄alkyl, wherein the amino group is unsubstituted or is monosubstituted or disubstituted by d-dalkyl or phenyl-d-dalkyl independently of one another, or it is phenyl-C C₄alkyl; R₄ is hydrogen or C C₄alkyl; or wherein an (hetero)aromatic radical phenylene, phenyl or pyridyl is independently unsubstituted or substituted once or several times by a substituent selected from the group consisting of d-C₄alkyl, C C₄alkoxy, halogen, CF₃, cyano and nitro. or a salt thereof.

3. A compound, according to claim 1 , of formula (I), wherein X is C ; Y is S; or a pharmaceutically acceptable salt, thereof.

4. A compound, according to claim 1 , of formula (I), wherein alk₁ is a bond; alk₂ is C╬╣-C₂alkylene;

X is the C atom and Y is S;

Ar is phenylene;

Ri is phenyl, phenyl disubstituted by oxy-methylene-oxy, pyridyl or thienyl;

R₂ is hydrogen, d-C₄alkyl, d-C₄alkoxy or phenyl;

R₃ is d-dalkyl, C╬╣-C alkoxy-d-C₄alkyl, C₃-C₆cycloalkyl-CrC₄alkyl, halogeno-d-C₄alkyl, aminocarbonyl-d-dalkyl, wherein the amino group is unsubstituted or independently monosubstituted or disubstituted by d-C alkyl, or it is furanyl-d-C₄alkyl; R is hydrogen; wherein an (hetero)aromatic radical phenylene, phenyl, phenyl disubstituted by oxy- methylene-oxy, pyridyl, thienyl is independently unsubstituted or substituted once or more by a substituent selected from the group consisting of d-C₄alkyl, C╬╣-C₄alkoxy-d-C alkyl, hydroxy, C C₄alkoxy, C╬╣-C₄alkoxy-d-C alkoxy, CF₃, halogen, nitro and cyano; or a pharmaceutically acceptable salt thereof.

5. A compound, according to claim 1 , of formula (I), wherein alk₁ is a bond; alk₂ is d-C₂- alkylene; X is the C atom and Y is S; Ar is 1 ,4-phenylene; Ri is phenyl, phenyl substituted by halogen or phenyl disubstituted by oxy-methylene-oxy; R₂ is hydrogen; R₃ is d-C alkyl, d-C₄alkoxy-C╬╣-C₄alkyl, C₃-C₆cycloalkyl-d-C alkyl, or halogeno-d-dalkyl; R₄ is hydrogen; or a pharmaceutically acceptable salt thereof.

6. A compound, according to claim 1 , of formula (I a),

wherein

Ri is phenyl, which is unsubstituted or substituted once or several times by a substituent selected from C╬╣-C₄alkyl and halogen;

R₃ is d-dalkyl, C╬╣-C₄alkoxy-d-C₄-alkyl, halogeno-C C₄alkyl or d-C alkyl, which is substituted by d-C₄alkylaminocarbonyl; or a pharmaceutically acceptable salt thereof.

7. A compound, according to claim 6, of formula (I a), wherein

R is phenyl or fluorophenyl; and R₃ is d-C₃alkyl; or a pharmaceutically acceptable salt thereof.

8. A compound, according to claim 6, of formula (I a), wherein

Ri is fluorophenyl; and R₃ is C₃-C₆cycloalkyl-d-C₃alkyl; or a pharmaceutically acceptable salt thereof.

9. A compound, according to claim 1 , selected from the group consisting of N-isopropyl-N-[4-(4-phenylthiazol-2-ylamino)benzyl]formamide, N-[4-(4-phenylthiazol-2-ylamino)benzyl]-N-(tetrahydrofuran-2-ylmethyl)formamide and N-cyclopropylmethyl-N-{4-[4-(3-fluorophenyl)thiazol-2-ylamino]benzyl}formamide or a pharmaceutically acceptable salt thereof.

10. A compound of claim 9 in the form of a hydrochloride.

11. A compound according to any one of claims 1 to 10 for use in the treatment of the human or animal body.

12. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of the claims 1-11 for the preparation of a medicament for the treatment of obesity and related diseases.

13. A pharmaceutical composition comprising a compound according to any one of the claims 1-11 and a pharmaceutically acceptable excipient or adjuvant.