Note: Descriptions are shown in the official language in which they were submitted.
ill844G
BACK~RVUND OF THE INV~ ON
1. ~eld o~ the Invention
'~!he present invention i9 concerned with new
compounds ha~ g high ~pa~molytic a¢tion . ~ore
particul0.rly, the inventio~l relates to certain
pr~io~amld~ deri~rstiYe~ their pharmaceutically
ac¢sptable ~alts and methoa~ of u~ th~se compound~
E~ 8pa8molyti.c agent~ in man and a~imal~.
2. Prior AFt
Among the produots u~ually ~mployed i~ therapy
a~ ~pa~molytlc, it i8 frequentl~r vb~erreà 1~hat the
~ction of 80~C o~ the~e known product~ 18 co~finsd
to the ga~trointe~inal tract . 3ho8c product~ that
after oral ~ ni~tration exert their aGtio~ also or~
organ~ and ~yst~m~ other tha~ th~ gastrointe~tinal
tract, howe~er, have atrop~n~-like ~ide e~fects.
_MMAMY OF T~IE INVEN'~ION
It ha~ been ~ound that the new cRmpounds either
rac~mio or opti~ally acti~e of the general ~ormula Is
aH3
CH - CONH - (CH2) _ N/ ~I)
n Et
wherein n is 2 or 3~ and Et i8 the ethyl group, C2~ -9
and their non-toxlc, phRrmaceutically aceeptable 8alt5
are p~rticulsrly suitable for oral or parenteral use.
~k
~84~6
TheSe n~w com~oun~ and thelr salts d~ffer f~om the already kncwn products
because: ¢a~ inhiblt the t~ansm~sslon o the ne~v~us impulse to the muscular
fiber tParaSYmPatho~yt~ actlvLty); ~b) inhiblt the contractlon of the sm~oth
mu~culature ~di~e~t myo~ytic activlty); and tc) have lower s~de effects on
the central and pe~iphe~al nervou~ ~ystem.
It has be3n found that the new compounds cor~esponding to the
general forn~la I and the~ nont~xic salts are partlcula~ly suitable for oral
as well as parenteral use and differ rom the already kncwn products for their
direct parasympathDlytic and myolytic actlvity and for their lcwer side
effects on the central and peripheral nerv~us system. Specific examples of
crmeowrLs related to the fo~mula I are:
1~ 2-t4-b~pbeny~-N-t2-dieth~la~lnoethyl) propLonamide; and
2) 2-~4-biph~ny)-N-~3~d-iethyla~ m apropyl) prop~onamide.
The bromide and iodide salts of 1) an~ 2) are especially useful as spasmolytic
agents.
Pharmaceutically acceptable salts of the above mentioned comp~unds
are, for instance, the non-boxic chloride, bromide, iodide, phosphate, and
sulphate salts, as well as the methyl b~cmide/ methyl icdide, ethyl brcmide,
eth~l iodide salts.
Ckmpounds of the fo~mula I are prepa~ed according to known methods.
In particular, these eompcunds are made by reaeting a functional derivative
of 2-~4-biphenyl) prop~Qnie aeid wlth N,N dieth~lethylenediamine or N,N-diethyl
-1,3-prc~ylenediamine in the presenee of a sultable solvent. As functional
derivative o 2-~4-biphenyl) propionie acid the ehloride or the correspcnding
anbydride o said aeid is very useul as well as an ester o bhe same acid and,
in partieular, a lo~er alkyl ester such as the methyl esber of said acid.
Using the ehloride of the acid as reagent, it is preferable to perform the
ecndensation reaetic~n with N,N-diethylethylenedia~lne or N,N-diethyl-1,3-
pro~ylenediamine in the presenee of a base.
The salts o the compounds of the formula I are also prepared
aecording to known me*hLds. The aLkylhalogen derivatives are prepared by
aLkylation of the bases aeeording to fc~mula I, with aIkylat~ng agents such
- 3 -
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asalkyl chloride, alkyl bromide or alkyl iodide in an organic
low boiling solvent including, for example, dioxane, acetone,
ethyl ether.
Example 1: Preparation of 2-(4-biphenyl)-N-(2-diethyl-
amino ethyl) propionamide.
To 11.6 g of N,N-diethyl ethylenediamine in 60 ml of
benzene are slowly added dropwise, with stirring, 24.4 g of
2-(4-biphenyl)-propionic acid chloride dissolved in 60 ml of
benzene. After 1 hour refluxing, the mixture is concentrated,
extracted with ethyl ether and water, and precipitation occurs
from the aqueous solution with soda; crystallization of the
desired product follows from hexane; melting point 67-68C.
