Stereoisomers of 1-(1'benzyl-2'pyrryl)-2-di-sec.-butylaminoethanol and pharmaceutical compositions comprising same

Novel stereoisomers of 1-(1'-benzyl-2'pyrryl)-2-di-sec.-butylaminoethanol of the formula: ##STR1## wherein R is fluoro or trifluoromethyl and the non-toxic therapeutically acceptable salts thereof; including pharmaceutical compositions comprising same. The said products and compositions have utility as analgesics.

This invention relates to novel stereoisomers of a 
1-(1'-benzyl-2'-pyrryl)-2-di-sec.-butylaminoethanol of the formula: 
##STR2## 
wherein R is fluoro or trifluoromethyl; to the non-toxic salts thereof and 
to pharmaceutical compositions comprising same as the active ingredient. 
The said products and compositions exhibit analgesic activity. 
BACKGROUND 
It is known from U.S. Pat. No. 3,629,435 that the following compounds 
possess analgesic activity: 
##STR3## 
wherein R is benzyl or substituted benzyl. In this patent R is broadly 
defined but it appears that only a few substituted benzyl derivatives were 
actually prepared, specifically, only the ortho-chlorobenzyl derivatives 
among which 1-[1'(o-chlorobenzyl)-2'-pyrryl]-2-di-sec.-butylaminoethanol 
is named: 
##STR4## 
This compound is said to be the most active compound within the disclosed 
class of aminoethanols and it has been marketed as a valuable analgesic 
under the name "VIMINOLO" (W.H.O. Chronicle, 1970, N.3, list 25). 
According to U.S. Pat. No. 3,629,435, the compounds II and III are prepared 
as a mixture of stereoisomers by reducing the corresponding keto 
precursors. Despite many attempts to resolve the said stereoisomeric 
mixture, which can be more or less complex because of the number of 
assymetric centers present in the molecule, it has been impossible up to 
now to do so. 
The U.S. Pat. No. 3,857,857 describes a method for directly synthetizing 
each optical isomer of 
1-[1'(o-chlorobenzyl)-2'-pyrryl]-2-di-sec.-butylaminoethanol (III) and 
using this method four isomers of optical purity were prepared and their 
analgesic activity determined. 
From this determination it was found that one of the four isomers, 
identified in said Patent as Compound "R.sub.2 ", is much more active than 
the other isomers and also, more active than the corresponding racemic 
compound "VIMINOLO". 
THE INVENTION 
It is an object of this invention to prepare two stereoisomers of optical 
purity never before prepared, not even as a racemic mixture. 
These stereoisomers have the formula: 
##STR5## 
wherein R is fluoro or trifluoromethyl. These new compounds have quite 
surprisingly shown an analgesic effect of a much higher order than that 
exhibited by VIMINOLO and, also, higher than that of the "R.sub.2 " 
Compound commonly considered as the best of the class. 
Moreover, this increase in activity is not accompanied, as is usually the 
case, by higher toxicity but, on the contrary, the new compounds have a 
reduced toxicity when compared against VIMINOLO and the "R.sub.2 " 
Compound. 
The new compounds of this invention possess therapeutic indexes which are 
exceptional in the field of analgesic products. 
These new compounds are prepared through a method of direct synthesis 
analogous to that described in U.S. Pat. No. 3,857,857 for the 
o-chloro-benzyl derivative. 
This method comprises the following essential steps: 
(1) Preparation of R,R(-) di-sec.-butylamine: 
(a) R(-) sec.-butylamine is separated from the racemic sec.-butylamine by 
means of L(+) tartaric acid, according to the procedure described in 
Thome-Ber. 1903, 36, 582. 
(b) The (-) sec.-butylamine thus obtained is treated with a racemic 
sec.-butyl derivative of the formula X-CH(CH.sub.3)C.sub.2 H.sub.5 wherein 
X is preferably bromo or chloro, in the presence of a polar organic 
solvent. 
(c) The separation of the resulting R,R(-) di-sec,-butylamine hydrobromide 
or hydrochloride is performed by fractional crystallization from acetone 
or ethanol. 
