WO1995006037A1

WO1995006037A1 - New imidazole derivatives having agonistic or antagonistic activity on the histamine h3 receptor

Info

Publication number: WO1995006037A1
Application number: PCT/NL1994/000206
Authority: WO
Inventors: Roelant Christiaan Vollinga; Wiro Michaël Petrus Bernardus MENGE; Hendrik Timmerman
Original assignee: Vrije Universiteit
Priority date: 1993-08-27
Filing date: 1994-08-29
Publication date: 1995-03-02
Also published as: AU7823894A

Abstract

The invention relates to new imidazole derivatives of formula (I) having agonistic and antagonistic activity on the histamine H3-receptor. More in particular the invention concerns 4- and 5-substituted aminoalkyl imidazoles and their derivatives. The invention further relates to the synthesis of these compounds, pharmaceutical compositions comprising the said compounds or pharmacological salts thereof, and the use of the compounds as agents having biological activity on the histamine H3-receptor or for the preparation of a pharmaceutical composition.

Description

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

The invention relates to novel imidazole derivatives having pharmacological activity. The invention is in particular directed to novel imidazole derivatives having agonistic or antagonistic activity on the histamine H₃ receptor. More in particular the invention concerns 4- and 5-substituted aminoalkyl imidazoles and their derivatives.

The invention further relates to the synthesis of such compounds, pharmaceutical compositions comprising such compounds or pharmacological acceptable salts thereof, and the use of the compounds as agents having biological activity, as agents with agonistic or antagonistic activity on the histamine H₃ receptor or for preparing a pharmaceutical composition.

The histamine H₃ receptor is a presynaptic receptor, located in both the central and peripheral nervous system, the skin and in several organs such as the lung, the intestine and probably also in the spleen and the gastro¬ intestinal tract. Stimulation of the H₃ receptor leads to inhibition of the release of histamine (autoreceptor) , but also of other neurotransmitters (heteroreceptor) , such as e.g. acetylcholine and serotonine.

A number of selective H₃ ligands have been described. For a review see Leurs et al., Progress in Drug Res. 39, p. 127-165 (1992) and Lipp et al., in The Histamine Receptor, iley-Liss, Inc., p. 57-72 (1992) . It has been shown that the H₃ receptor can be regarded as a general regulatory system and as a potential target for new therapeutics (Tim erman, J. Med. Che . 33, p. 4-11 (1990) and Schwartz et al., Agents and Actions 30, 1/2, p. 13-23 (1990) ) . Now a group of new imidazole derivatives showing agonistic or antagonistic activity on the H₃ receptor has been identified. These derivatives can be represented by the general formula:

wherein the substituents are as defined in claim 1.

The imidazole derivatives of the present invention show either antagonistic or agonistic activity on the histamine H₃-receptor and may therefore be used as the active ingredient of pharmaceutical compositions.

The compounds of the formulas

wherein R ¹ is hydrogen, methyl or ethyl and compounds of the formulas

S

II

(CH₂)_q -NH₂ (CH₂)_q -NH*C-NH-R"

HN . N HN_^ . N or

wherein q is 2-5 and R" is hydrogen, (C^C_j) alkyl, aryl or aryl-(C^C_j)alkyl have been previously disclosed. Of these compounds only derivatives of the formulas

.NH;

HN .N HN^N ^

and compounds of the formulas

wherein R' is hydrogen, methyl, ethyl. are known to have (ant)agonistic activity on the H₃-receptor.

The present invention comprises both linear and ringstructured compounds, all of which have the i idazole- part in common.

The linear compounds have for example one of the formulas

S (CH₂)_n-NH₂ ^(CH₂)_n-NH-C-NH-R

^HN^^N or HN^N

(II) (III)

Compounds of formula I may be synthesized in general through a process that is analogous to the process as described in Vollinga et al., Reel. Trav. Chim. Pays-Bas, 112, p. 123-125 (1993) . The process preferably comprises C5- lithiation of a 1,2-diprotected imidazole and subsequent treatment with a suitable electrophile. The electrophile may be selected from the group consisting of halogen, aldehyde, keton, nitrile, epoxide or acylhalide. in general compounds of formula I (compounds with

R⁴ is hydrogen excluded) can be prepared from compounds of formula I wherein R⁴ represents hydrogen. For example compounds of formula III can be made from the compounds of formula II by simple addition or condensation reactions e.g. VUF 4613 can be made by the addition of methylisothiocyanate to VUF 4702.

For the synthesis of compounds of formula II, 1- chloro-tø-iodoalkanes can be used as electrophiles. In this matter, an t)-chloroalkane is introduced on the C5-position of the 1, 2-diprotected imidazole. The chloro group can then be converted into an amino group and the protection groups removed. Other compounds of formula I (excluding the compounds of formula II and III) have been made using aldehydes or ketones as electrophiles with subsequent removal, conversion or elimination of the formed hydroxyl group. Of the imidazole derivatives of the invention

VUF 4702 (4 (5) -(5-aminopentyl) -1 H-imidazole dioxalate) shows a particular advantageous antagonistic activity, whereas VUF 4708 (4-[ (4 (5) -imidazolyl)methyl]piperidine) is a good agonist. 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 4 (5) -(5-aminopentyl) -imidazole dioxalate (VUF 4702) .

100 gram imidazole (1.5 mol) , 160 ml dimethylsulfamoylchloride (1.5 mol) and 210 ml triethylamine (1.5 mol) were dissolved in 1000 ml toluene. After 16 hours of stirring, the precipitate was filtrated and the filtrate was concentrated under vacuo. The product (1-(N,N-dimethyl- sulfamoyl) imidazole) was distilled. Boiling point : 110°C at 0.4 mm Hg.

17.5 g. of l-(N,N-Dimethylsulfamoyl) imidazole (0.1 mol) was dissolved in dry THF (400 ml) under an atmosphere of dry nitrogen and cooled to -70°C. n-Butyllithium in hexane (65 ml, 0.1 mol) was added dropwise (temperature should not exceed -65°C) . After 15 min, a solution of tert-butyl-dimethylsilyl chloride (15 g, 0.1 mol) in dry THF (30 ml) was added (10 min) and the solution was stirred at room temperature for 1 h. The mixture was cooled to -70°C again and n-butyllithium in hexane (65 ml, 0.1 mol) was added dropwise (temperature should not exceed -65°C) . After 0.5 h, a solution of l-chloro-5-iodopentane (23.3 g, 0.1 mol) in dry THF (20 ml) was added gradually and the mixture was allowed to (slowly) warm to room temperature overnight. The reaction mixture was poured into water (200 ml) and the THF was removed under reduced pressure. The product was extracted with CHC1₃ (3 x 150 ml) , dried (Na₂S0₄) and concentrated in vacuo.

