Histamine derivative, process for preparing it and its therapeutic use

The present invention relates to .alpha.,.beta.-dimethylhistamine, of the rmula: ##STR1## in racemic form, or an optical isomer form or mixture of diastereoisomers and its acid addition salts. It may be prepared from an alkyl 2-amino 3-(1H-imidazol-4-yl)-carboxylate.

The present invention relates to a new histamine derivative, a process for 
preparing it and to pharmaceutic compositions containing it. 
The above patent is concerned more particularly with compounds known as 
such, but whose agonist properties on the H.sub.3 receptors inducing 
release and synthesis of histamine were discovered. 
It has now be found that .alpha.,.beta.-dimethylhistamine, which compound 
is comprised in formula I above but has never been disclosed, has an 
agonist activity on the H.sub.3 receptors which is more selective and 
generally higher than for the other compounds of this structure. 
The present invention relates to .alpha.,.beta.-dimethylhistamine, of the 
formula: 
##STR3## 
in racemic form, or an optical isomer form or a mixture of 
diastereoisomers, and its addition salts with pharmaceutically acceptable 
acids. 
This compound having two asymmetric carbon atoms in its side chain exists 
in the form of 4 optical isomers. 
A process for preparing the compound of the invention is characterized in 
that a (C.sub.1 -C.sub.6)alkyl 2-amino 3-(1H-imidazol-4-yl)-butyrate is 
reduced by means of a metal hydride into 2-amino 
3(1H-imidazol-4-yl)-butanol, said butanol derivative is transformed into 
2-amino 1-chloro 3-(1H-imadazol-4-yl)-butane by means of a chlorinating 
agent, and said chloro derivative is catalytically reduced. 
The alkyl (e.g. methyl) 2-amino 3-(1H-imidazol-4-yl)-butyrate starting 
product in his process may be prepared for example from 
(1-triphenylmethyl-1H-imidazol-4-yl)carbaldehyde according to J. L. 
Kelley, C. A. Miller and Ed. W. Mc Lean, J. Med. Chem 20, 721 (1977), and 
the latter compound is available from (1H-imidazol-4-yl)methanol according 
to P. Dziuron and W. Schunack, Arch. Parm. (Weinheim, W. Germany) 306, 347 
(1973), and M. Barnabe and A. Burger, J. Med. Chem. 14, 883 (1971). 
The invention provides also a sterospecific process for preparing the 
compound of the invention, characterized in that a (C.sub.1 -C.sub.6)alkyl 
(1H-imidazol-4-yl)-carboxylate, the imidazole moiety of which has been 
protected (e.g. by a triphenylmethyl group), is transformed into erythro 
-.alpha., .beta.-dimehtylhistamine and the (+) and (-) enantiomers of this 
erythro compound are separated by means of an optically active acide.

The following Example shows the synthesis of the compound of the invention 
in the racemic form, namely from step i). 
EXAMPLE 1 
Preparation of [3-(1H-Imidazol-4-yl)but2-yl]amine or 
.alpha.,.beta.-dimethylhistamine 
##STR4## 
a) (1H-Imidazol-4-yl)methanol 
52.06 g (0.5 mol) formamidine acetate and 45.04 g (0.5 mol) 
1.3-dihydroxypropan-2-one are added in portions to 250 ml of liquid 
ammonia. The mixture is filled into a steelbomb and allowed to react for 
12 hours at 40.degree. C., 10 bar. Subsequently the mixture is delivered 
from the ammonia by evaporation. The resulting yellow sirup is dissolved 
in 500 ml 2-propanol and brought to pH 2 by dry HCl-gas. The voluminous 
precipitation is filtered off and extracted with 500 ml hot 2-propanol in 
3 portions. An addition of 200 ml diethyl ether to the combined filtrates 
and storing at -25.degree. C. results 57.1 g (84.9%) 
(1H-imidazol-4-yl)methanol hydrochloride, light brown crystals, melting 
point: 102.degree. C. 
C.sub.4 H.sub.6 N.sub.2 O.HCl (134.6) 
MS: m/z (rel. int. [%])=98 (M.sup.+, 47), 97 (53), 70 (15), 69 (44), 17 
(100). 
.sup.1 H-NMR data: ([D.sub.6 ]DMSO, TMS as internal standard) .delta.=4.51 
(s) 2H, 7.47 (d) 1H, 9.02 (d) 1H, ppm. 
b) (1-Triphenylmethyl-1H-imidazol-4-yl)methanol 
To a stirred solution of 18.8 g (140 mmol) (1H-imidazol-4-yl)methanol in 
140 ml dimethylformamide and 50 ml triethylamine 40.5 g (145 mmol) 
triphenylmethylchloride in 300 ml dimethylformamide are dropped. After 
stirring for 2 hours at ambient temperature the reaction mixture is poured 
upon 2 kg of crushed ice. The precipitate is washed with water and 
impurities are removed by digestion with 400 ml warm dioxane. Collection, 
washing with diethyl ether and drying in vacuo yields 41 g (86%) of 
(1-Triphenylmethyl-1H-imidazol-4-yl)-methanol as a white powder, melting 
point: 224.degree.-227.degree. C. 
