Note: Descriptions are shown in the official language in which they were submitted.
I
FIELD OF THE INVENTION
___~__
hi itch royalty to a new compound, 2-
-(hexahydroazepI~o)-N-(2,6-d~ et~ylphe~yl)-acetamide~
of formula I
Jo
C~2
\ / C~2 I Shea
Ctl3
to the hydrochloride thereof of formula It
INCH OH I clue (It)
end to a proves for the preparation of these, and to
pharmaceutical composition containing them.
Stall: OF THE ART
The above formula I compound it chemically related
to lidocaine. It fake the study ox the metabolism of
lidocaine, of formula II
SHEA
NO CO Schick H (II)
by the liver m~rv~o~nl enwomb, with a rapid deethylatio~
ox thy nitrog~ to produce monoethylglycinoxylidide which
it attacked in turn by a carboxy-peptidase to give 2,6-
-xylidine, among other oxidation products, led to the
conical that the first deethylation reaction could be
retarded or inhibited if both ethyl groups it the
lidocaine nitrogen were united by a two carbon atom bridge
to originate a 7 member Ed ring (hexahydroazepine)O The use
of a two carbon bridges instead of a ethylene bridge
arose prom ester considQration3, wince the 7 member Ed ring
admit a larger number of spatial conformations than the
6 member Ed ring (piperidine)~ whereby the first two carbons
attached to the nitrogen look more like those of lidocaine.
2-(hexahydroazepino)-N~2,6-dimethylphenyl~-acetamiire
exhibited in fact, a longer lasting local anesthetic
action, which teems to show a lower metabolization rate
if any. Furthermore, its anesthetizing potency was
observed to be superior to that of lidocaine, as will be
discussed hereinafter.
So MARY OF THE INVENTION
_ .
The generic name of Zecadaine (or alternatively
Azepicaine) it suggested for the new compound.
Chemically it may also be called 2-(hexame-thyl~
eneamino)~ 2,6-dimethylphenyl)-acetamide or p-hexamethy
Q
eneamlno-2~6-dlmethvlacetanilide.
here art de~eribed hereinafter fake chemical
properties ox -thy compound of the Munich, designated
abbreviatedly as IQB-~-81.
crystalline, odourle~ bitter last m g white
powder. When recry~talli3ed out ox Boone, it or
prismatic needle
PHYSICAL PROPERTIES
-
a) : Soluble in water, methanol and ethanol.
Insoluble in petroleum ether, deathly
ether and non-polar organic Lotte.
b) Molecular eta: 314.84
c) : in base form: 87~0QC at 2QC/mi~.
in hydrochloride form: 17503 I at
2 Q Cumin .
d) IT abrasion spew trump 1 my in a tablet with
200 my KBr:
-- I~B~-81 hydrochloride give the loll owing
characteristic bands:
- 3, 250 cm 1 corresponding to -the tension
vibration of the aside group NOAH
3~025 cm 13 corresponding to the tension
vibration o* C-H with up hybridization
2,950 cm 1 corTe~po~ding to a tension
vibration of C-H with pi hybridisatio~
2,500 2,600 clue corresponai~g to a tension
vibration ox the No
lg690 cm 1 band I 1 Tony vibration of
1 7 525 cm 1 band II¦ the -I NO
- 1~600 cm 1 tension vibration ox aureole
780 cm 1 flaxen voyeur jut ox the plane
I 3 a a asset aro~atio I,
- I~B-~81 bate: 1 g ox the hydrochloride it
dissolved in water it alkalinised with ON Noah
and extracted with three 10 ml portions ox
chloroform. the chloroform foe are pooled,
dried with Andre sodium sulfite and the
solvent it driven off it a current ox nitrogen.
A tablet it Cry it prepared with the residue.
The IT spectrum of IQB-M~81 bate shows
characteristic band similar to the hydrochloride
except those appearing at 2g500-2,600 cm 1 which
are proper to the hydrochloride.