The residue and phthalimide (15.0 g, mol) were dissolved in DMF (300 ml), Na₂C0₃ was added (12.0 g, mol) and the mixture was heated at 90°C. After 7 h the mixture was filtrated and the solvent was evaporated under reduced pressure. The residue was dissolved in CHC1₃ (150 ml) , washed with H₂0 (3 x 150 ml) , dried (Na₂SO and concentrated in vacuo. The crude product was dissolved in 30 % HBr (300 ml) and heated under reflux. After 16 h the mixture was cooled, filtrated and concentrated under vacuo. The residue was dissolved in absolute EtOH (300 ml) , heated under reflux for 0.5 h and concentrated under reduced pressure. The remaining dark oil was washed (under stirring) with portions (100 ml) of acetone. After several washings, the oil crystallized. The residue was dissolved in H₂0 and the pH was raised to 12 by adding K₂C0₃. The product was extracted with CDC1₃, dried on Na₂S0₄ and concentrated under vacuo. The product was dissolved in iso-propanol and an excess of a saturated solution of oxalic acid in iso-propanol was added (slowly) . The formed precipitate was collected by centrifugation and washed with iso-propanol (three times) . After recrystalization from ethanol/iso-propanol, VUF 4702 was obtained as white crystals. The melting point was 155.7-156.6°C.

EXAMPLE 2

Synthesis of 4(5)-( -aminoalkyl) imidazole-derivatives. Analogous to the preparation method of VUF 4702 from example 1, a number of compounds were synthesized according to formula II, using the corresponding 1-chloro-ιΛ -iodoalkane. The meaning of n, the melting points and the exact mass results are given in the table below.

compound n melt, salt ex. mass ex. mass point (measured) (calcu¬ (°C) lated)

VUF 4701 4 129.0-134.0 di HBr 139.1112 139.1109

VUF 4702 5 155.7-156.6 diox. 153.1266 153.1266 VUF 4732 6 132.0 diox.

VUF 4733 8 95-100 diox.

VUF 4734 10 154.5-155.0 diox.

EXAMPLE 3 Synthesis of N-methyl-N'-[6-(4 (5)-imidazolyl)hexyl]thiourea oxalate (VUF 4740)

3 mmol VUF 4732 as dihydrobromic acid, was added to a solution of 6 mmol sodium dissolved in absolute ethanol. This solution was refluxed for one half hour, and the formed precipitate (after cooling to roomtemperature) was filtrated.

9.0 mmol methylisothiocyanate was added to the filtrate. After refluxing the reaction mixture for 2 hours, the ethanol was evaporated and the product was purified on a column packed with flash-silicagel with first ethylacetate as eluent (product stays on column : R_f = 0-0.1; methylisothiocyanate eluted R_f = 1.0). The product was subsequently eluted with methanol as eluent (R_f = 1.0) . The product was dissolved in ethylacetate and an excess of a saturated solution of oxalic acid in ethylacetate was added (slowly) . The formed precipitate was collected by centrifugation and washed with ethylacetate (three times) . After recrystalization from absolute ethanol, VUF 4740 was obtained as white crystals. The melting point was 106.5-110.0°C. EXAMPLE 4

Synthesis of N-substituted-N'-ftf-(4 (5) -imidazolyl) alkyl]- thiourea-derivatives.

Analogous to the preparation method of VUF 4740 from example 3, a number of compounds were synthesized according to formula III, using the corresponding 4 (5)-fl -aminoalkyl) - imidazole-derivative. The meaning of n, the melting points and the exact mass results are given in the table below.

compound n R melt, point (°C) salt ex. mass ex.mass (measured) (calculated)

VUF 4577 2 methyl 99.9-100.8 HBr 184.0782 184.0783

VUF 4578 2 ethyl 164.5- 165.0 HBr 198.0940 198.0939

VUF 4579 2 n-propyl 172.6- 173.1 HBr 212.1 100 212.1096

VUF 4580 2 i-propyl 123.1 ox 212.1090 212.1096

VUF 4581 2 cyclohexyl 161.7 ox 252.1401 252.1409

VUF 4582 2 phenyl 148.6-148.9 HBr 246.0931 246.0939

VUF 4583 2 benzyl 153.7-155.0 ox 260.1 101 260. 1096

VUF 4584 2 phenylethyl 145.1 - 145.5 ox 274. 1253 274.1252

VUF 4631 3 ethyl 1 16.1 ox 212. 1092 212.1096

VUF 4632 3 n-propy! 123.2- 125.2 ox 226. 1265 226.1252

VUF 4633 3 i-propyl 146.0 ox 226.127 1 226.1252

VUF 4634 3 cyclohexyl 102.2 ox 266.1 572 266. 1565

VUF 4635 3 phenyl 126.7 o 260.1 108 260.1096

VUF 4636 3 benzyl 1 17.2 ox 274. 1250 274.1252

VUF 4637 3 phenylethyl 125.5 ox 288.14 14 288. 1409 compound n R melt, point (°C) salt ex. mass ex. mass (measured) (calculated)

VUF 4681 4 ethyl 120.3 ox 226.1250 226.1252

VUF 4682 4 n-propyl 146.9 ox 240.1409 240.1409

VUF 4683 4 i-propyl 151.3 ox 240.1401 240.1409

VUF 4684 4 cyclohexyl 109.5 ox 280.1724 280.1722

VUF 4685 4 phenyl 153.7 ox 274.1251 274.1252

VUF 4686 4 benzyl 109.1 ox 288.1400 288.1409

VUF 4687 4 phenylethyl 130.8- 132.2 ox 302.1560 302.1565

VUF 4613 5 methyl 1 1 1.0 ox 226.1251 226.1252

VUF 4614 5 ethyl 77.6 o 240.1410 240.1409

VUF 4615 5 n-propyl 1 15.5- 1 16.6 ox 254.1563 254.1565

VUF 4616 5 i-propyl 97.1 ox 254.1563 254.1565

VUF 4617 5 cyclohexyl 1 16.5 ox 294.1875 294.1878

VUF 4618 5 phenyl 108.9 ox 288.1402 288. 1409

VUF 4619 5 benzyl 152.1 - 152.4 ox 302.1560 302.1565

VUF 4620 5 phenylethyl 1 18.5- 1 19.5 ox 3 16.1716 3 16.1722

VUF 4740 6 methyl 106.5-1 10.0 ox

VUF 474 I 6 phenyl 121.0-125.5 ox

EXAMPLE 5

Synthesis of N-benzyl-4-(l-dimethylsulfamoyl-5-imidazo- lyl)piperid-4-ol (VUF 4765) . 10.0 g. of l-(N,N-Dimethylsulfamoyl) imidazole (57 mmol) was dissolved in dry THF ( 150 ml) under an atmosphere of dry nitrogen and cooled to -70°C. n-Butyllithium in hexane (35 ml, 57 mmol) was added dropwise (temperature should not exceed -65°C) . After 15 min, a solution of trimethylsilyl chloride (6.2 g, 57 mmol) in dry THF was added and the solution was stirred at room temperature for 1 h. The mixture was cooled to -70°C again and n-butyllithium in hexane (35 ml, 57 mmol) was added dropwise (temperature should not exceed -65°C) . After 1 h, a solution of N-benzyl-4-piperidone (10.8 g, 5.7 mmol) in dry THF was added gradually and the mixture was allowed to (slowly) warm to room temperature overnight. The reaction mixture was poured into water and the THF was removed under reduced pressure. The product was extracted with CHCl₃ (3 x 150 ml) , dried (Na₂S0₄) and concentrated in vacuo.