C.sub.23 H.sub.20 N.sub.2 O (340.4) 
MS: m/z (rel. int. [%])=340 (M.sup.+., &lt;1), 243 (100), 165 (64). 
.sup.1 H-NMR data: ([D.sub.6 ]DMSO, TMS as internal standard) .delta.=3.14 
(br) 1H, replaceable by D.sub.2 O, 4.56 (s) 2H, 6.77 (d) 1H, 7.20-7.40 (m) 
15H, 7.55 (d) 1H, ppm. 
c) (1-Triphenylmethyl-1H-imidazol-4-yl)carbaldehyde 
68.1 g (0.2 mol) (1-triphenylmethyl-1H-imidazol-4-yl)-methanol and 177.9 g 
(2 mol) manganese dioxide are refluxed for 3 hours in 1.3 l dioxane. The 
hot suspension is filtered over 100 ml Celite in a Buchner funnel and 
washed with 0.5 l hot dioxane in three portions. The solution is 
evaporated in vacuo and the white solid residue dried in vacuo. Yield: 
49.1 g (72.5%), melting point: 188.degree.-193.degree. C. 
C.sub.23 H.sub.18 N.sub.2 O (338.4) 
MS: m/z (rel. int. [%])=338 (M.sup.+, &lt;1), 243 (100), 165 (56). 
.sup.1 H-NMR data: ([D.sub.6 ]DMSO, TMS as internal standard) 
.delta.=7.01-7.43 (m) 15H, 7.53 (d) 1H, 7.61 (d) 1H, 9.87 (s) 1H, ppm. 
d) 1-(1-Triphenylmethyl-1H-imidazol-4-yl)ethanol 
To a freshly prepared solution of 290 mmol methyl magnesium iodide in 700 
ml diethyl ether 49.1 g (145 mmol) 
(1-triphenylmethyl-1H-imidazol-4-yl)-carbaldehyde in 200 ml 
tetrahydrofurane is dropped. The mixture is allowed to react 2 hours at 
ambient temperature, subsequently a solution of 19.4 g (0.36 mol) ammonium 
chloride in 70 ml water is added. After stirring overnight the precipitate 
is removed by filtration and washed with 300 ml tetrahydrofurane. The 
combined filtrates are diluted with 300 ml diethyl ether and washed with 
water. The organic phase is dried over sodium sulphate. Evaporation yields 
46.5 g (90.4%) of 1-(1-triphenylmethyl-1H-imidazol-4-yl)-ethanol as a 
white powder, melting point: 156.degree.-157.degree. C. 
C.sub.24 H.sub.22 N.sub.2 O (354.5) 
MS: m/z (rel. int. [%])=354 (M.sup.+,&lt;1), 243 (100), 165 (50). 
e) 1-Chloro-1-(1H-imidazol-4-yl)ethane 
46.1 g (130 mmol) 1-(1-triphenylmethyl-1H-imidazol-4-yl)ethanol are solved 
in 500 ml 2N hydrochloric acid and heated at 70.degree. C. for 1 hour. The 
precipitate is removed by filtration. The solution is washed with 300 ml 
diethyl ether in 2 portions and evaporated in vacuo to afford 
1-(1H-imidazol-4-yl)ethanol hydrochloride.sup.3) as a faintly yellow oil. 
100 ml thionyl chloride are dropped to the oil at 0.degree. C., and the 
solution is allowed to react at ambient temperature overnight. Evaporation 
and crystallization with diethyl ether/ethylene glycole dimethyl ether 
affords 19.1 g (88%) of 1-chloro-1-(1H-imidazol-4-yl)ethane hydrochloride. 
Yellow crystals, melting point: 101.degree.-104.degree. C. 
C.sub.5 H.sub.7 ClN.sub.2.HCl (167) 
MS: m/z (rel. int. [%]=130 (M.sup.+, 1), 95 (72), 94 (74), 38 (100). 
.sup.1 H-NMR data: ([D.sub.6 ]DMSO, TMS as internal standard) .delta.=1.88 
(d) 3H, 5.51 (q) 1H, 
7.77(d) 1H, 
9.19 (d) 1H, ppm. 
f) Diethyl 
2-acetamido-2-[1-(1H-imadazol-4-yl)ethyl]propane-1.3-dicarboxylate 
11.9 g (55 mmol) diethyl acetamidomalonate are added to a solution of 105 
mmol sodium ethylate in 100 ml ethanol. After stirring for 2 hours the 
solution is cooled to 0.degree. C. and 8.4 g (50 mmol) 
1-chloro-1-(1H-imidazol-4-yl)ethane hydrochloride are added. The mixture 
is stirred for 2 hours, concentrated in vacuo and solved in 100 ml of 2% 
hydrochloric acid. This solution is extracted with 50 ml diethyl ether, 
brought to pH 8 by addition of sodium carbonate and extracted with 200 ml 
methylene chloride in 4 portions. The methylene chloride layers are 
combined, dried over sodium sulphate and evaporated in vacuo, affording 
13.8 g (88.7%) diethyl 
2-acetamido-2-[1-(1H-imidazol-4-yl)ethyl]propane-1.3-dicarboxylate as a 
light brown oil. 
