IMIDAZOLE-DERIVATIVES HAVING AGONISTIC OR ANTAGONISTIC ACTIVITY ON THE HISTAMINE H3-RECEPTOR

Abstract: The invention relates to imidazole-derivatives of general formula (a). The invention in particular relates to derivatives having agonistic or antagonistic activity on the histamine H3-receptor. The novel imidazole-derivatives are isothio urea-, guanidine- and amidine-derivatives. The invention further relates to pharmaceutical compositions comprising the novel imidazole-derivatives as well as to methods for preparing the derivatives and for preparing pharmaceutical compositions having antagonistic and agonistic activity on the histamine H3-receptor.

Description: Imidazole-derivatives having agonistic or antagonistic acti- vity on the histamine H 3 -receptor. The invention relates to novel imidazole-derivati¬ ves. The invention in particular relates to novel imidazole- derivatives having agonistic or antagonistic activity on the histamine H 3 -receptor. More in particular it relates to isothiourea-, guanidine- and amidine-derivatives. The inven¬ tion further relates to the synthesis of such compounds, a pharmaceutical composition comprising such compounds or pharmacological acceptable salts thereof, the use of the compounds as agents having biological activity, as agents with agonistic or antagonistic activity on the histamine H 3 - receptor or for preparing a pharmaceutical composition. In addition to the already longer known histamine H,,- and H 2 -receptors there is also a third type histamine- receptor present in the human body, the so-called H 3 -recep- tor. De H 3 -receptor is a presynaptic receptor, i.e. it is located on a cell releasing histamine and stimulation of the receptor leads to inhibition of the histamine-release. Furthermore stimulation of the H 3 -receptor influences also the release of other neurotransmitters, such as e.g. seroto- nine and acetylcholine. H 3 -receptors are located in the central and peripheral nervous system, the lung tissue, the intestine and probably also in the spleen, the skin and the gastro-intestinai tract. A number of compounds having an effect on H 3 -receptors has already been described. For a review see Schwartz et al.. Agents and Actions 30, 1/2 (1990) p- 13-23. Chemical compounds can stimulate or inhibit the histamine H 3 -receptor (Timmerman, J. Med. Chem. 33, p. 4-11 (1990)). Now a group of new imidazole-derivatives showing an agonistic or antagonistic activity on the histamine H 3 -recepto s has been found. These derivatives are represented by the general formula: wherein: Z is a group of the formula (CH 2 ) m , wherein m = 1-5 or a group of the formula: R, H - C - C -, wherein R 6 = (C 1 -C 3 )alkyl H R 7 R 7 = (C C 3 )alkyl; wherein Z may optionally comprise other substituentε selected such that the activity of the derivative is not negatively affected, X represents S, NH or CH 2 ; R, represents hydrogen, (C.-C 3 )alkyl-, aryl(G,-*C 10 )alky1-, wherein aryl may optionally be sub¬ stituted, aryl, (C 5 -C 7 )cycloalkyl(C 1 -C 10 )alkyl-, or a group of the formula: wherein n = 1-4, g is aryl, aryl(C 1 -C 10 )alkyl-, (C 5 -C 7 )cycloalkyl- or (C 5 -C 7 )cycloalkyl(C 1 -C 10 )alkyl- and R p is hydrogen, (C,-C 10 )alkyl- or aryl; g and R g represent hydrogen, (C.-*C 3 )alkyl-, aryl or arylalkyl-, wherein aryl may optionally be substituted; R 3 represents hydrogen, (C 1 -C 3 )alkyl, aryl or aryl alkyl-, wherein aryl may be substituted; and R 4 represents hydrogen, amino-, nitro-, cyano-, halogen, (C^C j ) lkyl-, aryl or arylalkyl-, wherein aryl may optionally be substituted; wherein aryl is phenyl, substituted phenyl, naphthyl, sub- stituted naphthyl, pyridyl or substituted pyridyl; or phar¬ macological acceptable salts thereof. Of these compounds the imidazole-derivatives of formula I wherein: A) when Z is a group of the formula (CH 2 ) m , wherein m •= 1-5, and 1) when X is S, t represents (C.