EXAMPLE 6

Synthesis of 4-(1-dimethylsulfamoyl-5-imidazolyl)piperid- 4-ol (VUF 4764) . 1.0 gram of VUF 4765 (2.7 mmol) was dissolved in methanol. 0.1 gram Pd/C (10%) and 1 gram of ammoniumformate (16 mmol) was added and the mixture was refluxed for one hour. After filtration the product was concentrated in vacuo.

EXAMPLE 7

Synthesis of 4-(4 (5) -imidazolyl) 1,2, 3 , 6-tetrahydropyridine dihydrobromide (VUF 4736) .

8.5 gram of VUF 4764 was dissolved in 30% HBr and refluxed for 16 hours. The solution was evaporated in vacuo and the residue was refluxed in absolute ethanol. A white precipitate was collected by centrifugation and washed with acetone (three times) . The melting point was 271-275°C. EXAMPLE 8

Synthesis of 4-(4 (5) -imidazolyl)piperidine dihydrobromide (VUF 4735) .

1.0 gram of VUF 4736 was dissolved in methanol, 0.1 gram Pd/C (10%) was added and this mixture was hygrogenated for 16 hours with 20 at . of H₂ in an autoclave. The reaction mixture was filtrated, concentrated and washed with absolute ethanol. The melting point was 260-263°C.

EXAMPLE 9

Synthesis of 4-[ (1-dimethylsulfamoyl-5-imidazolyl)methyl]- piperidine oxalate (VUF 4709)

1.0 g. of l-(Ν,Ν-Dimethylsulfamoyl) imidazole (5.7 mmol) was dissolved in dry THF ( 50 ml) under an atmosphere of dry nitrogen and cooled to -70°C. n-Butyllithium in hexane (3.6 ml, 5.8 mol) was added dropwise (temperature should not exceed -65°C) . After 15 min, a solution of tert-butyl-dimethylsilyl chloride (0.9 g, 5.7 mmol) in dry THF (15 ml) was added (5 min) and the solution was stirred at room temperature for 1 h. The mixture was cooled to -70°C again and n-butyllithium in hexane (3.6 ml, 5.8 mmol) was added dropwise (temperature should not exceed -65°C) . After 0.5 h, a solution of 4-pyridinecarboxaldehyde (0.6 gram, 5.8 mol) in dry THF (15 ml) was added gradually and the mixture was allowed to (slowly) warm to room temperature overnight. The reaction mixture was poured into water (100 ml) and the THF was removed under reduced pressure. The product was extracted with CH₂C1₂ (3 x 150 ml) , dried (Na₂S0₄) and concentrated in vacuo. 11.53 gram (28.4 mmol) of the residue (made from a larger batch) was dissolved in 150 ml. of acetonitrile. 5.2 ml. of DBU (35 mmol) was added. 3.6 ml. acetic anhydride (38 mmol) was added after 10 min. and after 15 min. stirring at ambient temperature, the reaction mixture was concentrated in vacuo. The residue was dissolved in CH₂C1₂ and washed with H₂0 (three times) . The organic layer was dried on Na₂S0₄ and concentrated in vacuo. The product was purified by a column packed with flash-silicagel with ethylacetate as eluent (Rf on TLC = 0.51).

7.3 gram of the purified product (16.7 mmol) was dissolved in 50 ml. of acetic acid, 0.7 gram Pd/C (10%) was added and this mixture was hygrogenated for 16 hours with 50 atm. of H₂ in an autoclave. The reaction mixture was filtrated, concentrated and washed with absolute ethanol (2 times with 20 ml.). The hydrogenation was incomplete and repeated once more as described above. The residue was dissolved in H₂0 and the pH was raised to 12 by the addition of K₂C0₃ and extracted with CH₂C1₂. The organic layer was dried with Na₂S0₄ , concentrated under reduced pressure and dissolved in ethylacetate. An excess of a saturated solution of oxalic acid in ethylacetate was added (slowly) . The formed precipitate was collected by centrifugation and washed with ethylacetate (three times) . The melting point was 120.8-121.1°C.

EXAMPLE 10

Synthesis N-substituted-N'-[4-[1-dimethylsulfa oyl-

4(5) -imidazolyl)methyl]piperidine]thiourea.

Analogous to the preparation method of VUF 4740 from example 3, from VUF 4709, a number of compounds were synthesized with the formula :

The meaning of R, the melting points and the exact mass results are given in the table below. compound R melt.point ex.mass ex.mass

(°C) (measured) (calculated)

VUF 4711 methyl 131.7-134.5 VUF 4712 cyclo¬ hexyl 137.10138.8 EXAMPLE 11

Synthesis of 4-[ (4 (5) -imidazolyl)methyl]piperidine dihydrobromic acid (VUF 4708) .

5.5 gram (16.5 mmol) of VUF 4709 was refluxed in 30% HBr for 16 hours. The solution was concentrated under reduced pressure and the residue was dissolved and refluxed in absolute ethanol for one hour. This mixture was concentrated in vacuo and washed with acetone (three times) . The white crystals were collected and the melting point was 221.1-222.7°C.

EXAMPLE 12

Synthesis of N-substituted-N'-[4-[4 (5)-imidazolyl)methyl]- piperidine]thiourea. Analogous to the preparation method of VUF 4740 from example 3, from VUF 4708, a number of compounds were synthesized with the formula :

The meaning of R, the melting points and the exact mass results are given in the table below.

compound R melt. salt point (C°)

VUF 4713 methyl ox.

VUF 4714 cyclo¬ . 159.8-160.2 HBr hexyl

Table 1. ¹H NMR results of the compounds mentioned in the description.

VUF 4577 ( D₂0) : <5 2 . 87 ( s , 3H , CH₃) , 3 . 03 ( t , 2H , J=7

Hz , imidazole-CH₂ ) , 3 . 78 (t , 2H , J=7 Hz , CH₂ΝH) , 7.30 (s, 1H, imidazole-5 (4 ) H) , 8.62 (s, 1H, imidazole-2H) ppm.