I.R. (Nujol*), r max (cm 1): 3340 (NH), 1640 (CO)H-NMR (CC14),
(ppm): 1 (t, 2 x CH3) 1.6 (d, CH3) 2.3-2.6 (m, 3 x CH2) 3.3
(q, CH2) 3.6 (q, CH) 7.2-7.5 (m,C6H4 and C6H5).
Example 2: Preparation of 2-(4-biphenyl)-N-(3-diethyl-
aminopropyl) propionamide.
To 13 g of N,N-diethyl-1,3-propylenediamine in 60 ml of
benzene are slowly added dropwise, with stirring, 24.4 g of 2-
(4-biphenyl) propionic acid chloride dissolved in 60 ml of
benzene. After 2 hours refluxing, the mixture is concentrated,
extracted with ethyl ether and water; precipitation occurs with
soda from the aqueous solution, crystallization of the desired
product follows from hexane: m.p. 44-45C. I.R. (Nujol*), y max
(cm ): 3280 (NH), 1640 (CO) H-NMR (CDC13), ~ (ppm): 1.1 (t,
2 x CH3) 1.6-1.9 (m,CH3 and CH2) 2.4-2.7 (m, 3 x CH2) 3.5 (q,
CH2) 3.8 (q, CH) 7.5-7.9 (m,C6H4 and C6H5).
Example 3: Preparation of 2-(4-biphenyl)-N-(2-diethyl-
methylammonium-ethyl) propionamide bromide.
In 8 g of 2-(4-biphenyl)-N-(2-diethylamino-ethyl) propion-
am:ide dissolved in 20 ml of acetone 2.5 g of methyl bromide are
bubbled. The precipitate is filtered and crystallized from iso-
* Trademarks
-4-
1~L184~6
propyl alcohol: m.p. 161-163 C. I.R. (Nujol*) y max (cm ):
3150 (NH), 1650 (CO) H-NMR (CDC13), ~ (ppm): 1.3 (t, 2 x CH3)
1.6 (d, CH3) 3.2 (s, CH3) 3.4-4.0 (m, 4 x CH2 and CH) 7.4-7.7
(m, C6H4 and C6H5)
Example 4: Preparation of 2-(4-biphenylyl)-N-(3-diethyl-
methyl-ammonium propyl) propionamide bromide.
In 8.5 g of 2-(4-biphenylyl)-N-(3-diethylamino-propyl)
propionamide dissolved in 20 ml of acetone 2.5 g of methyl
bromide are bubbled. The precipitate is filtered and crystal-
lized from acetone/ethyl ether; the melting point of the desiredproduct is 116-118C and this product is characterized as follows:
I.R. (Nujol*), ~ max (cm 1): 3150 (NH), 1645 (CO) H-NMR (CDC13),
(ppm): 1.25 (t, 2 x CH3), 1.55 (d, CH3) 1.8-2.3 (m, CH2) 3
(s, CH3) 3.1-3.7 (m, 4 x CH2) 3.7-4.2 (q, CH) 7.4-7.7 (m, C6H4
6 5)
Example 5: Preparation of 2-(4-biphenyl)-N-(2-diethyl-
methyl-ammoniumethyl) propionamide iodide.
To 8.0 g of 2-(4-biphenyl)-N-(2-diethylamino-ethyl) pro-
pionamide dissolved in 25 ml of ethyl alcohol 4 g of methyl io-
dide are added. The mixture is dried under vacuum and crystall-
ized from acetone: yielding the desired product whose melting
point is 132-134C. This product has the following characteris-
tic properties: I.R. (Nujol*) ~ max (cm ): 3200 (NH), 1655
(CO) H-NMR (CDC13), ~ (ppm): 1,3 (t, 2 x CH3) 1.6 (d, CH3) 3.1
(s, CH3) 3.3-4.0 (m, 4 x CH2 and CH) 7.4-7.65 (m, C6H5 and C6H4).
Example 6: Biologic Activity: Use of Formula I compounds
as spasmolytic agents in animals.
The potential myolytic activity of the compounds of the
present invention was determined by measuring the transit of a
charcoal meal in mouse intestine, stimulated by BaC12, according
to P.A.J. Janssen and A. Jageneau, J. Pharm. Pharmacol. 9, 381,
1957.
* Trademarks
--5--
B
1~184~6
~ he potential parasympatholytic activity of the compounds
of the present invention was tested by evaluating in the anesthet-
ized guinea pig their antagonism toward the carbachol induced
bronchoconstriction (according to M.E. Rosenthale and A. Pervinis,
A ch. Int. Pharmacodyn. 1, 172, 1968), and bradycardia and hypo-
tension (according to J.P. Long and C.Y. Chiou, J. Pharm. Sciences
59, 133, 1970).
