CA1183437A - 4-hydroxy-3-methoxy-n-[2-[2-(1-methyl-2- piperidinyl)-ethyl]phenyl]benzamide - Google Patents

Abstract

4-Hydroxy-3-Methoxy-N-[2-[2-(1-Methyl-2-Piperidinyl)-Ethyl]Phenyl}Benzamide Abstract of the Disclosure 4-Hdroxy-3-methoxy-N-[2-[2-(1-methyl-2-piperidinyll)ethyl]-phenyl]benzamide is an antiarrhythmic agent having relatively low toxicity and increased duration of action.

Description

3~

4-HYDROXY-3-~lETilO~Y-N-~2- [2- (1-~l~THYL-'~-PIP~3RIDINYL)-ETHYLI PHENYL~; ~ENZAMII)E

This application is a division o:E Canadian Ser;al N~. 3~36,216, Eiled September 18, 1981.
Field of th~ InvenSlo 4-~gdro~ netho~r-~12-~2~ ~thyl-2-p~perid~yl~ethyl~c, phenyl~ben~ hc~Procycl~c carbos ~ound of ~e p~p~r~dine E:erle~ hav~g n ~dd~eional rLn8 and ba~riDg ~troge~ at~ached lDd:Lrectly to the piperidin~ rlllg by Don-ionic ~o~d~Dg.

Summar~L of th ~nverltion Thi3 ln~entlc~ co-lcen~d ~lth the 4-hytrox~-3-~et21o~
benzanillde analog of e~cainida ~hich h~ th~ follo~ing struotural formNl~.

J

HO $~ 3 ]. 5 CH30 Thl~ ~ub~t~nce i~ tabolltQ 1L man of ~nc~inide ~nd an improved antia~rhythmlc a~eat with r~ga~d to lt~ extended durat~on of ~ction r~lat~vo to ~n~inide.

~LI 334:~17

2~g~ `, Encainide hydroc'nloride i8 an antlarrhythmic compound which ~9 al~o referred to in the llterature ns MJ 9067 ~USAN A~d ~he ~SP
Dictionary of Drug Mame~ l9aO, page 122, ~nited States Pharmacopeial Co~ventlo~, Inc.~ 12601 ~wiubrook Parkway, Rorkville9 MD 20852, Librar~ of CoDgress C~talog Card ~o. 72-88571~. Enca~nide ha~ the follow~ng structural formula.

- C~2C~2 ~ N

3 ~ ~ C~3 The followi~g publieations descr~be the ch~lcal ~ynthe~is of encainlde, a nu~ber of analogs thereof, and the a~tiarrhyth~ic propert~es of the~e co~pounds in an~mal~.
Dy~tra, et al., J. ~ed. Chem., 16, 1015-1020 (19733.
Dykstra and MiDlelli, U. S. Pstent No_ 3~931;195 patented Jauuary 6, 1976.
Byrne, et ~1., J. Pharmacolo~y snt Exper~mental Therapeutlcs, 15 200, 147-154 (1977).
Assay method~ for enca~lte and ~t~ ~et~bol$tes are disclosed the follo~lng refereDces.
~ayol snt Gammans, Therap. Drug Monl~or~ng, 1, 507-524 ~1979).

~lB34;~7 Detailed De~cription o the Invent~on The ~trueture~ of enc~inide and a ~umber of analogs thereof which are de~cxibed in ths foregoing Dykstra, at al. publicatlon and patent are shown in the follo~Dg table iu compar~on to the structure of thP cc~ound of the pre~e~t lnven~ion. The co~pound num~er~ ussd in the ~able are the same ~ ehe examyle ~u~bers ~mployed 1~ the Dykstra, et al~ patent. Compound No. A ~ ehe co~po~d of ~he present lnventio~. -Strrctureo CH2CH2--~N