VUF 4578 (D,0) δ 1.12 (t, 3H, J=7 HZ, CH₃) , 3.03 (t, 2H, J=7 Hz, imidazole-CH₂) , 3.32(q, 2H, J=7 HZ, CH₂CH₃) , 3.78 (t, 2H, J=7 Hz , CH₂NH) , 7.39 (s, 1H, imidazole-5 (4) H) , 8.62 (s, 1H, imidazole-2H) ppm

VUF 4579 (D₂0) : δ 0.88 (t, 3H, J=7 Hz, CH₃) , 1.53 (m, 2H, CH₂CH₃) , 3.04 (t, 2H, J=7 Hz , imidazole-CH₂) , 3.10-3.45 (m, 2H, CH₂CH₂CH₃ ) , 3.70-3.92 (m, 2H, CH₂NH) , 7.30 (s, 1H, imidazole-5(4)H) , 8.64 (s, 1H, imidazole-2H) ppm.

VUF 4580 (D,0) δ 1.01 (d, 6H, J=7 Hz, 2*CH₃) , 2.90 (t, 2H, J=7 Hz, imidazole-CH₂) , 3.58-3.75 (m, 2H, CH₂NH) , 3.75-4.10 (b s, 1H, CH) , 7.16 (s, 1H, imidazole-5(4)H) , 8.49 (s, 1H, imidazole-2H) ppm.

VUF 4581 (D_?0) δ 0.99-1.85 (m, 10H, CH₂) , 2.97 (t, 2H, J=7 Hz, imidazole-CH₂) , 3.50-3.90 (m, 3H, CH and CH₂NH) , 7.22 (s, 1H, imidazole-5(4)H) , 8.53 (s, 1H, imidazole-2H) ppm.

VUF 4582 (D₂0) <S 2.94-3.03 (m, 2H, imidazole-CH₂) , 3.75-3.97 (m, 2H, CH₂NH) , 7.11-7.57 (m, 6H, phenyl-H and imidazole-5(4)H) , 8.61 (s, 1H, imidazole-2H) ppm.

VUF 4583 (DMSO-d₆) δ 2.89 (t, 2H, J=7 Hz, imidazole-CH₂) , 3.59-3.83 (m, 2H, CH₂NH) , 4.53-4.77 (m, 2H, CH₂-phenyl) , 7.18-7.38 ( , 6H, phenyl-H and imidazole-4 (5) H) , 7.85-8.00 (m, 1H, NH) , 8.72 (t, 1H, J=6 Hz, NH) , 8.72 (s, IH, imidazole-2H) , 11.15-11.85 (m, NH and oxalate) ppm.

VUF 4584 (D,0) δ 2.66-2.91 (m, 4H, imidazole-CH₂ and CH₂-phenyl) , 3.32-3.80 (m, 4H, CH₂NH and CH₂CH₂-phenyl) , 7.15 (s, IH, imidazole-5(4)H) , 7.10-7.34 (m, 5H, phenyl-H) , 8.47 (s, IH, imidazole-2H) ppm.

VUF 4613 (D₂0) δ 1.31 (m, 2H, (CH₂CH₂) ₂CH₂) , 1.62 (m, 4H, (CH₂CH₂)₂CH₂) , 2.67 (t, 2H, J=7 Hz , imidazole-CH₂) , 2.82 (m, 3H, CH₃) , 3.33 (m, 2H, CH₂NH) , 7.14 (s, IH, imidazole-5(4)H) , 8.50 (s, IH, imidazole-2H) ppm.

VUF 4614 (D₂0) δ 1.12 (t, 3H, J=7 Hz, CH₃) , 1.35 (m, 2H, (CH₂CH₂)₂CH₂) , 1.65 (m, 4H, (CH₂CH₂)₂CH₂) , 2.72 (t, 2H, J=7 Hz, imidazole-CH₂) , 3.47 (m, 4H, CH₂NH) , 7.19 (s, IH, imidazole-5(4)H) , 8.55 (s, IH, imidazole-2H) ppm.

VUF 4615 (D,0) δ 0.82 (t, 3H, J=7 Hz, CH₃) , 1.30 (m, 4H, (CH₂CH₂)₂CH₂) + CH₂CH₃) , 1.60 (m, 4H, (CH₂CH₂)₂CH₂) , 2.67 (t, 2H, J=7 Hz, imidazole-CH₂) , 3.30 (m, 4H, CH₂NH) , 7.13 (s, IH, imidazole-5(4)H) , 8.50 (s, IH, imidazole-2H) ppm.

VUF 4616 (D_?0) δ 1.08 (s, 6H, CH₃) , 1.28 (m, 2H, (CH₂CH₂)₂CH₂) , 1.57 ( , 4H, (CH₂CH₂) ₂CH₂) 2.65 (t, 2H, imidazole-CH₂) , 3.32 (m, 2H, CH₂NH) , 4.00 (m, IH, CH) , 7.13 (s, IH, imidazole-5(4)H) , 8.47 (s, IH, imidazole-2H) ppm. VUF 4617 (D-,0) δ 1.05-2.05 (m, 16H, (CH₂CH₂)₂CH₂ + (CH₂CH₂)₂CH₂ + cyclohexyl-CH₂) , 2.73 (t, 2H, J=7 Hz, imidazole-CH₂) , 3.43 (m, 3H, CH₂NH + CHNH) , 7.22 (s, IH, imidazole-5(4)H) , 8.58 (s, IH, imidazole-2H) ppm.

VUF 4618 (D_?0) δ 1.35 (m, 2H, (CH₂CH₂) ₂CH₂) , 1.67 (m, 4H, (CH₂CH₂)₂CH₂) , 2.75 (t, 2H, J=7 Hz, imidazole-CH₂) , 3.53 ( , 2H, CH₂NH) , 7.37 (m, 6H, imidazole-5(4)H + phenyl-H) , 8.59 (s, IH, imidazole-2H) ppm.

VUF 4619 (D₂0) δ 1.27 (m, 2H, (CH₂CH₂)₂CH₂) , 1.60 (m, 4H, (CH₂CH₂)₂CH₂) , 2.67 (t, 2H, J=7 Hz, imidazole-CH₂) , 3.43 (m, 2H, CH₂NH) , 4.63 (m, 2H, CH₂-phenyl) , 7.17 (s, IH, imidazole-5(4)H) , 7.36 ( , 5H, phenyl-H) , 8.53 (s, IH, imidazole-2H) ppm.

VUF 4631 (D_?0) δ 1.12 (t, 3H, J=7 Hz, CH₃) , 1.95 (m, 2H, CH₂CH₂NH) , 2.77 (t, 2H, J=8 Hz, imidazole-CH₂) , 3.15-3.62 (m, 4H, CH₂NH) , 7.23 (s, IH, imidazole-5 (4 ) H) , 8.57 (s, IH, imidazole-2H) ppm.