C.sub.14 H.sub.21 N.sub.3 O.sub.5 (311.3) 
MS: m/z (rel. int. [%])=311 (M.sup.+,48), 252 (60), 238 (43), 196 (54), 174 
(42), 160 (56), 148 (61), 96 (79), 95 (90), 29 (100). 
.sup.1 H-NMR data: ([D.sub.6 ]DMSO, TMS as internal standard) d=0.99-1.44 
(m) 9H, 1.95 (s) 3H, 3.62-4.14 (m) 5H, 6.84-6.96 (m) 1H, 7.69 (d) 1H, 7.98 
(br) 1H, replaceable by D.sub.2 O, ppm. 
g) 2-Amino-3-(1H-imidazol-4-yl)butyric acid 
13.1 g (42 mmol) diethyl 
2-acetamido-2-[1-(1H-imidazol-4-yl)ethyl]propane-1.3-dicarboxylate are 
heated under reflux for 12 hours in 100 ml concentrated hydrochloric acid. 
After cooling and evaporation in vacuo 9.8 g (96%) of 
2-amino-3-(1H-imidazol-4-yl)butyric acid dihydrochloride are obtained as a 
foam. 
C.sub.7 H.sub.11 N.sub.3 O.sub.2.2HCl (242.1) 
.sup.1 H-NMR data: ([D.sub.6 ]DMSO, TMS as internal standard) 
.delta.=1.32-1.42 (m) 3H, 3.61-3.69. (m) 1H, 4.36-4.46 (m) 1H, 7.54 (d) 
1H, 8.5-9.1 (br) 3H, replaceable by D.sub.2 O, 9.16 (d) 1H, 14.75 (br) 2H, 
replaceable by D.sub.2 O, ppm. 
h) Methyl 2-amino-3-(1H-imidazol-4-yl)butyrate 
9.40 g (38.9 mmol) of 2-amino-3-(1H-imidazol-4-yl)butyric acid 
dihydrochloride are solved in 100 ml methanol. Dry HCl-gas is bubbled 
through the solution while heating under reflux for 4 hours. After cooling 
the excess hydrochloric acid is removed by evaporation in vacuo. Yield: 
9.8 g (98%) methyl 2-amino-3-(1H-imidazol-4-yl)butyrate hydrochloride as 
an amorphous solid. 
C.sub.8 H.sub.13 N.sub.3 O.sub.2.2HCl (256.1) 
MS: m/z (rel. int. [%])=183 (M.sup.+,&lt;1), 124 (20), 109 (6), (94), 95 
(100). 
.sup.1 H-NMR data (base): ([D.sub.6 ]DMSO, TMS as internal standard) 
.delta.=1.09-1.27 (m) 3H, 2.89-3.72 (m) 5H, 5.84 (br) 2H, replaceable by 
D.sub.2 O, 6.76 (d) 1H, 7.49 (d) 1H, ppm. 
i) 2-Amino-3-(1H-imidazol-4-yl)butanol 
7.7 g (30 mmol) methyl 2-amino-3-(1H-imidazol-4-yl)butyrate hydrochloride 
are added at 0.degree. C. to a stirred suspension of 3.4 g (90 mmol) 
lithium aluminium hydride in 125 ml tetrahydrofurane. Subsequently, the 
mixture is refluxed for 3 hours, cooled to 0.degree. C. and and hydrolysed 
by addition of 6.5 ml water in 15 ml tetrahydrofurane. Stirring with 20 ml 
5N sodium hydroxide solution affords a coarse-grained precipitate which is 
filtered off and extracted by means of 100 ml ethanol in 3 portions. 
Concentration of the fractions affords an oil which is treated with 
anhydrous ethanol to separate inorganic material. Filtration and 
evaporation yield 4 g (85.9%) 2-amino-3-(1H-imidazol-4-yl)butanol wich is 
converted into the oily dihydrochloride. An analytical sample is converted 
into dipicrate and recrystallized from ethanol/water. Yellow crystals, 
melting point 168.degree. C. 
C.sub.7 H.sub.13 N.sub.3 O.2 C.sub.6 H.sub.3 N.sub.3 O.sub.7 (613.4) Molar 
mass 155 (FAB-MS) Calc.: C 37.20, H 3.12, N 20.55, Found: C 37.23, H, 
3.08, N 20.40. 