The aside band I and II undergo a
hyperchromic effect, namely they show
displacement tenured a longer wavelength.
e) US absorption ~ectrum:
A solution ox 10 my ox IQB-M-81 it 0~1 N Hal
owe a mix at 202 no
A 0.847
I)
It stows the follow my characteri~tie band in
dimethyl~ulphoxide:
- ~ultiplet centered at J= 1q6 due to the 12~ ox
the hexamethyleneami~e nucleus
- Singlet. at I= 2~1 due to the OH ox the two
methyls ox the roommate nucleus
- Multiple centered at I= 2~4 due to the DMS0
solvent
~ultiplet centered at I- 3.3 due to the NH and
the Hal proton and to the two hydrogen ox the
water molecule
- Singlet at I= 4.3 due to the OH ox the
-C0-CH2-N ethylene group
- Singlet at I- 7.0 due to the 3 aromatic H
The integration curve correspond to the number
ox protons assigned to each band ox the spectrum
IDENTIFICATION REACTIONS
a) Pirate formation Add lo picnic acid in water
.
to a dilute solution of IQB~-81 in distilled water until
the appearance ox a yellow solid corresponding to the
6.
I
pirate.
b) 1 ml of dilute nitric acid a 3 ml ox mercuric
nitrate solution art added to a I owlish m water. Heat
mixture to boiling: a yellow or yellow greet coloring
should occur.
c) s Add a
ferrous sulfite crystallite to the alkaline solution
; ob~ainad by melting about 100 my ox IQB-M-81 with sodium
and boil for one minute Allow to cool end a prune bulb
precipitate appear on ac}dulat m g with dilute ~ulphuric
acid r
PURITY TESTS
__
a) : Weigh out 1 g of the product
in an analytical balance and heat to 105QC lentil a
constant weight it obtained. It should jot lose more than
lo o* its wright.
b) Water ox cr~stalli~ation: Whey determined by thy
Karl Fisher method, it should lie between 5 and 7~6%.
c) Inn ion r _ idle: Mien determined according to the
method described it NO XIV wage 955~ 1 g of product should
not leave more than 1% residue.
The process for the preparation ox 2-(hexahydro-
azepino)-N-(2,6-di~ethylphenyl~-acetamide it characterized
7.
~.23L~
by reacting 2~5-dimethyl-anili~ yowled) ox formula
III SHEA
NH2 (III~
with chloracetyl chloride ox formula IVY
ClCH2-COCl (IV)
-to produce 2-chloro~N-(296-dimethylphenyl) acetamide
owe ormolu V SHEA
O~NH~OCH2C1 ( V)
which on reaction with hexahydroazepine ox formula VI
NH 2 2 1 2 VOW)
SHEA CH2-ch2
gives toe compound o* formula I.
2~(hexahydroazepino) N-(2,6-dimethylphenyl)-
-acetamide hydrochloride it prepared by reacting
2-(hexahydroazep mo)-N-(29~-dimethylphenyl) acetamids
with dilute hydrochloric acid in an alcohol medium
EXL'~PLE I
chlorine ? 96-dimethylphen~lL-ace-tamid
In a flask equipped with stirrer, reflex cooler
and heater therm were delved 30 g ox 2~6-dimethyl-
aniline m 125 I of b~nzene. the solution aye heated to
reflex with stirring and once the rollicks temperature was
reached, the heat~rlg eras interrupted and I ml of
chloracetyl chloride were added yo-yo at a rat
sufficient to maintain a gentle reflex. Under these
condition, the addition lasted 45 minute. Thereafter
the mixture way reflexed for 2 hour. This reaction
mixture way capable of being used or the following
step, or 2-chloro-N-(2~-dimethylphenyl~acetamide~ which
crystallizes on cooling Jay be isolated.
E ISLE II
2-(hexahydroazepino)-N~(2,6-dimet
The reaction mixture ox Example I was held slightly
below the reflex temperature and 24.5 g of hexahydroazepin
were added slowly (about 45 Monet At the end ox the
reaction the mixture way reflexed for 4 hour. the
mixture was cooled to room temperature and was washed with
100 ml ox water. The Bunsen phase way extracted with two
portions ox ON hydrochloric acid ho acid extracts were
pooled and were Wylie alkalini~ed with 20% sodium hydroxide
to pi = 10. The 2-(hexahydroazepino) N-(2,6-di-~ethyl~
phenyl)-acetamide slowly cry tallied and way removed by
filtration.
The solid baa dry mod, air dried and thin di~solvcd
in methanol water way added drop by drop until turbidity
was heated to boiling and was let to cool, with
cry~tallisation of 2~(hexahydroazepino)-ND(2,6-dimethyl
phenyl)-acetamide, mop. 87-88QC, with on overall yield
from the two step of 60%. The structure aye confirmed by
IRK NOR and microanalysis.