(2) Preparation of the chloroglyoxyl-pyrryl derivative: 
A benzyl-pyrrole of the formula: 
##STR6## 
wherein R is fluoro or trifluoromethyl, is treated with oxalylchloride in 
the presence of an inert, anhydrous, organic solvent, at a temperature of 
-15.degree. C., under stirring. There is thus obtained a compound of the 
formula: 
##STR7## 
wherein R has the above-indicated meaning. 
(3) Preparation of the pyrryl-glyoxylamide: 
The chloroglyoxyl-pyrryl derivative obtained in the preceding step is 
treated with R,R(-) di-sec.-butylamine or an acid addition salt thereof in 
an inert organic solvent, at a temperature below 0.degree. C. and in the 
presence of a basic substance suitable for blocking the formation of 
hydrohalogenic acid to afford 
N,N-di-sec.-butyl-1-(o-R-benzyl)-2-pyrrylglyoxylamide. 
(4) Preparation of the amino-pyrryl-ethanol derivative: 
The N,N-di-sec.-butyl-1-(o-R-benzyl)-2-pyrryl-gloxyl amide obtained 
according to step (3) above is reduced by means of a metallo- or 
organo-metallo hydride, in the presence of an inert organic solvent at a 
temperature of between about 20.degree. C. and the reflux temperature. 
There is thus obtained 
1-[1'-(o-R-benzyl)-2'-pyrryl]-2-di-sec.-butylamino-(1R+ 1S) ethanol. 
The mixture of the two diastereoisomers thus obtained is treated with 
p-hydroxybenzoic acid to afford the corresponding p-hydroxybenzoates and 
these are separated by fractional crystallization from a polar organic 
solvent, preferably, acetone. 
By repeating the crystallization from acetone, the two diastereoisomers are 
obtained at practically 100% optical purity. Although it is not possible 
to state which of the two isomers has the (R) configuration and which 
possesses the (S) configuration, nevertheless, the two isomers have been 
isolated and identified. 
Only one of said isomers, identified hereinafter as the one which 
precipitates upon cooling the diastereoisomeric solution in boiling 
acetone, is critical to this invention. 
The absolute space configuration of the asymmetric carbon atoms indicated 
with an asterisk in the formula (I), is defined according to JU 
Tentative Rules for the Monenclature of Organic Chemistry 1970, 35, 
2849-2869. 
The absolute configuration of di-sec.-butylamine is based on the absolute 
configuration of sec.-butylamine (see A. Kjaer, S. E. Hausen, Acta Chemica 
Scandinavia 1957, II - 1898). 
The isomers of 1-[1'-(o-R-benzyl)-2'-pyrryl)]-2-di-sec.-butylamino (1 R+ 
1S) ethanol, which have shown a surprising analgesic activity and which 
are thus the object of the present invention, are identified hereinafter 
in unequivocal manner through their physical characteristics. 
Isomer A: 
1-[1'-(o-fluorobenzyl)-2'-pyrryl]-2-di-(R,R)-sec.-butylaminoethanol; m.p. 
of p-hydroxybenzoate: 144.degree.-145.degree. C. 
[.alpha.].sub.d.sup.20 (in methanol c= 1%): -31.degree. C..+-.3.degree. C. 
[.alpha.].sub.d.sup.20 (in methanol c= 2%): -29.degree. C..+-.3.degree. C. 
[.alpha.].sub.436.sup.20 (in methanol C= 1%): -59.degree. C..+-.3.degree. 
C. 
[.alpha.].sub.436.sup.20 (in methanol c= 2%: -58.degree. C..+-.3.degree. C. 
Isomer B: 
1-[1'-(o-trifluoromethylbenzyl-2'-pyrryl]-2-di-(R,R)-sec.-butylaminoethanol 
: m.p. of p-hydroxybenzoate: 148.degree.-150.degree. C. 
[.alpha.].sub.d.sup.20 (in methanol c= 1%): -27.degree. C..+-.3.degree. C. 
[.alpha.].sub.d.sup.20 (in methanol c= 2%): -26.degree. C..+-.3.degree. C. 