.sup.1 H-NMR data: ([D.sub.6 ]DMSO, TMS as internal standard) .delta.=1.32 
(m) 3H, 3.26-3.79 (m) 5H, 1H replaceable by D.sub.2 O, 7.49-7.56 (m) 1H, 
7.87 (br) 3H, replaceable by D.sub.2 O, 8.63 (s) 4H, 9.12 (d) 1H, ppm. 
j) 2-Amino-1-chloro-3-(1H-imidazol-4-yl)butane 
3 g (13.2 mmol) 2-amino-3-(1H-imidazol-4-yl)butanol dihydrochloride are 
solved in a mixture of 25 ml tetramethylenesulfone and 10 ml thionyl 
chloride and stirred 12 hours at room temperature. Dropwise addition of 
200 ml chloroform affords 2-amino-1-chloro-3-(1H-imidazol-4-yl)butane 
dihydrochloride. Yield: 2.87 g (88.2%) of a hygroscopic precipitate. 
C.sub.7 H.sub.12 ClN.sub.3.2HCl (246.6) 
MS: m/z (rel. int. [%])=173 (M.sup.30 , &lt;1), 137 (7), 96 (98), 95 (100). 
.sup.1 H-NMR data: ([D.sub.6 ]DMSO, TMS as internal standard) .delta.=1.37 
(d) 3H, 3.42-3.55 (m) 1H, 3.77-3.86 (m) 1H, 4.03 (d) 2H, 7.49-7.56 (m) 1H, 
8.75 (br) 3H, replaceable by D.sub.2 O, 9.15 (d) 1H, 14.7 (br) 2H, 
replaceable by D.sub.2 O, ppm. 
An analytical sample is converted into the dipicrate, yellow crystals, 
melting point 196.degree.-198.degree. C. from ethanol/water. 
C.sub.7 H.sub.12 ClN.sub.3.2 C.sub.6 H.sub.3 N.sub.3 O.sub.7 (631.9) Calc.: 
C 36.12; H 2.87; N 19.95; Found: C 36.25; H 2.76; N 19.86. 
k) [3-(1H-Imidazol-4-yl)but-2-yl]amine (R.S:R.S) 
A mixture of 2 g (8.1 mmol) 2-amino-1-chloro-3-(1H-imidazol-4-yl)butane 
dihydrochloride, 1.3 g (16.2 mmol) sodium acetate and 100 ml 10% acetic 
acid, are hydrogenated over 0.5 g 10% palladium on activated carbon for 10 
days at 10 bar and ambient temperature. The catalyst is removed by 
filtration and the filtrate brought to pH 1 by addition of concentrated 
hydrochloric acid. After evaporation the oily residue is dissolved in dry 
ethanol and inorganic material is removed by filtration. By addition of 
petrolether the title compound crystallizes as dihydrochloride. 
Recrystallization from methanol/acetonitrile yields 0.72 g (40.4%) 
[3-(1H-imidazol-4yl)but-2-yl]amine.2HCl.0.25 methanol as colorless 
crystals, melting point: 249.degree.-254.degree. C. (decomp.). 
C.sub.7 H.sub.13 N.sub.3.2 HCl.0.25 CH.sub.4 O (220.1) Calc.: C 39.56; H 
7.33; N 19.09; Found: C 39.50; H 7.40; N 19.15. 
MS: m/z (rel. int. [%])=140 (11), 139 (M.sup.+, 1), 124 (14), 96 (95), 81 
(35), 44 (100). 
.sup.1 H-NMR data: ([D.sub.6 ]DMSO, TMS as internal standard) 
.delta.=1.10-1.36 (m) 6H, 3.28 (m) 1H, 3.40 (m) 1H, 7.51-7.58 (m) 1H, 8.36 
(br) 3H, replaceable by D.sub.2 O, 9.12 (d) 1H, 14.76 (br) 2H, replaceable 
by D.sub.2 O,ppm 
EXAMPLE 2 
Preparation of (-)- and (+)-erythro-[3-(1H-Imidazol-4-yl)but-2-yl]amine 
1) Methyl (1H-imidazol-4-yl) carboxylate 
112.09 g (1 mol) (1H-imidazol-4-yl)carboxylic acid are added to 1.3 l 
methanol. Dry HCl-gas is bubbled through the mixture which is heated under 
reflux for 4 hours. Cooling to room temperature and evaporation to 300 ml 
afford 98 g of the title compound as white crystals. Repeated evaporation 
leads to 46.5 g additional material (total: 144.5 g, 88.9%). An analytical 
sample is recrystallized from methanol, melting point: 
173.degree.-174.degree. C. (ref..sup.1) mp: 156.degree. C.). 
C.sub.5 H.sub.6 N.sub.2 O.sub.2.HCl (162.6) Calc.: C 36.94; H 4.34; N 
17.23; Found: C 36.93; H 4.44; N 17.23. 
MS: m/z (rel.int. [%])=126 (M.sup.+, 63), 95 (100), 67 (41), 40 (68). 