EXAMPLE III
___
Since 2-(hexahydroazepino)-N-(296-dimethylphenyl)-
-acetamid~ it rather insoluble in water as it it, to
facilitate parenteral admini~trat ion the corresponding
hydrochloride which it readily soluble in aqueous silent
has to be prepared. The hydrochloride way prepared by
disallowing 7401 g of base 2 (hexahydroazepino)-N-(276-
-dimethylphenyl)-acetQmide in 100 ml ox i~opropanol,
followed by the addition under stirring of 49 ml ox a
6 N solution of Hal in i~opropanol. I cooling thy
hydrochloride precipitated in form of white needles. Waco
recruit Ed Out Ox ethanol Mop = 175 176QC9
PHA~5ACOLOGI CAY ACTIVE TRY
1" LUKE anae~thetic: The activity ox 2-~hexahydro-
azepino)-N-(296-dlmethylphenyl)-acetamide a a local
10 1,
anae~theti~ way studied in kippers ~ithlidocaine;
myopic me and bupi~acaine, three jell known local
anae3thetios~ by the method of zipping a mouse's tail
with a arterial clamp at certain period of time after
intradermic injection of Out ml ox different concern-
traction ox the above drugs In this test eider
aæepino)-N~(2,6-dImethylphenyl~-acetamide was clearly
superior both in activity and in duration ox the
anae3thetic effete to lidocaine and mepiYacaine~ it
effect being comparable to that of bupivacains Allah
in all Casey the onset ox the anae~thetic effect way
much quicker with 2-(hexahydroazepino)~N-(2,~-dimethyl-
phenyl)-acetamide.
Similar results have. been obtained in a further
series of texts such that if lidocaine it arbitrarily
assigned an anae~thetic potency equal to 1, the Rosetta
are: mepivacaine = 0~8; lidocain~ a 1; bupi~acaine = 2-
~(hexahydroaæep mo)-N-(2~6-dimethylphenyl)-ac0tamide = 4-5
I Anti- : the activity of 2~(hexahydro-
azepino)-N-(~,6-dimethylphenyl)-acetamide as an
anti-arrhythmic way compared nit that of lidocai~e and
tokened two well known anti-arrhythmic~9 by calculating
the EDDY capable of inhibiting the ventricular
arrhythmia caused on subjecting group of mice to a
chloroform atmo~pherer The drug were administered
1 1 7
subcutalleousl~r it crying Dow and the anomaly were
en inked for 15 inlets *ollo~ring administratiorl to loo
or iguana ox ~eurotoxi~it~ Rich are us yo-yo ester
by attics LOBE of holding reflex 108~ of balailce9 etch,
thereafter arrhythmias were ducked Vito chlorofo~ ail
the ~ti-arrhyth~ and attics EDDY were conspired or the
3 drugs under study.
the results of these studies ovoid that the
protector EDDY against chloroform induced arrhythmias
was 60.8 mug for lidocaine, 25û mg/kg for tokened
and 40 mg/kg for 2-~hexahydroazepino)-N (2,6-dimethyl-
phenyl)-acetamide. On the contrary, theataxic EDDY were
I m ~kg7 146 m g and 45 mg/kg, respectively, for the
three drug, which shows that 2-(hexahydroazepino)~N-
-(296-dimethylphenyl)-ace-tamiae it the only one ox the
tested drug having a protective effect against
arrhythmia at a dose level not cays m g attics.
3. Acute toxicity: the acute toxicity of 2-
-(hexahydroazepino)-N-(2~6-dimethylphenyl)-ace-tammode way
determined by interwoven and subcutaneous administration
in comparison with other local anesthetic. The result,
summarized it Viable I below:
~23L5~
Table ID Acute toxicity it mice ox 2 (hexahydroazepino~-
~N-(296-dimethylphenyl~-acetamide it comparison with
other local anesthetic
LD50
Dry In~ravenou~Subcutaneoua
2-(hexahydroazepino3-N-
-(2,~-dimethylphenyl)-
-acetamide ~9(15~4-23,4)140(128,1 152,8)
Lidocai~c pow)
~upi~acai~e 6,4(5,5-793)45~38 54)
Tetracaine 4~1(299-593)32(25 - 423
show that the toxicity follow this sequence:.
tetracaino < bupivacaine 2-(hexahydroazepi~o)~N-
-(2,6-dimethylphenyl)acetamide ~lidoca me.
It the therapeutic induce namely the effective
dose toxic doze, it used as comparison criterion ye
best corresponds to 2-(hexahydroazepino)-N-(296-dimethyl-
phenyl)~acetamide, both a local anae~thetic and a anti-
-arrhythmia.
What eye claim it:
13
