CA1215048A

CA1215048A - 2-(hexahydroazepino)-n-(2,6-dimethylphenyl)- acetamide, the hydrochloride thereof, a process for the preparation thereof and pharmaceutical compositions containing them

Info

Publication number: CA1215048A
Application number: CA000432227A
Authority: CA
Inventors: Alvaro Galiano Ramos; Alberto Stampa Diez Del Corral
Original assignee: Medichem SA
Current assignee: Medichem SA
Priority date: 1982-07-14
Filing date: 1983-07-12
Publication date: 1986-12-09
Also published as: NL8302507A; SE8303862D0; IT1169538B; ES8305724A1; GB2124223A; IT8322053A0; SE8303862L; BE897281A; GB8319108D0; JPS5951272A; DE3325004A1; FR2530244B1; IT8322053A1; GB2124223B; FR2530244A1; ES513980A0

Abstract

ABSTRACT OF THE DISCLOSURE

A new compound, 2-(hexahydroazepino)-N (2,6--dimethylphenyl)-acetamide, and the hydrochloride thereof, the process for the preparation thereof and pharmaceutical compositions containing them. The new compound and the derivative thereof have application for their local anaesthetic activity and anti-arrhythmic activity. The new compound is prepared by reacting 2,6-dimethylaniline with chloracetyl chloride to give 2-chloro-N-(2,6--dimethylphenyl)-acetamide which is reacted in turn with hexahydroazepine.

1.

Description

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 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 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:

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of 2-(hexahy-droazepino)-N-(2,6-dimethylphenyl)-acetamide having the formula:

(I) and the hydrochloride thereof having the formula:

(Ia) which comprises:
a) reacting 2,6-dimethyl-aniline of the formula:

with chloracetyl chloride of the formula:
ClCH2-COCl to form 2-chloro-N-(2,6-dimethylphenyl)-acetamide of the formula:

which is thereafter reacted with hexahydroazepin of the formula:

to obtain the desired compound of formula (I), and b) when desired, converting the compound of formula (I) thus obtained into the corresponding hydrochloride of the formula (Ia).

2. A process according to claim 1, for the pre-paration of 2-(hexahydroazepino)-N-(2,6-dimethyl-phenyl)-acetamide of the formula (I), wherein 2,6-dimethyl-aniline is reacted with chloracetyl chloride to form 2-chloro-N-(2,6-dimethylphenyl)-adetamide which is thereafter reacted with hexahy-droazepin to obtain the desired compound of formula (I).

3. A process according to claim 1, for the pre-paration of 2-(hexahydroazepino)-N-(2,6-dimethyl-phenyl)-acetamide hydrochloride of the formula (Ia), wherein 2,6-dimethyl-aniline is reacted with chlo-racetyl chloride to form 2-chloro-N-(2,6-dimethyl-phenyl)-acetamide which is thereafter reacted with hexahydroazepin to obtain 2-(hexahydroazepino)-N-(2,6-dimethylphenyl)-acetamide which is then converted into the corresponding hydrochloride of the formula (Ia).

4. A process according to claim 3, wherein 2-(hexahydroazepino)-N-(2,6-dimethylphenyl)-aceta-mide is reacted with dilute hydrochloric acid in an alcohol medium to obtain the corresponding hydrochlo-ride of the formula (Ia).

5. 2-(Hexahydroazepino)-N-(2,6-dimethylphenyl)-acetamide having the formula:

(I) and the hydrochloride thereof having the formula:

(Ia) whenever prepared by a process according to claim 1 or its obvious chemical equivalents.

6. 2-(Hexahydroazepino)-N-(2,6-dimethylphenyl)-acetamide, whenever prepared by a process according to claim 2 or its obvious chemical equivalent.

7. 2-(Hexahydroazepino)-N-(2,6-dimethylphenyl)-acetamide hydrochloride, whenever prepared by a process according to claims 3 or 4, or their obvious chemical equivalents.