.sup.1 H-NMR data: ([D6]DMSO, TMS as internal standard) .delta.=12.97 (br) 
2H, replaceable by D.sub.2 O, 9.29 (d) 1H, 8.37 (d) 1H, 3.90 (s) 3H, ppm. 
m) Methyl (1-triphenylmethyl-1H-imidazol-4-yl)carboxylate 
To a solution of 151.79 g (1.5 mol) triethylamine in 1 l methylene chloride 
97.55 g (0.6 mol) methyl (1H-imidazol-4-yl)carboxylate are added. After 
stirring for 1 hour at ambient temperature a solution of 183.99 g (0.66 
mol) triphenylmethylchloride in 500 ml methylene chloride is dropped to 
the mixture, which subsequently is allowed to react for 1 hour. When the 
reaction is completed the mixture is washed 4 times with 200 ml water, 
dried by means of sodium sulphate and evaporated to dryness. The resulting 
oil crystallizes on standing overnight. Pulverizing and washing 3 times 
with 200 ml warm diethyl ether lead to 210.2 g (95.1%) methyl 
(1-triphenylmethyl-1H-imidazol-4-yl)carboxylate as light yellow crystals. 
An analytical sample was recrystallized from methanol resulting white 
crystals, melting point: 147.degree.-152.degree. C. (ref..sup.2) 
145.degree.-146.degree. C.). 
C.sub.24 H.sub.20 N.sub.2 O.sub.2 (368.5) Calc.: C 78.24; H 5.47; N 7.60; 
Found: C 77.96; H 5.23; N 7.66. 
MS: m/z (rel. int. [%])=368 (M.sup.+, 30), 258 (100). 
.sup.1 H-NMR data: (CDCl.sub.3, TMS as internal standard) .delta.=7.58 (d) 
1H 7.47-7.01 (m) 16H, 3.85 (s) 3H, ppm. 
n) Ethyl 3-oxo-3-(1-triphenylmethyl-1H-imidazol-4-yl)propionate 
202.65 g (0.55 mol) methyl (1-triphenylmethyl-1H-imidazol-4-yl)carboxylate 
are dissolved in 0.8 l dry toluene at 85.degree. C. 44 g (1.1 mol) sodium 
hydride (60% dispersion in mineral oil) are added. To the stirred mixture 
96.92 g (1.1 mol) ethyl acetate are dropped over 2 hours. The mixture is 
allowed to react 16 hours at 70.degree. C. Subsequently the toluene is 
removed under reduced pressure. The resulting mixture is introduced into 
the following step without purification. For analytical purposes a small 
amount of the brown oily residue is dissolved in methylene chloride, 
washing with aqueous ammonium chloride solution and water, drying by means 
of sodium sulphate and evaporation lead to an oil. Crystallization with 
diethyl ether and recrystallization from ethanol/diethyl ether afford the 
title compound as white crystals, melting point 136.degree.-139.degree. C. 
C.sub.27 H.sub.24 N.sub.2 O.sub.3 (424.5) Calc.: C 76.39; H 5.70; N 6.60; 
Found: C 76.30; H 5.66; N 6.47. 
MS: m/z (rel. int. [%])=424 (M.sup.+, &lt;1), 244 (19), 243 (100). 
.sup.1 H-NMR data: (CDCl.sub.3, TMS as internal standard) .delta.=7.62 (d) 
1H, 7.55-6.99 (m) 16H, 4.61 (q) 2H, 3.99 (s) 2H, 1.24 (t) 3H, ppm. 
o) 1-(1-Triphenylmethyl-1H-imidazol-4-yl)ethanone 
The residue from n) is dissolved in a mixture of 75 g potassium hydroxide, 
140 ml water and 1.3 l ethanol. The solution is heated under reflux for 10 
hours. Solid material is removed by filtration. After evaporation and 
dissolving in methylene chloride it is washed 3 times with 400 ml water 
(addition of 2-propanol separates the layers), dried by sodium sulphate 
and evaporated. Stirring and addition of diethyl ether afford 115.3 g 
1-(1-triphenylmethyl-1H-imidazol-4-yl)ethanone (59.5% based on m)) as 
light yellow crystals. An analytical probe is recrystallized from ethanol: 
white crystals, melting point 164.degree.-165.degree. C. 
C.sub.24 H.sub.20 N.sub.2 O (352.4) Calc.: C 81.79; H 5.72; N 7.95; Found: 
C 81.67; H 5.64; N 8.03. 
MS: m/z (rel.int. [%])=352 (M.sup.+, &lt;), 244 (22), 243 (100), 183 (85). 
.sup.1 H-NMR data: (CDCl.sub.3, TMS as internal standard) .delta.=7.45-7.20 
(m) 17H, 3.06 (s) 3H, ppm. 
p) (Z)-Ethyl 2-methyl-3-(1-triphenylmethyl-1H-imidazol-4-yl)2-butenate 
11.7 g (0.3 mol) sodium amide are suspended in 300 ml tetrahydrofurane 
under nitrogene. 71.47 g (0.3 mol) triethyl 2-phosphonopropionate are 
dropped to the stirred mixture which is kept at ambient temperature for 2 
hours subsequently. 30.5 g (86.5 mmol) 
1-(1-triphenylmethyl-1H-imidazol-4-yl)ethanone are added and the mixture 
is held under reflux for 16 hours. Evaporation and dissolving in 1 l 
chloroform/2-propanol (3:1) is follwed by washing 3 times with water. 