-C 3 )alkyl- or aryl(C,-C 1cl )alkyl-, wherein aryl may optionally be substituted, when m = 1 or 5, or (C 2 -C 3 )alkyl- or aryl(C 2 -C 10 )alkyl-, wherein aryl may optionally be substituted, when m = 2, 3 or 4; aryl, (C 5 -C 7 )cycloalkyl(C,-C 10 )alkyl-, or a group of the formula: wherein n = 1-4, R g is aryl, aryl(C.,-C 1( -,)alkyl-, (C 5 -C 7 )cycloalkyl- or (C 5 -C 7 )cycloalkyl(C 1 - C 10 )al- kyl- and R p is hydrogen, (C.-C 10 )alkyl- or aryl; R 2 represents hydrogen, (C.,-C. 3 )alkyl-, aryl or arylalkyl-, wherein aryl may optionally be substi¬ tuted; and R 3 , R 4 and R g represent hydrogen; or 2) when X is NH, Rp. represents hydrogen, (C.-C 3 )alkyl-, aryl, aryl(C 1 -C 10 )alkyl-, wherein aryl may optionally be substituted, (C 5 -C 7 )cycloalkyl(C 1 -C 10 )alkyl-, or a group of the formula: H -(CH 2 ) n - s - C - R 8 , wherein n = 1-4, R 8 is aryl, aryl(C,.-C 10 )alkyl-, (C 5 -C 7 )cycloalkyl- or (C 5 -C 7 )cycloalkyl(C 1 -C 10 )alkyl- and Εim, is hydrogen or (C.-C 10 )alkyl-; R 2 represents hydrogen, (C.-C 3 )alkyl-, aryl or arylalkyl-, wherein aryl may be optionally substi- tuted; and R 3 , R 4 and g represent hydrogen; or 3) when X is CH 2 , R, represents hydrogen, (C 1 -C 3 )alkyl-, aryl(C.-C.,, } )alkyl-, wherein aryl may optionally be substituted, aryl, (C 5 -C 7 )cycloalkyl(C 1 -C 10 )alkyl-, or a group of the formula: wherein n = 1-4, R 8 is aryl, aryl(C 1 -C 10 )alkyl-, (C 5 -C 7 )cycloalkyl- or (C 5 -C 7 )cycloalkyl(C 1 -C 10 )alkyl- and R ς , is hydrogen, (C 1 -C l0 )alkyl- or aryl; R 2 and R g represent hydrogen, (C 1 -C 3 )alkyl-, aryl or arylalkyl-, wherein aryl may optionally be substi¬ tuted; R 3 represents hydrogen, (C j -C j )alkyl, aryl or arylalkyl-, wherein aryl may be substituted; and R 4 represents hydrogen, amino-, nitro-, cyano-, halogen, (C 1 -C 3 )alkyl-, aryl or arylalkyl-, wherein aryl may optionally be substituted; B) when Z is a group of the formula : - (C.-C 3 ) lkyl (C 1 -C 3 )alkyl; wherein Z may optionally comprise other substituents selected such that the activity of the derivative is not negatively affected, X represents S, NH or CH 2 ; Rp, represents hydrogen, (C.-C 3 )alkyl-, aryl(C 1 -C 10 )alkyl-, wherein aryl may optionally be substituted, aryl, (C 5 -C 7 )cycloalkyl(C.,-C 10 )alkyl-, or a group of the formula: wherein n - 1 - 4, R 8 is aryl, aryl(C^C^)alkyl-, (C 5 -C 7 )cycloalkyl- or (C 5 -C 7 )cycloalkyl(C 1 -C 10 )alkyl- and 9 is hydrogen, (C,-C 10 )alkyl- or aryl; R 2 and R g represent hydrogen, (C^C- j )alkyl-, aryl or arylalkyl-, wherein aryl may optionally be substi- tuted; R 3 represents hydrogen, (C.-C 3 )alkyl, aryl or arylalkyl-, wherein aryl may be substituted; and R 4 represents hydrogen, amino-, nitro-, cyano-, halogen, (C^C j )alkyl-, aryl or arylalkyl-, wherein aryl may optionally be substituted; wherein aryl is phenyl, substituted phenyl, naphthyl, sub¬ stituted naphthyl, pyridyl or substituted pyridyl, are novel derivatives. Agonistic activity is in particular shown by compounds of formula I, wherein R R 2 , R 3 , R 4 and R g are hydrogen, is 2, and X is S or NH. The compound S-[2-(4- imidazolyl)ethyl]isothiourea shows a strong agonistic acti¬ vity and is therefore preferred as the active ingredient in a pharmaceutical composition having histamine H 3 -agonistic activity. Antagonistic activity is in particular shown by compounds of formula I, wherein R 3 , R 4 and R g are hydrogen; m is 2 or 3, I., is a group of the formula -(CH 2 ) n R 10 , wherein R 10 is aryl or substituted aryl, n>l and X is S or NH. Preferred compounds are S-[2-(imidazol-4-yl) ethyl]-N-(2-phenylethyl)- isothiourea, N-benzyl-S-[3-(4(5)-imidazolyl)propyl]isothi¬ ourea, S-[3-(4(5)-imidazolyl)propyl]-N-(2-phenylethyl)is¬ othiourea, S-[3-(4(5)-imidazolyl)propyl]-N-(3-phenylethyl- )isothiourea, S-[3-(4(5)-imidazolyl)propyl]-N-(3-phenylbu- tyl)isothiourea, S-[3-(4(5)-imidazolyl)propyl]-N-(4-chloro- benzyl)isothiourea, N-cyclohexylmethyl-S-[3-(4(5)-imidazo- lyl)propyl]isothiourea and S-[3-(4(5)-imidazolyl)propyl]-N- (4-iodophenylethyl)isothiourea. Other compounds showing strong antagonistic acti¬ vity are compounds of formula I, wherein R 3 , R 4 and R g are hydrogen, m is 1, 2 or 3; and R 1 is a group of the formula -(CH 2 ) r -S -y φ, wherein φ is aryl, r is l, 2 or 3; and R is hydrogen, (0,-0, 0 )alkyl- or aryl. A preferred compound is N-[2-(benzyl- thio)ethyl]-S-[3-(imidazol-4-yl)propyl]isothiourea. Compounds of formula I can in general be synthesi¬ zed in a for analogous compounds known manner. Favourable methods for synthesizing consist in condensation of a i ida- zole-compound of the general formula: R 3 (II) wherein Y represents Br, OH, or 0-alkyl, with a thiourea- derivative having the general formula: H I R - N - C - NRgR, (III) S or condensation of a imidazole of formula II wherein Y represents NH 2 , with a isothiourea-derivative having the general formula: H R - N - C = NH (IV) f SR 12 wherein in the formulas III and IV R represents hydrogen, (C^C^)alkyl-, aryl(C^C.^)alkyl- or aryl, and R 12 represents (C j -C.,,-,)alkyl. As solvents polair solvents are used such as ethanol or propanol. The condensations are carried out at temperatures between roomtemperature and the boiling point of the solvents for between 30 minutes and 10 hours. Reactions take place in acid environment, e.g. hydrobromic acid, or in neutral environment. The obtained product can be processed in the usual way. If desired it is further possi¬ ble to convert the obtained compounds of formula I in other compounds of formula I. The following examples illustrate the synthesis of compounds of the present invention but are never intended to limit the scope thereof. EXAMPLE 1 Synthesis of N-benzyl-S-[2-(imidazol-4-yl)ethyl]isothiourea dipicrate (VUF 9028) . 3.5 gram (13.7 mmol) 4(5)-(2-bromoethyl)imidazo- le.HBr and 2.3 gram N-benzylthiourea were refluxed for 60 hours in 30 ml ethanol. The ethanol was evaporated and the product was purified by means of columnchromatography, using methanol/ethylacetate as eluent. Subsequently the solvent was evaporated and the residue dissolved in methanol whereto 10 gram picric acid in methanol was added. After addition of water an oil was formed, which after stirring with water became solid. The solid matter with melting point 166.9-169.8°C was subse¬ quently filtrated. The NMR-results of this compound are given in table 1. EXAMPLE 2 Synthesis of S-[3-(4(5)-imidazolyl)alkyl]-N-(2-(substitu¬ ted)-arylalkyl)isothiourea-derivatives. Analogous to the preparation method of VUF 9028 from example 1 a number of compounds were synthesized with the formula: n R The meaning of n, m and R, the solvent of the condensation reaction and the melting points of the compounds are given in the table below. The NMR-results are given in table 1. Compound R 2 R n m melt.point salt solvent * Radioactively labeled compound, e.g. for use as a tracer- molecule EXAMPLE 3 Synthesis of N-[2-(imidazol-4-yl)ethyl]-N*-phenyl guanidine dipicrate (VUF 9006) . Step 1: Synthesis of S-ethyl-N-phenylisothiourea. 4 gram N-phenylisothiourea (33 mmol) and 5 ml ethylbro ide were refluxed for 10 hours in ethanol. Again 5 ml ethylbro¬ mide was added. The reaction course was followed by thin layer chromatography (ethylacetate/petroleumether 3:7). Subsequently the solvent was evaporated and the residu crystallised from ethanol/ethylacetate. Step 2: 15 mmol histamine.2HC1 was added to 30 mmol sodiumethanolate in ethanol (prepared by dissolving 30 mmol sodium in etha¬ nol) . Subsequently it was refluxed for one half hour, after which the mixture was cooled in ice and the formed NaCl was filtrated. To the filtrate 15 mmol S-ethyl-N-phenylisothiou- rea was added. Next the reation mixture was refluxed for 35 hours (control with thin layer chromatography (ethylacetate/ petroleumether 1:1, saturated with ammonia)). Subsequently the solvent was evaporated and the residue dissolved in methanol. 