[.alpha.].sub.436.sup.20 (in methanol c= 1%): -50.degree. C..+-.3.degree. 
C. 
[.alpha.].sub.436.sup.20 (in methanol c= 2%): -48.degree. C..+-.3.degree. 
C. The analgesic activity (ED.sub.50) of isomers A and B has been 
determined via the hot plate test on mice (N/.B Eddy et Coll. J. 
Pharmacol. 98, 121, 1950) and via the "tail flick" test on rats (D'Amour 
and Smith; J. Pharmacol. 1941, 72, 74). The resulting values are set forth 
in the following Table and compared with the values given under identical 
conditions for VIMINOLO and the "R.sub.2 " Compound referred to 
hereinabove (Pharmacological Research Communications 8, 111 (1976)). 
The acute toxicity values (LD.sub.50) have been determined by the method of 
Litchfield and Wilcoxson (J. Pharmacol. 1949, 96, 99) both for the new 
compounds of this invention and for VIMINOLO and the "R.sub.2 " Compound. 
______________________________________ 
ED.sub.50 mg/kg 
ED.sub.50 mg/kg 
LD.sub.50 
hot plate Tail Flick mg/kg 
Compound s.c s.c. i.p. T.I. 
______________________________________ 
Isomer A 0.65 0.44 384 872 
Isomer B 0.60 0.38 358 942 
"R.sub.2 " Compound 
1.15 0.71 230 324 
VIMINOLO 12.5 167 13.36 
______________________________________ 
From the above data it is evident that the analgesic activity of the new 
compounds A and B R+nearly twice that of the Compound "R.sub.2 " which in 
turn was surprisingly more active than VIMINOLO. 
It is also apparent that the LD.sub.50 is much higher for new compounds A 
and B, that is, they are much less toxic than the Compound "R.sub.2 " and 
VIMINOLO. The superiority of new Compounds A and B is also evident from 
the therapeutic indexes which have been calculated as a ratio of LD.sub.50 
/ED.sub.50' taking as the ED.sub.50 value that which is obtained by the 
tail flick test. 
The new compounds of this invention can be administered per os, and by 
injection. The present compounds are useful in treating a number of 
diseases which cannot be satisfactorily treated with analgesics 
administered per os and which are thus slowly assumed by the organism. 
This invention will now be described by reference to specific examples. 
However, it is to be understood that these examples are illustrative only 
and not limitative. Therefore, any substitution of equivalent materials or 
modification in the reaction conditions is considered as being within the 
scope of this invention and not a departure therefrom.

EXAMPLE 1 
1-[1'-(o-Fluorobenzyl)-2'-Pyrryl]-2-Di-(R,R)-Sec.-Butylamino (1 R+ 1S) 
Ethanol, p-Hydroxybenzoate 
Step A: R,R(-) Di-Sec.-Butylamine Hydrobromide 
R(-) sec.-butylamine is dissolved in absolute ethanol and to this solution 
is added (R+S) 2-bromobutane in excess and the resulting mixture is then 
refluxed over about 60 hours. 
Following reflux the solution is hot filtered and the filtrate is cooled 
and then kept at -15.degree. C. over about 48 hours. The resulting R,R(-) 
di-sec.-butylamine hydrobromide is separated by filtration and then 
purified by successive crystallization from acetone. 
Step B: 1-(o-Fluorobenzyl)-2-Pyrrylglyoxylic Acid Chloride 
A solution of oxalylchloride in anhydrous pentane is put into a flask 
provided with a stirrer, thermometer, reflux cooler and tube for nitrogen 
bubbling. The solution is maintained under a nitrogen atomosphere at 
-15.degree. C. 
A solution of 1-(o-fluorobenzyl)pyrrole in anhydrous pentane is then 
dropped into the flask with stirring. 
The ratio between the reactants is on the order of about 1.5 moles of 
oxalyl chloride per mole of 1-(o-fluorobenzyl)pyrrole. 
The temperature of the mixture is maintained at -15.degree. C. for a few 
minutes after the addition of the 1-(o-fluorobenzyl)pyrrole is completed. 
Then the temperature is slowly raised to 40.degree. C. under a slight 
vacuum and under a nitrogen stream to completely remove excess oxalyl 
chloride and solvent. 