VUF 4632 (D_P0) δ 0.87 (t, 3H, J=7 Hz, CH₃) , 1.53 (m, 2H, CH₂CH₃) , 1.97 (m,2H, CH-.CH₂NH) , 2.77 (t, 2H, J=7 Hz, imidazole-CH₂) , 3.10-3.65 (m, 4H, CH₂NH) , 7.23 (s, IH, imidazole-5(4)H) , 8.56 (s, IH, imidazole-2H) ppm.

VUF 4633 (D₂0) δ 1.13 (d, 6H, J=7 Hz, CH₃) , 1.94 ( , 2H, CH₂CH₂NH) , 2.77 (t, 2H, J=7 Hz, imidazole-CH₂) , 3.37-3.58 ( , 2H, CH₂NH) , 3.89-4.17 (m, IH, CH) , 7.23 (s, IH, imidazole-5(4)H) , 8.57 (s, IH, imidazole-2H) ppm.

VUF 4634 (D₂0) δ 0.93-1.97 (m, 12H, CH₂CH₂NH + 5*CH₂) , 2.70 (t, 2H, J=8 Hz, imidazole-CH₂) , 3.23-3.90 (m, 3H, CH₂NH + CHNH) , 7.18 (s, IH, imidazole-5(4)H) , 8.52 (s, IH, imidazole-2H) ppm.

VUF 4635 (D,0) δ 1.90 (m, 2H, CH₂CH₂NH) , 2.70 (t, 2H, J=7 Hz, imidazole-CH₂) , 3.39-3.65 (m, 2H, CH₂NH) , 7.27 (s, IH, imidazole-5(4)H) , 8.50 (s, IH, imidazole-2H) ppm.

VUF 4636 (D₂0) δ 1.84 (m, 2H, CH₂CH₂NH) , 2.39-2.79 (m, 2H, imidazole-CH₂) , 3.30-3.57 (m, 2H, CH₂NH) , 4.42-4.73 (m, 2H, CH₂~phenyl) , 7.10 (s, IH, imidazole-5(4)H) , 7.29 ( , 5H, phenyl-H) , 8.47 (s, IH, imidazole-2H) ppm.

VUF 4637 (D₂0) δ 1.73 (m, 2H, CH₂CH₂NH) , 2.58 (t, 2H, J=8 Hz, imidazole-CH₂) , 2.82 (t, 2H, J=7 Hz, CH₂-phenyl) , 3.10-3.44 (m, 2H, CH₂NH) , 3.44-3.79 (m, 2H, CH₂CH₂-phenyl) , 7.12 (s, IH, imidazole-5(4)H) , 7.16-7.36 (m, 5H, phenyl-H) , 8.49 (s, IH, imidazole-2H) ppm.

VUF 4681 (D,0) δ 1.08 (t, 3H, J=7Hz, CH₃) , 1.61 (m, 4H, CH₂CH₂) , 2.72 (t, 2H, J=7 Hz, imidazole-CH₂) , 3.22-3.51 (m, 4H, CH₂NH) , 7.17 (s, IH, imidazole-5 (4 ) H) , 8.52 .(s, IH, imidazole-2H) ppm. VUF 4682 (D₂0) δ 0.84 (t, 3H, J=7Hz, CH₃) , 1.42-1.78 (m, 6H, CH₂CH₃ + CH₂CH₂) , 2.73 (t, 2H, J=7 Hz, imidazole-CH₂) , 3.10-3.62 (m, 4H, CH₂NH) , 7.18 (s, IH, imidazole-5(4)H) , 8.53 (s, IH, imidazole-2H) ppm.

VUF 4683 (D,0) δ 1.16 (d, 6H, J=7 Hz, CH₃) , 1.65 (m, 4H, CH₂CH₂) , 2.76 (t, 2H, J=7 Hz, imidazole-CH₂) , 3.43 (m, 2H, CH-.NH) , 4.08 (m, IH, CH) , 7.21 (s, IH, imidazole-5(4)H) , 8.55 (s, IH, imidazole-2H) ppm.

VUF 4684 (DMSO-d,) δ 1.00-1.95 (m, 14H, CH₂CH₂ + cyclohexyl-CH₂) , 2.64 ( , 2H, imidazole-CH₂) , 3.37 ( , 2H, CH₂NH) , 3.93 (m, IH, CH₃) , 7.20 (s, IH, imidazole-5(4)H) , 7.28-7.62 (m, 4H, NH + C0₂H) , 8.50 (s, IH, imidazole-2H) ppm.

VUF 4685 (D,0) δ 1.59 (m, 4H, CH₂CH₂) , 2.70 (t, 2H, imidazole-CH₂) , 3.49 ( , 2H, CH₂NH) , 7.31 (m, 6H, imidazole-5 (4 ) H + phenyl-H) , 8.50 (s, IH, imidazole-2H) ppm.

VUF 4686 (DMSO-d,) 5 1.53 (m, 4H, CH₂CH₂) , 2.59 (t, 2H, J=7 Hz, imidazole-CH₂) , 3.40 (m, ^' 2H, CH₂NH) , 4.63 (m, 2H, CH₂-benzyl) , 7.13 (s, IH, imidazole-5(4)H) , 7.28 (m, 5H, phenyl-H), 7.71 ( , IH, N-H) , 7.99 (m, IH, N-H), 8.39 (s, IH, imidazole-2H) ppm.

VUF 4687 (DMSO-d,) <5 1.55 (m, 4H, CH₂CH₂) , 2.62 (t, 2H, J=7 Hz, imidazole-CH₂) , 2.78 (t, 2H, J=7 Hz, CH₂-phenyl) , 3.37 (m, 2H, CH₂NH) , 3.57 (m, 2H, CH₂CH₂-phenyl) , 7.27 (m, 6H, imidazole-5(4)H + phenyl-H) , 7.63 (m, 2H, N-H) , 8.67 (s, IH, imidazole-2H) ppm.

VUF 4701 (D,0) δ 1.77 (m, 4H, CH₂CH₂) , 2.80 (t, 2H, J=8 Hz, imidazole-4(5)-CH₂) , 3.06 (t, 2H, J=8 Hz, CH₂NH) , 7.28 (s, IH, imidazole-5(4)H) , 8.59 (s, IH, imidazole-2H) ppm.

VUF 4702 (D,0) δ 1.37 (m, 2H, (CH₂CH₂) ₂CH₂) , 1.63 (m, 4H, (CH₂CH₂)₂CH₂) , 2.68 (t, 2H, J=7 Hz , imidazole-CH₂) , 2.93 (t, 2H, J=7 Hz, CH₂NH) , 7.16 (s, IH, imidazole-5 (4) H) , 8.49 (s, IH, imidazole-2H) ppm.

VUF 4708 (D₂0) δ 1.48 (qd, 2H, J=13 , 3 Hz, 3 , 5-H_ax) , 1.94 (dm, 2H, J= 13 Hz, 3,5-H_eq) , 2.00 (m, IH, 4-H) , 2.72 (d, 2H, J=7 Hz, imidazole-CH₂) , 2.98 (t , 2H, J=13 Hz, 2,6-H_ax) , 3.41 (dm, 2H, J=13 Hz, 2,6-H_eq) , 7.28 (s, IH, imidazole-5 (4 ) H) , 8.59 (s, IH, imidazole-2H) ppm.