35 mmol picric acid were added. The product was seperated by the addition of water and was subsequently crystallised from methanol/water. The melting point was 235-238°C. Analogous to the synthesis of VUF 9006 N-[2-(imi- dazol-4-yl)ethyl]-N'-phenyl-ethylguanidine dipicrate (VUF 9007; meltingpoint 196-198°C) was prepared. The NMR-resluts are given in table 1. EXAMPLE 4 Synthesis of N-[2-(arylalkylthio)alkyl]-S-[3-(imidazol-4- yl)alkyl]isothiourea- and -guanidine-derivatives. Analogous to example 1 compounds were synthesized having the formula: The meaning of the symbols m, X and R, the solvent of the condensation reaction and the melting points of the com¬ pounds are given in the table below. The NMR-results are given in table 1. Compounds m X melting point salt solvent VUF 8404 2HBr 2-prop, VUF 8405 dipicr. ethano1 VUF 8409 dipicr. ethanol VUF 8414 dipicr. ethanol EXAMPLE 5 Synthesis of N-alkyl-S-[2-(4-imidazolyl)alkyl]isothiourea- and -guanidine-derivatives. .Analogous to example 1 compounds were synthesized having the formula: The meaning of the symbols m, X and R, the solvent of the condensation reaction and the melting points of the com¬ pounds are given in the table below. The NMR-results are given in table 1. Compound m melting point salt solvant TABLE 1. NMR-results of the compounds mentioned in the description. COMPOUNDS AGONISTS VUF8325 3.06 ppm triplet 3.56 ppm triplet 7.61 ppm singlet 9.01-9.27 ppm multiplet VUF8621 2.93 ppm singlet 3.07 ppm triplet 3.59 ppm triplet 7.60 ppm singlet 9.11 ppm doublet ANTAGONISTS VUF9028 3.06 ppm triplet 3.54 ppm triplet 4 4..5D8» ppppmm ssimngglieetr 7.29-7.49 ppm multiplet n 52 ppm singlet 8.62 ppm singlet 9.08 ppm doublet SUBSTITUTE KsaΞT VUF9006 2.90 ppm triplet 3.51 ppm triplet 7.14-7.50 ppm multiplet 7.69-7.86 ppm multiplet 8.59 ppm singlet 8.97 ppm singlet VUF9007 2.74-2.92 ppm multiplet 3.32-3.51 ppm multiplet 7.18-7.50 ppm multiplet 8.63 ppm singlet 9.05 ppm doublet VUF8404 2.66 ppm triplet 3.06 ppm triplet 3.40-3.72 ppm multiplet 3.81 ppm singlet 7.28 ppm singlet 7.58 ppm singlet 9.07 ppm doublet VUF8405 1.64 ppm quintet 2.38-2.84 ppm multiplet 3.06-3.56 ppm multiplet 3.80 ppm singlet 7.26-7.44 ppm multiplet 8.60 ppm singlet 9.02 ppm singlet VUF8409 2.56 ppm triplet 3.03 ppm triplet 3.26-3.70 ppm multiplet 5.40 ppm singlet 7.10-7.56 ppm multiplet 8.60 ppm singlet 9.02 ppm singlet VUF8414 1.94 ppm quintet 2.60-2.94 ppm multiplet 3.20 ppm triplet 3.30-3.68 ppm multiplet 3.78 ppm singlet 7.28-7.42 ppm multiplet 8.60 ppm singlet 9.00 ppm doublet VUF9107 1.86-2.05 ppm multiplet 2.76 ppm triplet 3.20-3.51 ppm multiplet 4.60 ppm singlet 7.26-7.52 ppm multiplet 9.01 ppm doublet VUF9151 1.81-1.98 ppm multiplet 2.73 ppm triplet 1V3 2.89 ppm triplet J = 7.0 Hz 2H 3.22 ppm triplet J = 7.0 Hz 2H 3.34 ppm singlet 6H 3.52-3.68 ppm multiplet 2H 7.20-7.40 ppm multiplet 5H 7.48 ppm singlet 1H 9.02 ppm doublet J = 1.3 Hz 1H VUF9152 1.78-2.06 ppm multiplet 4H 2.64 ppm triplet J = 7.6 Hz 2H 2.77 ppm triplet J = 7.3 HZ 2H 3.19-3.50 ppm multiplet 10H 7.18-7.40 ppm multiplet 5H 7.49 ppm singlet 1H 9.01 ppm doublet J = 1.3H 1H VUF9153 1.86-2.06 ppm multiplet 2H 2.77 ppm triplet J = 7.2 HZ 2H 3.22-3.49 ppm multiplet 6H 4.60 ppm singlet 2H 7.32-7.58 ppm multiplet 6H 9.04 ppm doublet J = 1.3H 1H VUF9163 0.80-1.77 ppm multiplet 11H 1.86-2.03 ppm multiplet 2H 2.74 ppm triplet J = 7.0 Hz 2H 3.08-3.25 ppm multiplet 4H 3.35 ppm