Drying with sodium sulphate and evaporation result an oil which mainly 
consists of E-ethyl 
2-methyl-3-(1-triphenylmethyl-1H-imidazol-4-yl)2-butenate. Treating this 
residue with diethyl ether affords 10.9 g of a solid material mainly 
consisting of the Z-isomer. Purification via column chromatography 
(silicagel 63-200 .mu.m, eluent: petrol ether/diethyl ether [2:2]) leads 
to 5.6 g (14.8%) of the title compound as a white solid. An analytical 
sample was recrystallized from diethyl ether/ethanol resulting colourless 
crystals, melting point 166.degree.-168.degree. C. 
C.sub.29 H.sub.28 N.sub.2 O.sub.2 (436.6) Calc.: C 79.79; H 6.46; N 6.43; 
Found: C 79.49; H 6.43; N 6.34. 
MS: m/z (rel. int. [%])=436 (M.sup.+, 2), 244 (20), 243 (100), 165 (23). 
.sup.1 H-NMR data: (CDCl.sub.3, TMS as internal standard) .delta.=7.58-7.11 
(m) 16H, 6.76 (d) 1H, 4.07 (q) 2H, 1.98 (s) 6H, 1.17 (t) 3H, ppm. 
q) erythro-Ethyl 3-(1H-imidazol-4-yl)2-methylbutanate 
10.2 g (23.4 .sup.mmol) Z-ethyl 
2-methyl-3-(1-triphenylmethyl-1H-imidazol-4-yl)2-butenate are dissolved in 
350 ml tetrahydrofurane, 1.5 g 10% palladium on activated carbon are 
added. The mixture is hydrogenated for 3 days at ambient temperature and 
10 bar. After removal of the catalyst by filtration the solution is 
evaporated to dryness. The residue is purified by column chromatography 
(silicagel 63-200 .mu.m, eluent 1: diethyl ether, eluent 2: 
chloroform/methanol saturated with ammonia [1:1]) leading to 3.9 g (84.9%) 
erythro-ethyl 3-(1H-imidazol-4-yl)2-methylbutanate as a colourless oil. A 
small amount is converted into the hydrogenmaleate resulting white 
crystals, melting point 91.degree.-94.degree. C. (ethanol/diethyl ether). 
C.sub.10 H.sub.16 N.sub.2 O.sub.2.C.sub.4 H.sub.4 O.sub.4 (312.3) Calc.: C 
53.84; H 6.45; N 8.97; Found: C 53.72; H 6.60; N 8.82. 
MS: m/z (rel. int. [%])=196 (M.sup.+, 11), 123 (30), 95 (100); obtained 
from a sample of q.HCl. 
.sup.1 H-NMR data: ([D6]DMSO, TMS as internal standard) .delta.=8.88 (s) 
1H, 7.46 (s) 1H, 6.05 (s) 2H, 4.08 (q) 2H, 3.10 (dq) 1H, 2.70 (dq) 1H, 
1.22-1.13 (m) 6H, 0.95 (d) 3H, ppm. 
(r) erythro-3-(1H-Imidazol-4-yl)2-methylbutanoic acid 
3.8 g (19.4.sup.mmol) erythro-ethyl 3-(1H-imidazol-4-yl)2-methylbutanate 
are dissolved in 60 ml 6M hydrochloric acid and heated under reflux for 5 
hours. Evaporation affords erythro-3-(1H-imidazol-4-yl)2-methylbutanoic 
acid hydrochloride as a hygroscopic oil which is introduced into the next 
step without purification. 
C.sub.8 H.sub.12 N.sub.2 O.sub.2 .multidot.HCl (204.7) 
MS: m/z (rel.int. [%])=168 (M.sup.+, 17), 123 (19), 95 (100), 68 (10). 
.sup.1 H-NMR data: ([D6]DMSO, TMS as internal standard) .delta.=9.04 (s) 
1H, 7.51 (s) 1H, 3.10 (m) 1H, 2.63 (m) 1H, 1.24 (d) 3H, 0.93 (d) 3H, ppm. 
(s) erythro-[3-(1H-Imidazol-4-yl)but-2-yl]amine 
To a solution of erythro-3-(1H-imidazol-4-yl)2-methylbutanoic acid 
hydrochloride in 20 ml concentrated sulphuric acid 125 ml chloroform are 
added. The mixture is stirred and 5.85 g (90 mmol) sodium azide are added 
over 1 hour at 0.degree. C. Subsequently the reaction mixture is held at 
45.degree. C. for 14 hours. After addition of some ice the organic layer 
is removed. The aqueous phase is brought to pH 8.5 and evaporated to 
dryness. Soxhletizing of the resulting solid material for 3 hours by means 
of 2-butanol affords the title compound as a crude oil which is purified 
via column chromatography (silicagel 63-200 .mu.m, eluent: 
chloroform/methanol saturated with ammonia [85:15]) affording 2.32 g 
(85.9% based on q) erythro-[3-(1H-imidazol-4-yl)but-2-yl]amine as a 
colourless oil. An analytical sample is converted into the dipikrate: 
yellow crystals, melting point: 228-232.degree. C. (ethanol). 