VUF 4709 (D,0) δ 1.47 (qm, 2H, J=13 Hz, 3,5-H_ax) , 1.97 (dm, 2H, J=14 Hz, 3,5-H_eq) , 2.03 (m, IH, 4-H) , 2.87 (d, 2H, J=7 Hz, imidazole-CH₂) , 2.97 (tm, 2H,^' J=13 Hz, 2,6-H_ax) , 3.04 (s, 6H, N(CH₃ )₂) , 3.42 (dm, 2H, J=13 Hz, 2,6 H_eq) , 7.43 (s, IH, imidazole-5H) , 9.16 (s, IH, imidazole-2H) ppm.

VUF 4711 (CDCl₃) δ 1.18 (qm, 2H, J=13 Hz, 3,5-H_Bx) , 169 (dm, 2H, J=13 Hz, 3 , 5-H_eq) , 1,88 (m, 2H, 4-H) , 2.62 (d, J=7 Hz, imidazole-CH₂) , 2.82 (s, 6H, N(CH₃ )₂) , 2.90 (t , 2H, J=13 Hz, 2,6-H_ax) , 3.07 (d, 3H, J=6 Hz, CH₃) , 4.58 (dm, 2H, J=13 Hz, 2,6-H_eq) , 6.04 (m, IH, NH) , 6.76 (s, IH, imidazole-5H) , 7.80 (s, IH, imidazole-2H) ppm.

VUF 4712 (CDCl,) <S 0.98-2.10 (m, 15H, CH(CH₂CH₂) ₂NH + (CH₂)₅), 2.63 (d, 2H, J=7Hz, Imidazole-CH₂) , 2.82 (s, 6H, NMe₂) , 2,88 (tm, 2H, J=13 Hz, 2 , 6-H_ax(pip) ) , 4.27 (m, IH, NHCH) , 4.54 (dm, 2H, J=13Hz, 2,6-H_eq(pip) ) , 5.46 (d, IH, J=7Hz, NH) , 6.78 (s, IH, Imidazole-5 H) , 7.80 (s, IH, (Imidazole-2 H) ) ppm.

VUF 4713 (D,0) δ 1.04-1.32 (m, 2H, 3 , 5-H_ax) , 1.72 (dm, 2H, J=14Hz, 3,5-H_eq) , 1,97 (m, IH, 4-H) , 2.64 (d, 2H, J=7Hz, Imidazole-CH₂) , 3,01 (s, 3H, CH₃) , 3,06 (tm, 2H, J=14 Hz, 2,6-H_ax) , 4.48 (dm, 2H, J=13Hz , 2,6-H_eq), 7.12 (s, IH, Imidazole-4 (5) H) , 8.28 (s, IH, Imidazole-2H) ppm.

VUF 4714 (D₂0) : δ 0.98-2.10 (m, 15H, CH ( CH₂CH₂ ) ₂NH + (CH₂)₅), 2.67 (d, 2H, J=7Hz, Imidazole-CH₂) , 3,00 (tm, 2H, J=13 Hz, 2,6-H_ax(pip)) , 4.10 (m, IH, NHCH) , 4.48 (dm, 2H, J=13Hz, 2 , 6-H_eq(pip) ) , 7.22 (s, IH, Imidazole-4(5)H) , 8.54 (s, IH, Imidazole-2H) ppm.

VUF 4732 (D₂0) δ 1.33 (m, 4H, (CH₂CH₂) ₂ (CH₂) ₂) , 1.61 (m, 4H, (CH₂CH₂)₂CH₂CH₂) , 2.68 (t, 2H, 3=1 Hz, imidazole-CH₂) , 2.93 (t, 2H, 3=1 Hz, CH₂NH) , 7.14 (s, IH, imidazole-5 ( 4 ) H) , 8.50 (s, IH, imidazole-2H) ppm. VUF 4733 (D₂0) δ 1.38 (m, 8H, (CH₂CH₂)₂(CH₂)₄) , 1.60 (m, 4H, (CH₂CH₂)₂(CH₂) ) , 2.66 (t, 2H, 3=1 Hz, imidazole-CH₂) , 2.93 (t, 2H, 3=1 Hz, CH₂NH) , 7.13 (s, IH, imidazole-5 (4)H) , 8.49 (s, IH, imidazole-2H) ppm.

VUF 4734 (D₂0) δ 1.27 (m, 12H, (CH₂CH₂) ₂ (CH₂) ₆) , 1.62 (m, 4H, (CH₂CH₂)₂(CH₂)₆) , 2.67 (t, 2H, 3=1 Hz, imidazole-CH₂) , 2.94 (t, 2H, 3=1 Hz, CH₂NH) , 7.14 (s, IH, imidazole-5 (4 ) H) , 8.50 (s, IH, imidazole-2H) ppm.

VUF 4735 (D₂0) δ 2,03 (m, 2H, 3,5-H_ax) , 2,39 (dm, 2H, J=13 Hz, 3,5-H_eq) , 3.29 (m, 3H, 2,6-H_ax + 4-H) , 3,63 (dm, 2H, J=13 Hz, 2,6 H_eq) , 7.48 (s, IH, imidazole-5(4)H) , 8.77 (s, IH, imidazole-2H) ppm.

VUF 4736 (D₂0) δ 2.72 (Ξ, 2H, CH₂-CH₂-N) , 3.56 (t, 2H, J = 7 Hz, N-CH₂-CH₂) , 3.98 (s, 2H, N-CH₂-CH) , 6.36 (s, IH, CH) , 7.59 (s, IH, imidazole-4(5)H) , 8.73 (s, IH, imidazole-2H) ppm.

VUF 4740 (D_?0) δ 1.20-1.78 (m, 8H, CH2-(CH₂)₄-CH₂) , 2.72 (t, 2H, J = 7Hz, imidazole-CH₂) , 2.90 (s, 3H, CH₃) , 3.18-3.58 ( , 2H, CH₂NH) , 7.18 (s, IH, imidazole-4 (5)H) , 8.53 (s, IH, imidazole- 2H) ppm.

VUF 4741 (D,0) δ 1.22-1.79 (m, 8H, im-CH₂~ (CH₂) _A~CH₂) , 2.70 (t, 2H, J = 7 Hz, imidazole-CH₂) , 3.34-3.59 (m, 2H, CH₂NH) , 7.09-7.52 (m, 6H, phenyl-H + imidazole-4 (5) H) , 8.50 (s, IH, imidazole-2H) ppm.