singlet 10H 7.46 ppm singlet 1H 8.49 ppm singlet 4H 8.98 ppm doublet J = 1.3H 1H VUF4571 1.47-1.70 ppm multiplet 4H 1.84-2.03 ppm multiplet 2H 2.42-2.66 ppm multiplet 5OH 2.74 ppm triplet J = 7.2 Hz 2H 3.19 ppm triplet J = 7.2 Hz 2H 3.26-3.38 ppm multiplet 2H 3.46 ppm multiplet 10H 7.11-7.35 ppm multiplet 5H 7.47 ppm singlet 1H 8.59 ppm singlet 4H VUF4586 1.89 ppm multiplet 2H 2.74 ppm triplet J = 7.2 HZ 2H 2.83 ppm triplet J = 7.0 HZ 2H 3.24 ppm multiplet 2H 3.57 ppm multiplet J = 7.2 HZ 2H 7.05-7.20 ppm multiplet 2H 7.60-7.75 ppm multiplet 2H 7.50 ppm singlet 1H 9.03 ppm singlet 1H SUBSTITUTESHEET 12 Pharmacological experiments The agonistics and antagonistics activities on the H 3 -receptor of the various compounds were determined compared to histamine. The testmethods used therefor are described in Van der Werf et al. , Agents and Actions 20, 3/4 (1987) p. 239-243 and Menkveld et al., European Journal of Pharma¬ cology, 186 (1990) p. 343-347. The results of the experiments are given in the tables below. pD 2 is the negative logarithm of the concen- tration of the testcompound at which 50% agonistic activity was measured. pA 2 is the negative logarithm of the concen¬ tration of the testcompound at which the concentration of the agonist had to be doubled to obtain the same effect as obtained when the antagonist was absent. Pharmaceutical compositions, comprising compounds of formula I as defined in claim 19 as the active ingredient for therapeutically influencing the human and animal histam- inergic system have the form of powders, suspensions, solu¬ tions, sprays, emulsions, unguents or creams and can be used for local application, intranasal, rectal, vaginal and also for oral or parenteral (intravenous, intradermal, intramus¬ cular, intrathecal etc.) administration. Such compositions can be prepared by combining (i.e. by mixing, dissolving etc.) of the active compound of formula I in the form of a free acid or salt with farmaceutically acceptable excipients with neutral character (such as aquous or non-aquous sol¬ vents, stabilizers, emulsifiers, detergents, additives) , and further if neccesary colouring agents and flavouring agents. The concentration of the active ingredient in a farmaceuti- cal composition can vary between 0.1% and 100%, depending on the nature of the influence and the method of administra¬ tion. The dose of the active ingredient that is administered can further be varied between 0.1 mg and 100 mg per kg body- weight. 13 TABLE 2. Antagonistic activity Compound pA, testmethod ratcortex ileum guinea pig ileum guinea pig ileum guinea pig ileum guinea pig ileum guinea pig ileum guinea pig ileum guinea pig ileum guinea pig ileum guinea pig ileum guinea pig ileum guinea pig ileum guinea pig ileum guinea pig ileum guinea pig ileum guinea pig ileum guinea pig ileum guinea pig ileum guinea pig TABLE 3. Agonistic activity Compound pD 2 testmethod ratcortex ileum guinea pig ratcortex ileum guinea pig

Claims: 14 C A I M S 1. Imidazole-derivatives of the general formula: K 3 wherein: A) when Z is a group of the formula (CH 2 ) m , wherein m = 1-5, and 1) when X is S, R, represents (C.-C 3 )alkyl- or aryl(C.-C 10 )alkyl-, wherein aryl may optionally be substituted, when m = 1 or 5, or (C 2 -C 3 )alkyl- or aryl(C 2 -C 10 ) alkyl-, wherein aryl may optionally be substitu¬ ted,when m = 2, 3 or 4; aryl, (C 5 -C 7 )cycloalkyl(C 1 -C 10 )alkyl-, or a group of the formula: H -(CH 2 ) n - S - C - R g , K wherein n = 1-4, g is aryl, aryl(C^C^)alkyl-, (C 5 -C 7 )cycloalkyl- or (C 5 -C 7 )cycloalkyl(C 1 - C 10 )al¬ kyl- and R, is hydrogen, (C.--C 10 )alkyl- or aryl; R 2 represents hydrogen, (C j -C^)alkyl-, aryl or arylalkyl-, wherein aryl may optionally be substi- tuted; and R 3 , R 4 and R g represent hydrogen; or 2) when X is NH, R 1 represents hydrogen, (C.