C.sub.7 H.sub.13 N.sub.3.2 C.sub.6 H.sub.3 N.sub.3 O.sub.7 (597.4) Calc.: C 
38.20; H 3.21; N 21.10; Found: C 38.22; H 3.15; N 21.14. 
.sup.1 H-NMR data: ([D6]DMSO, TMS as internal standard) .delta.=9.09 (s) 
1H, 8.60 (s) 4H, 7.81 (br) 3H, replaceable by D.sub.2 O, 7.55 (s) 1H, 3.40 
(m) 1H, 3.15 (m) 1H, 1.30 (d) 3H, 1.09 (d) 3H, ppm. 
t) (-)-erythro-[3-(1H-Imidazol-4-yl)but-2-yl]amine 
di[(+)-2S,3S-di-O-(4-toluoyl)hydrogentartrate] monohydrate 
0.56 g (4 mmol) erythro-[3-(1H-imidazol-4-yl)but-2-yl]amine are dissolved 
in 30 ml hot ethanol/water (1:1) and added to a hot solution of 3.13 g 
(8.1 mmol) (+)-2S,3S-di-O-(4-toluoyl)tartaric acid in 80 ml hot 
ethanol/water (1:1). After standing for 3 days at room temperature the 
resulting white crystals are recrystallized from ethanol/water (1:1) until 
melting point and optical rotation are constant: 0.79 g (42.5%) of the 
title compound as white crystals, melting point 181.degree. C. 
C.sub.7 H.sub.13 N.sub.3.2 C.sub.20 H.sub.18 O.sub.8.H.sub.2 O (929.9) 
Calc.: C 60.71; H 5.53; N 4.52; Found: C 60.39; H 5.41; N 4.76. 
[.alpha.].sub.D.sup.20 =+110.6(2).degree. (c=0.1, MeOH) 
u) (-)-erythro-[3-(1H-Imidazol-4-yl)but-2-yl]amine 
0.77 g (-)-erythro-[3-(1H-Imidazol-4-yl)but-2-yl]amine 
di[(+)-2S,3S-di-O-(4-toluoy)hydrogentartrate] monohydrate (0.83 mmol) are 
dissolved in 60 ml ethanol/water (2:1) and 0.5 ml of hydrobromic acid 
(47%) are added. Evaporation and redissolving in 20 ml water and 20 ml 
methylene chloride are followed by 4 times extraction with 20 ml methylene 
chloride. The aqueous solution is evaporated and delivered from excess 
hydrobromic acid by multiple dissolving in ethanol and evaporation. Adding 
diethyl ether and 2-propanol followed by stirring afford 0.18 g (72%) 
(-)-erythro-[3-(1H-imidazol-4-yl)but-2-yl]amine dihydrobromide as white 
crystals, melting range: 207.degree.-230.degree. C. 
C.sub.7 H.sub.13 N.sub.3.2 HBr (301.0) Calc.: C 27.93; H 5.02; N 13.96; 
Found: C 27.80; H 5.05; N 13.65. 
.sup.1 H-NMR data: ([D6]DMSO, TMS as internal standard) .delta.=14.22 (br) 
2H, replaceable by D.sub.2 O, 9.14 (s) 1H, 7.98 (br) 3H, replaceable by 
D.sub.2 O, 7.59 (s) 1H, 3.37 (m) 1H, 3.23 (m) 1H, 1.32 (d) 3H, 1.12 (d) 
3H, ppm. 
[.alpha.].sub.D.sup.20 =-6.2(1).degree. (c=0.5, H.sub.2 O) 
v) (+)-erythro-[3-(1H-Imidazol-4-yl)but-2yl]amine 
di[(-)-2R,3R-di-O-(4-toluoyl)hydrogentartrate] monohydrate 
The filtrate of the first crystallisation under t) is evaporated to dryness 
and converted into the dihydrobromide (analogously to t). Dissolving in 
dry ethanol and addition of an equivalent amount potassium tert. butylate 
result after filtration and evaporation 0.17 g (1.2 mmol) 
erythro-[3-(1H-Imidazol-4-yl)but-2-yl] amins as free base. The base is 
dissolved in 10 ml hot ethanol/water (1:1) and given to a solution of 1.07 
g (2.5 mmol) (-)-2R,3R-di-O-(4-toluoyl)tartaric acid in 30 ml hot 
ethanol/water (1:1). After standing for 3 days at ambient temperature the 
resulting white crystals are recrystallized from ethanol/water (1:1) until 
melting point and optical rotation are constant, resulting 0.21 g (11.3% 
based on the educt in t)) white crystals, melting point 181.degree. C. 
C.sub.7 H.sub.13 N.sub.3.2 C.sub.20 H.sub.18 O.sub.8.H.sub.2 O (929.9) 
Calc.: C 60.71; H 5.53; N 4.52; Found: C 60.52; H 5.34; N 4.69. 