There is thus obtained a precipitate of 
1-(o-fluorobenzyl)-2-pyrrylglyoxylic acid chloride. 
Step C: N,N-Di-Sec.-Butylamide of 1-(o-Fluorobenzyl)-2-Pyrrylglyoxylic Acid 
1-(o-Fluorobenzyl)-2-pyrrylglyoxylic acid chloride (26.5 g.) is dissolved 
in chloroform (200 ml.) and the resulting solution, cooled at -15.degree. 
C., is added dropwise to a solution of R,R(-) di-sec.-butylamine 
hydrobromide (21 g.) and triethylamine (21 g.) in chloroform (200 ml). 
The mixture is heated slowly up to 50.degree. C., stirring is maintained 
for one hour and the mixture is then cooled and washed successively with 
water, sodium carbonate and water. 
The organic layer is removed, dried over sodium sulphate and then 
evaporated to dryness. 
The residue consists of crude (-) N,N-di-sec.-butylamide of 
1-(o-fluorobenzyl)-2-pyrrylglyoxylic acid. 
Step D: 1-[1'-(o-Fluorobenzyl)-2'-Pyrryl]-2-Di-(R,R)-Sec.-Butylamino (1 R= 
1S) Ethanol, p-Hydroxybenzoate 
The (-) N,N-di-sec.-butylamide of 1-(o-fluorobenzyl)-2-pyrrylglyoxylic acid 
obtained as an impure product in Step C, is dissolved in anhydrous toluene 
(300 ml). and the resulting solution is introduced dropwise, with 
stirring, into a solution of LiAlH.sub.4 and tetrahydrofuran in toluene. 
The LiAlH.sub.4 constitutes about a 30% molar excess over the amide 
reactant. 
The reaction mixture is maintained at 25.degree.-30.degree. C. until the 
addition of the reactants is completed and the mixture is then refluxed 
for one hour. 
The mixture is then cooled, excess hydride is decomposed with water and 
sodium hydroxide (V. M. Micovic and M. C. J. Mihailovic J. Org. Chem. 
1953, 1190) and the solvent is eliminated by evaporation. 
An oily residue is obtained (24.5 g.) and this is dissolved in 
methylethylketone (200 ml.) and then treated with a solution of 
p-hydroxybenoic acid (14 g.) in methylethylketone (50 ml.). 
The mixture is allowed to rest overnight and the resulting precipitate is 
filtered with a water vacuum-pump. 
There is thus obtained 29.5 grams of 
1-[1'-(o-fluorobenzyl)-2'-pyrryl]-2-di-(R,R)-sec.-butylamino (1 R+ 1S) 
ethanol, p-hydroxybenzoate (m.p.: 128.degree.-142.degree. C. with 
decomposition). 
The mixture of diastereoisomers thus obtained is dissolved in a strong 
excess of boiling acetone under stirring. 
Upon cooling the acetonic solution to room temperature a crystalline 
product precipitates rich in one of the two diastereoisomers, namely, the 
isomer identified as A in this specification. 
Upon crystallizing the precipitate three times, and upon cooling the 
boiling acetone solution, the compound A is obtained in the form of a pure 
p-hydroxybenzoate having a m.p. of 144.degree.-145.degree. C. 
The specific rotatory power of the compound A with different polarized 
lights and at various concentrations are set forth hereinabove. 
The method described in Example 1 was repeated in an identical manner, 
except that 1-(o-trifluoromethylbenzyl)pyrrole was substituted for the 
1-(o-fluorobenzyl)pyrrole of Step B. 
Upon the conclusion of this method, after several crystallizations from 
acetone, a single optically pure isomer was obtained from the mixture of 
diastereiosimers. This product is 
1-[1'-(o-trifluoromethylbenzyl)-2'pyrryl]-2-di-(R,R)-sec.-butylaminoethano 
l. 
The pure compound in the form of its p-hydroxybenzoate has a melting point 
of 148.degree.-150.degree. C. This product has been identified 
unequivocally through its rotatory power with different polarized lights 
at various concentrations.