-C 3 )alkyl-, aryl, aryl(G,-C 10 )alkyl-, wherein aryl may optionally be substituted, (C 5 -C 7 )cycloalkyl(0,-0, 0 )alkyl-, or a group of the formula: 15 H - (CH 2 ) n - S - C - R g , wherein n = 1-4, R g is aryl, aryl(C,,-C 10 )alkyl-, (C 5 -C 7 )cycloalkyl- or (C 5 -C 7 )cycloalkyl(C 1 -C 10 )alkyl- and R, is hydrogen or (C.-C 10 )alkyl-; R 2 represents hydrogen, (C^C j )alkyl-, aryl or arylalkyl-, wherein aryl may be optionally substi¬ tuted; and R 3 , R 4 and R g represent hydrogen; or 3) when X is CH 2 , R, represents hydrogen, (C 1 -C 3 )alkyl-, aryl (C^-C w )alkyl-, wherein aryl may optionally be substituted, aryl, (C 5 -C 7 )cycloalkyl(0,-0^)alkyl-, or a group of the formula: H / -(CH 2 ) n - s - C - R g , *9 wherein n = 1-4, R g is aryl, aryl(C.-C 10 )alkyl-, (C 5 -C 7 )cycloalkyl- or (C 5 -C 7 )cycloalkyl(C 1 -C 10 )alkyl- and R ς , is hydrogen, (C.,-C 10 )alkyl- or aryl; R 2 and R g represent hydrogen, (C,-C 3 )alkyl-, aryl or arylalkyl-, wherein aryl may optionally be substi¬ tuted; R 3 represents hydrogen, (C 1 -C 3 )alkyl, aryl or arylalkyl-, wherein aryl may be substituted; and R 4 represents hydrogen, amino-, nitro-, cyano-, halogen, (C..-C 3 )alkyl-, aryl or arylalkyl-, wherein aryl may optionally be substituted; B) when Z is a group of the formula : R 6 H » V - C - C -, wherein R 6 = (C^C- j )alkyl H R 7 R 7 = (C«-C 3 )alkyl; wherein Z may optionally comprise other substituents selected such that the activity of the derivative is not negatively affected, X represents S, NH or CH 2 ; 16 - R, represents hydrogen, (0,-0 3 )alkyl-, aryl(0,-0, 0 )alkyl-, wherein aryl may optionally be substituted, aryl, (C 5 -C 7 )cycloalkyl(C,-C, 0 )alkyl-, or a group of the formula: H -(CH 2 ) n - S - C - R g , wherein n = 1 - 4, R g is aryl, aryl(C,-C 10 )alkyl-, (C 5 -C 7 )cycloalkyl- or (C 5 -C 7 )cycloalkyl(0,-0, 0 )alkyl- and R p is hydrogen, (C,-C, 0 )alkyl- or aryl; R 2 and g represent hydrogen, (C,-C 3 )alkyl-, aryl or arylalkyl-, wherein aryl may optionally be substi¬ tuted; R 3 represents hydrogen, (C,-C 3 )alkyl, aryl or arylalkyl-, wherein aryl may be substituted; and R 4 represents hydrogen, amino-, nitro-, cyano-, halogen, (0,-0 3 )alkyl-, aryl or arylalkyl-, wherein aryl may optionally be substituted; wherein aryl is phenyl, substituted phenyl, naphthyl, sub¬ stituted naphthyl, pyridyl or substituted pyridyl. 2. Imidazole-derivatives according to claim 1, having the formula I, wherein R 3 , R 4 and R g are hydrogen; m is 2; R, is a group of the formula (CH 2 ) n R, 0 wherein R 10 is a substituted or non-substituted arylgroup, n≥l; and X is S or NH. 3. Imidazole-derivatives according to claim 2, characterized in that R 2 is hydrogen; m is 2; and X is S. 4. Imidazole-derivatives according to claim 3, characterized in that the derivative is S-[2-(imidazol-4-yl) ethyl]-N-(2-phenylethy1)isothiourea. 5. Imidazole-derivatives according to claim 2, characterized in that R 2 is hydrogen; is 3; and X is S. 6. Imidazole-derivatives according to claim 5, characterized in that the derivative is N-benzyl-S-[3-(4(5)- i idazolyl)propyl]isothiourea. 7. Imidazole-derivatives according to claim 5, characterized in that the derivative is S-[3-(4(5)-imidazo- lyl)propyl]-N-(2-phen lethy1)isothiourea. 17 8. Imidazole-derivatives according to claim 5, characterized in that the derivative is S-[3-(4(5)-imidazo- lyl)propyl]-N-(3-phenylpropyl)isothiourea. 9. Imidazole-derivatives according to claim 5, characterized in that the derivative is S-[3-(4(5)-i idazo- lyl)propyl]-N-(4-phenylbutyl)isothiourea. 10. Imidazole-derivatives according to claim 5, characterized in that the derivative is S-[3-(4(5)-imidazo- ly1)propyl]-N-(4-chlorobenzy1)isothiourea. 11. Imidazole-derivatives according to claim 5, characterized in that the derivative is N-cyclohexylmethyl- S-[3-(4(5)-imidazoly1)propyl]isothiourea. 