VUF 4764 (D,0) δ 2.12-2.28 ( , 4H, CH₂CH-NH) , 2.79 (s, 6H, (CH₃)₂N) , 3.36-3.56 ( , 5H, CH₂CH₂NH + CHOH), 4.36 (s, 2H, CH₂~phenyl) , 7.40 (s, IH, imidazole-5H) , 7.48 (s, 5H, phenyl-H), 8.64 (s, IH, imidazole-2H) ppm.

VUF 4765 (D₂0) δ 1.98-2.31 (m, 4H, CH₂CH₂ΝH) , 2.52 (s, 6H, (CH₃)₂N) , 3.16-3.42 (m, 5H, CH₂CH₂NH + CHOH) , 7.17 (s, IH, imidazole-5H) , 7.87 (s, IH, imidazole-2H) ppm.

Pharmacological experiments

The agonistic and antagonistic activities on the histamine H₃ receptor of the various compounds were determined with a test system, described in Vollinga et al., Meth. Find. Clin. Exp. Pharmacol., 14(10), p. 747-751 (1992) .

The results of the experiments are given in the tables 2 and 3 below. pD₂ is the negative value of the concentration of the test compound at which 50% agonistic activity was measured. pA₂ is the negative logarithm of the concentration 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 the active ingredient for therapeutically influencing the human and animal histaminergic system have the form of powders, suspensions, solutions, sprays, emulsions, unguents or creams and can be used for local application, intranasal, rectal, vaginal and also for oral or parenteral (intravenous, intradermal, intramuscular, 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 pharmaceutically acceptable excipients with neutral character (such aquous or non-aquous solvents, stabilizers, emulsifiers, derergents, additives) , and further if neccesary colouring agents and flavouring agents.

The concentration of the active ingredient in a pharmaceutical composition can vary between 0.1% and 100%, depending on the nature of the influence and the method of administration. The dose of the active ingredient that is administered can further be varied between 0.1 mg and 100 mg per kg bodyweight. Table 2. Antagonistic activity

Compound pA₂

VUF 4613 8.0

VUF 4614 8.0

VUF 4615 7.7

VUF 4616 7.7

VUF 4617 7.5 VUF 4618 7.6

VUF 4619 7.7 VUF 4620 . 7.5

VUF 4680 7.0

VUF 4681 7.5 VUF 4682 7.4

VUF 4683 7.5

VUF 4684 7.2

VUF 4685 7.6

VUF 4686 6.8 VUF 4687 7.0

VUF 4701 7.7

VUF 4702 8.4

VUF 4732 7.8

VUF 4733 6.0 VUF 4734 6.0

VUF 4740 8.0

VUF 4741 7.9

Table 3. Agonistic activity

Compound pD₂

VUF 4708 8.0

Claims

1. Imidazole-derivatives of the general formula:

wherein : A is

1) a group of the formula (CH₂)_m, wherein m = 0-9; or

2) a group of the formula:.

wherein R⁵ represents hydrogen, (C,-C₃)alkyl-, aryl(C₁- C₃) alkyl-, aryl-, wherein aryl may optionally be substituted, hydroxyl-, (C^C_j) alkoxy-, halogen, amino-, cyano- or nitro; and R⁶ represents hydrogen, (C^C_j) alkyl-, aryl(C,-^)alkyl-, or aryl-, wherein aryl may optionally be substituted; or

3) a group of the formula:

R⁵ R⁵

I I

—C—C—

I I

R⁶ R⁶

wherein R^{5 a}nd R⁶ are as defined above; or

4) a group of the formula:

if B is a group of the formula: -<

such that A and B together form a group of the formula:

^R\ /^C=C\

wherein R⁶ is as defined above; or 5) a group of the formula:

wherein R⁶ is as defined above; or 6) a group of the formula:

if B is a group of the formula:

-<

such that A and B together form a group of the formula:

wherein R⁶ is as defined above; or 7) a group of the formula:

—(CH₂)_x-S-(CH₂)_y—

wherein x+y = m-1; B is 1) a group of the formula:

R⁵

I

—C— I

wherein R⁵ is as defined above; or 2) a group of the formula:

if A is a group of one of the formulas:

such that A and B together form a group of one of the formulas:

wherein R⁶ is as defined above; or 3) a group of the formula:

>= if X is a group of the formula:

H

<

(CH₂)_P—

such that B and X together form a group of the formula

wherein p = 1-3; or X is

1) a group of the formula (CH₂)_n, wherein n = 2-4; or

2) a group of the formula:

H =c

(CH₂)_P-

if B is a group of the formula:

>=

such that X and B together form a group of the formula:

\ ^H ^N(CH₂)_p—

wherein p = 1-3; or 3) two hydrogens (one on the carbon and one on the nitrogen) ; or 4) one hydrogen on the carbon atom and one R⁷ group on the nitrogen atom, wherein R⁷ represents hydrogen, (C,-C₁₀)alkyl-, aryl(C.- C₁₀) alkyl-, or aryl, wherein aryl may optionally be substituted;

Y is a group of the formula (CH₂)_k, wherein k = 0-2; R¹ represents hydrogen, (C^-C-.)alkylsulfonamide-, (C₁-C₃)- alkyl-, aryl(C,-C₃)alkyl- or aryl, wherein aryl may optionally be substituted; R² represents hydrogen, (C^C^)alkylsilyl-, (C,-^) alkyl-, aryl(C₁-C₃) alkyl- or aryl, wherein aryl may optionally be substituted; R³ represents hydrogen, halogen, amino-, nitro-, hydroxyl-, mercaptan, (C₁-C₃)alkoxy-, (C_j- _j)alkylsulfide-; R⁴ represents hydrogen, (C^-C^)alkyl-, (C₁-C₃) alkyl¬ sulfonamide-, aryl(C^C._g)alkyl-, aryl, wherein aryl may optionally be substituted; or a group of the formula :

X

or a group of the formula

X II

— C-NR⁷R7

wherein X represents 0, S, or NH, R⁷ is as defined as above;

R⁸ represents (C^C,,.)alkyl-, aryl(C,-C₁₀) alkyl- or aryl, wherein aryl may optionally be substituted and wherein aryl is phenyl, substituted phenyl, naphtyl, substituted naphtyl, pyridyl; or pharmacological acceptable salts thereof, excluding derivatives of one of the formulas:

wherein R' is hydrogen , methyl , ethyl ; and derivatives of the formulas :

S . ^(CH^ ^'NH2 / <^CH2)q -Nf+C-NH -R"

HN N H

^ _or \^>

wherein q is 2-5 and R" is hydrogen, (C,-C₃)alkyl, aryl or aryl(C₁-C₃)alkyl.