The results are reported in the following Table 1.
-5a-
34~
. l . I ~ _ 1
Y~ ~r
~1 ~
~ ~; ~ ,, ~,~
--r
L L~
A~ -6-
These results clearlv indicate that presence of the propionamide
structure is required to better spasmolytic activity. In act the alrea~y
kncwn 2-~4-biphenyl)-~-~2-daethylamLnoeth~vl) acetamide ~G. Cavallini, F.
Ravenna, Farm. Sci. ~ecn. 3, 648 ~1948) has a direct p æ asympatho~ytic and
myolitic activity deinitely lower than that o 2-~4-biph~nyl)-N-~2-diethyl-
aminoethyl) propiQnamide. Furthermo~e, this latter is 1.5 times as eective
as dicyclcmine in antagonizing smooth muscle contraction ~d-irect myolytic
effect) and 10 tLmes as effective as dicyclcmine in antagonizing the trans-
mission o the nervcus impulses to the muscular fiber ~paras~mpathol~tic
effect).
The atropinelike side effects o these ccmpounds have been studied
with the oxDtremorane test accordang to the methcd described by Leslie G.,
Hayman G., Ireson J. D. and Smith S., Arch. Int. Pha~nacodyn. 197, 108, 1972,
evaluating the central eects ~tremars) and peripheral efects ~salivation,
lacrimation, diarrhea) and with the aFcmo~pbine test according to the method
descri-ked by J. Scheel-K~ger, Acta Pha~macol. Toxicol. ~J 1~ 1970,
evaluat mg the central antichli~er~ic activity. The data are reported in
Table 2.
~,
J~J
~ABLE 2
, ~ .
Central anticholmergac activity Central an~ Feripheral effects
Potentiation of Inhibition of oxotremorine
apcmorphine efects accordang effects ~b)
to Scheel-Kr~ger ~a)
. . . .
CompcNnds Activity index Compounds ALtivlty index
.
Dicyclomine HCl 1 Dicyclomine HCl 1
_
2 ~c) 0.5 2 ~c~ 0.2
, _
AtrcpLne sulpha~e 1.3 Scopola~ine 1.2
_ butyL b~onide
~a) Average effect of (b) Average effect of 3
3 doses ~30-60-90 mg/Kg/os) doses ~28.6-51.2-114.4 mg/Kg/os)
o the ccnpound5 admLnistered o the caicurds administered
to emale mice ~17-25 g) 1 hour to male mice ~18-25 g) 1 hour
befo~e apomorphine ~10 mg/Xg/ before oxctremQLine ~0.5
s.c.). The gnawing intensaty mg/Kg/s.c.). The effect on
is evaluated fo~ the products lacrimation, salivation,
and the control ~H2O) cr a 40 diarrhea and tremor in comparison
m m ute pe~iod. with contrc~s ~H~O) is evaluated
in 15-30-60 and ~20 m m. after
oxc,tremorine.
Compound 2 ~c) = 2-~4-biphen~1)-N-~2-diethy1aminoethy1) prc,pionamide
~1~34~
It is seen from Table 2 that m comparison with 2-~4-biphenyl)-N-
~2-diethylaminoethyl) propionamlde, dicvclomlne and scopola~lne butyl bromlde
have respectively 5 or 6 t~mes h~gher central and perlpheral side-effects. As
to the central antlcholinergic activlty, dic~vclom me and atropine sulphate
have about 2 times higher side-effects in relation to 2-~4-biphenyl)-N-
~2-diethylaminoethyl) proplonamide.
None of the mentioned prodw ts exhibits antiphlogistic property
as deteLmined by the carragee~an pa~ edema test according to W~nter, A.C.,
Risley, E.A., and Nuss, G.W., Proc. Soc~ Exp. Biol. Med. 111, 544, 1962.
The present invention further provides pharmaceutical compositions
ccmprising at least one oompound of formula I in association with a pharma-
ceutical carrier or excipient. The phaLmaceutical compositions may be
presented in a orm su-it~ble, for example, for oral or parenteral or rectal
administration in doses ranglng ~rom 5 to 40 mg o active ing~edients.
EXamples o suitable forms o administLation include, vials,
tablets, coated tablets, capsules, lozenges, dispersible p~ders, syrups,
elixirs and suppc~itories. Preerably the comFos~tions are presented in
dosage unit form.