12. Imidazole-derivatives according to claim 5, characterized in that the derivative is S-[3-(4(5)-imidazo- lyl)propyl]-N-(4-iodophenylethyl)isothiourea. 13. Imidazole-derivatives according to claim 1, having the formula I, wherein R 3 , R 4 and R g are hydrogenatoms; m is l, 2 or 3; R, is a group of the formula wherein φ is an arylgroup, r is 1, 2 or 3 and R,, is hydro¬ gen, (C,-C, 0 )alkyl- or aryl. 14. Imidazole-derivatives according to claim 13, characterized in that is 3, r is ' 2, R,, is hydrogen and X is S or NH. 15. Imidazole-derivatives according to claim 14, characterized in that the derivative is N-[2-(benzylthio)- ethyl]-S-[3-(imidazol-4-yl)propyl]isothiourea. 16. Method for preparing imidazole-derivatives, characterized in that compounds of formula I are being synthesized in a for analogous compounds known manner. 17. Method for preparing imidazole-derivatives, characterized in that compounds of formula I are prepared by condensation of an imidazole-derivative of the general formula: 18 R 3 wherein Y represents Br, OH, or O-alkyl; and a thioureade¬ rivative of the general formula: H R - N - C - NR g R, (III) tl S wherein R represents hydrogen, (C,-C, 0 )alkyl, aryl(C,-C, 0 )alkyl- or aryl, and R, 2 represents (C,-C,0)alkyl-. 18. Method for preparing imidazole-derivatives according to claim 17, characterized in that compounds of formula I are being prepared by condensation of an imidazo- le-derivative of the general formula: wherein Y represents NH 2 ; and a thioureaderivative of the general formula H 1 R - N C ■ NH (IV) I SR 12 19. Pharmaceutical composition having antagonistic or agonistic activity on the histamine H 3 -receptor, characte¬ rized in that it comprises as an active ingredient a com- pound of formula I, wherein : Z is a group of the formula (CH 2 ) m , wherein m = 1-5 or a group of the formula: 19 R A H - C 1 - L0 -, wherein R 6 = (C,-C 3 )alkyl H R 7 R 7 = (C,-C 3 )alkyl; wherein Z may optionally comprise other substituents selected such that the activity of the derivative is not negatively affected, X represents S, NH or CH 2 ; R, represents hydrogen, (C,-C 3 )alkyl-, aryl(C,-C 10 )alkyl-, wherein aryl may optionally be sub- stituted, aryl, (C 5 -C 7 )cycloalkyl(C,-C 10 )alkyl-, or a group of the formula: wherein n = 1-4, g is aryl, aryl(0,-0^)alkyl-, (C 5 -C 7 )cycloalkyl- or (C 5 -C 7 )cycloalkyl(C,-C, 0 )alkyl- and R, is hydrogen, (C,-C 10 )alkyl- or aryl; R 2 and R g represent hydrogen, (C,-C 3 )alkyl-, aryl or arylalkyl-, wherein aryl may optionally be substituted; R 3 represents hydrogen, (C,-C 3 )alkyl, aryl or arylalkyl-, wherein aryl may be substituted; and R 4 represents hydrogen, amino-, nitro-, cyano-, halogen, (0,-0 3 )alkyl-, aryl or arylalkyl-, wherein aryl may optionally be substituted; wherein aryl is phenyl, substituted phenyl, naphthyl, sub¬ stituted naphthyl, pyridyl or substituted pyridyl; or phar¬ macological acceptable salts thereof. 20. Pharmaceutical composition according to claim 19, characterized in that it comprises as the active ingre- dient a compound of formula I or pharmacological acceptable salts thereof, wherein R,, R 2 , R 3 , R and R g are hydrogen¬ atoms; m is 2; and X is S or NH. 21. Pharmaceutical composition according to claim 20, characterized in that it comprises as the active ingre- dient S-[2-(4-imidazolyl)ethyl]isothiourea or a pharmacolo¬ gical acceptable salt thereof. 