2. Imidazole derivatives of formula I, wherein A is a group of the formula (CH₂)_m, wherein m = 1-9, and 1) when X represents two hydrogens (one on the carbon and one on the nitrogen) ; B represents a group of the formula:

H

I

—C—

Y represents a group of the formula (CH₂)_k, wherein k = 0; or 2) when X represents one hydrogen on the carbon atom and one R⁷ group on the nitrogen atom, wherein R⁷ is as defined in claim 1;

B represents a group of the formula: H

I

— C—

Y represents a group of the formula (CH₂)_k, wherein k ^*= 0; and represents hydrogen, (C₁-C₃)alkyl-, aryl-

(C₁-C₃) alkyl- or aryl, wherein aryl may optionally be substituted; R³ represents hydrogen; and

R¹ and R⁴ are as defined in claim 1.

3. Imidazole derivatives of formula I, wherein A is a group of the formula (CH₂)_m, wherein m = 0, and 1) when B is a group of the formula:

R⁵

I

—C-— I

wherein R⁵ is as defined in calim 1;

X represents a group of the formula (CH₂)_n, wherein n = 2-4 and Y represents a group of the formula (CH₂)_k, wherein k = 0-2, with the restriction that n+k = 3 or 4; or 2) when B and X together form a group of the formula:

wherein p = 1-3, Y represents a group of the formula (CH₂)_k, wherein k = 0-2, with the restriction that p+k = 2 or 3 ; R >3-^*- represents hydrogen; and

R¹ , R² and R⁴ are as defined in claim 1.

4. Imidazole derivatives of formula I, wherein: when A is a group of the formula: R⁵

I

-C—

I

R⁶

wherein R⁵ and R⁶ are as defined in claim 1 ; B represents a group of the formula :

R⁵

I

—C—

wherein R⁵ is as defined in claim 1; X represents a group of the formula (CH₂)_n, wherein n = 2-4; and

Y represents a group of the formula (CH₂)_k, wherein k = 0-2, with the restriction that n+k = 3 or 4; and R¹, R², R³ and R⁴ are as defined in claim 1.

5. Imidazole derivatives of formula I, wherein A is a group of the formula:

wherein R⁵ and R⁶ are as defined in claim 1; B represents a group of the formula:

R⁵

I

—C—

wherein R⁵ is as defined in claim 1; X represents a group of the formula (CH₂)_n, wherein n = 2-4; Y represents a group of the formula (CH₂)_k, wherein k = 0-2, with the restriction that n+k = 3 or 4; R³ represents hydrogen; and R¹ , R² and R⁴ are as defined in claim 1.

6. Imidazole derivatives of formula I, wherein when A and B together form a group of the formula:

wherein R⁶ is as defined in claim 1; X represents a group of the formula (CH₂)_n, wherein n = 2-4; Y represents a group of the formula (CH₂)_k, wherein k = 0-2, with the restriction that n+k = 3 or 4; R³ represents hydrogen; and R¹, R² and R⁴ are as defined in claim 1.

7. Imidazole derivatives of formula I, wherein when A is a group of the formula:

wherein R⁶ is as defined in claim 1; B represents a group of the formula:

R⁵

I

—C—

wherein R⁵ is as defined in claim 1; X represents a group of the formula (CH₂)_n, wherein n = 2-4; Y represents a group of the formula (CH₂)_k, wherein k = 0-2, with the restriction that n+k = 3 or 4; R³ represents hydrogen; and R¹, R² and R⁴ are as defined in claim 1.

8. Imidazole derivatives of formula I, when A and B together form a group of the formula:

wherein R⁶ is as defined above; X represents a group of the formula (CH₂)_n, wherein n = 2-4; Y represents a group of the formula (CH₂)_k, wherein k = 0-2, with the restriction that n+k = 3 or 4; R³ represents hydrogen; and

R , R² and R⁴ are as defined in claim 1.

9. Imidazole derivatives of formula I, wherein A is a group of the formula - (CH₂)_χ - S - (CH₂)_X -, wherein x+y = m-1, and 1) when X represents two hydrogens (one on the carbon and one on the nitrogen) ; B represents a group of the formula:

H

I —C—

Y represents a group of the formula (CH₂)_k, wherein k = 0; or 2) when X represents one hydrogen on the carbon atom and one R⁷ group on the nitrogen atom, wherein R⁷ is as defined in claim 1; B represents a group of the formula:

Y represents a group of the formula (CH₂)_k, wherein k = 0; and

R² represents hydrogen, (C.-C₃) alkyl-, aryl-

R¹ and R⁴ are as defined in claim 1.

10. Imidazole derivative as claimed in claim 2 having the formula/wherein the derivative is Ν-methyl- Ν ' - [ 6- ( 4 ( 5) -imidazolyl) hexyl] thiourea .

11. Pharmaceutical composition having agonistic or antagonistic activity on the histamine H₃-receptor comprising a suitable excipient and as the active ingredient an imidazole derivative of the formula I

wherein the substituents are as defined in claim 1, excluding the derivatives of the formulas

and derivatives of the formulas

wherein R ¹ is hydrogen , methyl , ethyl ;

12. Pharmaceutical composition as claimed in claim 11, wherein the active ingredient is a derivative of the formulas

^(CH₂)_n -NH,

___^^(CH₂)_n -NHC-_NH-R⁷

HN N

N*^ or HN j .N

wherein n is 5 or 6 and R⁷ is hydrogen, (C^C^) alkyl-, aryl(C,-^)alkyl-, or aryl, wherein aryl may be optionally be substituted.

13. Pharmaceutical composition as claimed in claim 11 or 12, wherein the active ingredient is 4 (5) -(5- aminopentyl)-imidazole or 4 (5)-(6-aminohexyl) -imidazole.

14. Pharmaceutical composition as claimed in claim 11 or 12, wherein the active ingredient is N-methyl-N'-[5-

(4 (5)-imidazolyl)pentyl]thiourea or N-methyl-N'-[6-(4 (5)- imidazolyl)hexyl]thiourea.

15. Pharmaceutical composition as claimed in claim 11 or 12, wherein the active ingredient is 4-(4 (5)- i idazolyl-methyl)piperidine.

16. Method of preparing imidazole derivatives as defined in claim 11, by C5-lithiation of a 1, 2-diprotected imidazole and subseguent treatment thereof with a suitable electrophile.

17. Method as claimed in claim 16, wherein the electrophile is a halogen, aldehyde, keton, nitrile, epoxide or acylhalide.

18. Use of the derivatives as defined in claim 11 as a biological active agent.

19. Use of the derivatives as defined in claim 11 as an agent having agonistic or antagonistic activity on the histamine H₃-receptor.

20. Use of derivatives as defined in claim 11 as a pharmaceutical composition showing agonistic or antagonistic activity on the histamine H₃-receptor.

21. Use of the derivatives as defined in claim 11 as a medicament for the treatment of H₃-receptor related disorders.

22. Use of the derivatives as defined in claim 11 for the preparation of a pharmaceutical composition showing agonistic or antagonistic activity on the histamine H₃- receptor.

23. Use of the derivatives as defined in claim 11 for the preparation of a medicament for the treatment of H₃- receptor related disorders.