[.alpha.]D20=-109.4(2).degree. (c=0.1, MeOH) 
w) (+)-erythro-[3-(1H-Imidazol-4-yl)but-2-yl]amine 
0.2 g (0.22 mmol) (+)-erythro-[3-(1H-imidazol-4-yl)but-2-yl]amine 
di[(-)-2R,3R-di-O-(4-toluoyl)hydrogentartrate] monohydrate are converted 
into the dihydrobromide in the way described in .mu.) resulting 60 mg 
(86.7%) (+)-erythro-[3-(1H-Imidazol-4-yl)but-2-yl]amine as white crystals, 
melting range 209.degree.-230.degree. C. (diethyl ether/2-propanol). 
C.sub.7 H.sub.13 N.sub.3.2 HBr (301.0) Calc.: C 27.93; H 5.02; N 13.96; 
Found: C 27.65; H 5.07; N 13.60. 
[.alpha.]D20=+5.7(1.5).degree. (c=0.5, H.sub.2 O) 
Pharmacological investigation. 
The compound of the invention was investigated in racemic and 
stereoisomeric form. 
a) The inhibition of the release of histamine induced by depoliarization of 
slices of rat brain was studied according to the method described by 
Arrang and al. (Nature, 1983, 302, 832-837). The maximal inhibition 
induced by the compound of the invention is identical to that induced by 
histamine (it is a complete agonist) and its 50% inhibitory concentration 
(IC50) is the following: 
racemic form: 12.times.10.sup.-9 M 
erytro form: 6.times.10.sup.-9 M 
(+)erythro isomer: 3.4.+-.2, 0.times.10.sup.9 M 
(-)erythro isomer: 48.+-.31.times.10.sup.-9 M 
threo form: 200.times.10.sup.-9 M 
It may be seen that the activity of the compound of the invention on the 
H.sub.3 receptors is selectively provided by one of the four 
stereoisomers, i.e. the (+) erythro enantiomer. The activity of the (-) 
erythro enantiomer is probably lower than above, as this compound was 
about 85% pure and contained some (+) erythro enantiomer. 
b) Contraction of the isolated ileum of guinea pig: the compound is a 
complete agonist, but has less than 1/1000th of the activity of histamine. 
c) Contraction of the isolated auricle of guinea a pig: the compound is a 
partial agonist (the maximal effect is 60% of that of histamine) and about 
1000 times less active than histamine. 
The results are summarized in the following table. 
TABLE 
______________________________________ 
Activity of he compound of the invention com- 
pared with that of histamine (activity = 100) on the 
three classes of histaminergic receptors. 
H.sub.3 .sup.(a) 
H.sub.1 .sup.(b) 
H.sub.2 .sup.(c) 
______________________________________ 
histamine 100 100 100 
.alpha.,.beta.-diethylhistamine 
racemic 516 0.06 0.01 
erythro 1030 
(+)erythro 1800 
(-)erythro 129 
______________________________________ 
Further the compound was found active in vivo since at the dose of 20 mg/kg 
(racemic) by the oral route it inhibits the synthesis of histamine in the 
rat brain (mesured according to the test of Arrang et al., Nature 1987, 
327, 117). 
This investigation shows that the compound of the invention has a very high 
and particularly selective H.sub.3 activity, whereas its activity on the 
H.sub.1 and H.sub.2 receptors is insignificant, about 10 to 100 times 
lower than that of the best compounds known form Kokai 62-123 174. 
Consequently it can be a powerful and selective H.sub.3 agonist which may 
be used in therapy in better conditions of security. 
In consequence, it is likely to decrease histaminergic transmission in the 
digestive tract and in the nervous, cardiovascular and immune systems. It 
can be used in therapy as a drug having sedative effects, as a sleep 
regulator, anticonvulsant, regulator of hypothalamo-hypophyseal secretion, 
antidepressant, modulator of cerebral circulation, and the like. 
Furthermore, inhibition of the release of inflammation messengers in 
various allergic conditions (e.g. asthma) is expected to result from the 
stimulation of the H.sub.3 receptors of the lung, for example. 
In gastroenterology, the inhibition of release of gastric histamine is 
likely to exert antisecretory and anti-ulcerative effects. Modification of 
release of the messengers of immune responses is likely to modulate the 
latter responses. 
By virtue of these novel and unexpected properties, the compound of the 
invention mainly in the form of its (+) erythroisomer, may be used for 
treating diseases which involve histamine synthesis and release in the 
human or animal body. Thus, the invention provides a method for treating a 
patient suffering from such a disease by administering a therapeutically 
effective amount of the compound of the invention. From its mode of 
action, its diverse pharmacological effects and its low toxicity in 
animals, apllications of this derivative may be predicted both in human 
and veterinary medicine, at doses of the order of 0.1 to 10 mg/kg 
administered, in particular, orally or parenterally. 
It can be presented, in particular, in the form of tablets, dragees, 
gelatine capsules, aerosols, injectable solutions or suppositories.