22. Pharmaceutical composition according to claim 20 19, characterized in that it comprises as the active ingre¬ dient a compound of the formula I or pharmacological accep¬ table salts thereof, wherein R 3 , R 4 and R g are hydrogenatoms; m is 2; R, is a group of the formula (CH 2 ) n R, 0 , wherein R 10 is a substituted or non-substituted aryl, n > 1 and X is S or NH. 23. Pharmaceutical composition according to claim 22, characterized in that it comprises as the active ingre¬ dient a compound of the formula I or pharmacological accep- table salts thereof, wherein R 2 is hydrogen; m is 2; and X is S. 24. Pharmaceutical composition according to claim 23, characterized in that it comprises as the active ingre¬ dient S-[2-(imidazol-4-yl)ethyl]-N-(2-phenylethyl)isothio- urea or a pharmacological acceptable salt thereof. 25. Pharmaceutical composition according to claim 23, characterized in that it comprises as the active ingre¬ dient a compound of the formula I or pharmacological accep¬ table salts thereof, wherein R 2 is hydrogen; m is 3; and X is S. 26. Pharmaceutical composition according to claim 25, characterized in that it comprises as the active ingre¬ dient the derivative is N-benzyl-S-[3-(4(5)-imidazolyl)pro¬ pyl]isothiourea or a pharmacological acceptable salt there- of. 27. Pharmaceutical composition according to claim 25, characterized in that it comprises as the active ingre¬ dient the derivative S-[3-(4(5)-imidazolyl)propyl]-N-(2-phe- nylethyl)isothiourea or a pharmacological acceptable salt thereof. 28. Pharmaceutical composition according to claim 25, characterized in that it comprises as the active ingre¬ dient the derivative S-[3-(4(5)-imidazolyl)propyl]-N-(3- phenylpropyl)isothiourea or a pharmacological acceptable salt thereof. 29. Pharmaceutical composition according to claim 25, characterized in that it comprises as the active ingre- 21 dient the derivative S-[3-(4(5)-imidazolyl)propyl]-N-(4- phenylbutyl)isothiourea or a pharmacological acceptable salt thereof. 30. Pharmaceutical composition according to claim 5 25, characterized in that it comprises as the active ingre¬ dient the derivative S-[3-(4(5)-imidazolyl)propyl]-N-(4- chlorobenzyl)isothiourea or a pharmacological acceptable salt thereof. 31. Pharmaceutical composition according to claim 10 25, characterized in that it comprises as the active ingre¬ dient the derivative N-cyclohexylmethyl-S-[3-(4(5)-imida¬ zolyl)propyl]isothiourea or a pharmacological acceptable salt thereof. 32. Pharmaceutical composition according to claim 15 25, characterized in that it comprises as the active ingre¬ dient the derivative S-[3-(4(5)-imidazolyl)propyl]-N-(4- iodophenylethy1)isothiourea or a pharmacological acceptable salt thereof. 33. Pharmaceutical composition according to claim 20 19, characterized in that it comprises as the active ingre¬ dient a compound of the formula I or pharmacological accep¬ table salts thereof, wherein R 3 , R 4 and R g are hydrogen; m is 1-3; R, a group is of the formula -(CH 2 ) r -S-τ— φ R,, 5 wherein φ is aryl, r is l, 2 or 3 and R,, is hydrogen, (C,-C, 0 )alkyl- or aryl. 34. Pharmaceutical composition according to claim 33, characterized in that is 3, r is 2, R,, is hydrogen and X is S or NH. 0 35. Pharmaceutical composition according to claim 34, characterized in that it comprises as the active ingre¬ dient N-[2-(benzylthio)ethyl]-S-[3-(imidazole-4-yl)propyl]- isothiourea or a pharmacological acceptable salt thereof. 36. Use of compounds of formula I as defined in 5 claim 1 as an agent having biological activity. 37. Use of compounds of formula I as defined in claim 19 as an agent having agonistic or antagonistic acti- 22 vity on the histamine H 3 -receptor. 38. Use of a compound of the formula I as defined in claim 19 for preparing a farmaceutical composition having agonistic or antagonistic activity on the histamine H 3 - receptor.

Inventors: GOOT HENDERIKUS VAN DER, TIMMERMAN HENDRIK, TIMMERMAN, HENDRIK, VAN DER GOOT, HENDERIKUS
Applicants: SEED CAPITAL INVESTMENTS, SEED CAPITAL INVESTMENT (SCI) B.V.
Application year: 1992
Main classification: C07D401
IPC codes: A61K31, A61P43, C07D233, C07D401