nl ~ ~ COXC ~ R3, Compo~cl No. Rl R2 R

89 (0-demethylencainlde, or ODE) ~0- ~~ CH3-107 (enc ~ de, or E) ~ 0- ~~ c~3-108 ~- C~30- ~3-109 C~30- C~30- C~3 139 (~-demethylencalnide, C~30- ~- H-~
or ~DE) A (3-~etho~y-0-demet~yl- ~~ CH30- C~3-eucalnide, or 3-methosy ODE) Co~pound Nos. B9 and 139 have been ldentiflet by Mayol ~nd 2C Gammans (op. cit.~ ~ metabolites of encainlde ~Compound No. 107) in : ~hich publieation the former le referred to ~8 GDE ~nd ~he lattes as ~DE. The former ~ODE) has be~n identlfied a8 a principal ~etabol~te ~8~4~7 ~hlch i~ ~ometime~ present i~ pla~ma in amounts several time~ the concentration of encainlde follo~ln~ trentment wlth the lntter. AB a re3ult of an inpr~voment of ~he hi~h pressure liquld chromatography ~s~ay method desc~ibed in ~he Mayol acd GammanA publication, which ~provement co~stitute~ part of the pre~ent lnvention, ie hs~ been found ehat Compo~nd A 18 al~o a principal met~bolite of e~cainide in man followlng orsl a~m~nl~tratlon of th~ latter~ snd thnt it is pre~ent ~n concentration~ ~n the blood pl~Bma ~ubstantially greater than that Compound No. 89 two or more hour~ followiDg the admiD~stra~io~
of a 50 ~g. do~e of encainide kydrochloride orall~. ~he BPLC assay method describet in the ~ayol and Gamm2ns publicatio~ haR now been found to &a~e been incapable of disting~lsh~ng between Compound Nos~ 89 and Compound A. It 18 thought that Compousd A ~ produced In t~e body from Compou~d No. 89 by ~ btologlcal traD3formation proces~.
For comparat~ve purposes the biological actlvlty of ~he co~pounds whose stIuCtureS are shoun in the above table are pre~ented ln the folloN~næ table in ubich co3parat~ve antiarr~ythmic actlv$ty is glven ae determlned by the laboratory ~creeDiDg te~t referred to in the Dykst~a, et al_ paper above. Th$9 i~ refersed to in the ~sble 20 88 Test I~ Test II i8 ~n approximatio~ of the oral toxielty of the~e c~mpound~ $n mice, and Te~ts III and IV refer to the huDan metabolism results observed following oral admini8tration of an an~arrhythmic oral dose of 75 m8. total dose of encainide hydrochloride to patients.

4 -1183~37 ~b~
T~ ~nt~Rrrhvtkmlc activlty for ventricular nrrhythmis ln mice produced by chlorofor~ ~nha~at~o~; ED O expres~ed a~ mg/kg body weight~ lntraperltoneal admlni~t~ati~n, J. W. Isw~on, J. Ph~rmacol. Expt. Thar. loO, 22 (1968).
II. ALD tATD 0 mouse treated orally; ~LD50 i~ the approx~mate let~l do~e for hslf the an~mal~; ATD50 is the appro~lmate lowest dose wh~re 81gD9 of physiologic or neurologic deficit ~ppear in half the anlmal~, e~pressed as ~glkg body ~lght.
IIIJ Tlme follouin~ oral doslng of huma~s ~lth 75 mg. of enca~nide hydrochlorlde for clearance (plas~a concentration ~20 ng./ml.) ~rom blood plasma; ho~r~.
IV. Approxlmate half life i~ huma~ bloot plas~a following oral do~ing ~ith encainide hydrochlorlde; hours.
15Compound No. I II ~II IV
ô9 1.7-2.8* ~5_50t5-10 ~16 4-6 107 (encainlde) 5.3-15* 50-lOOt5-10 6 2.5-3 108 10 10~/10-2~ ** **
109 10 100/25 ** **
20139 28 147tl5.7 ~ ~
A 9.5 250/31.3-62.5 ~16 4-6 *Range of ~ariou~ dete~mlnation~.
**Compounds h2ve ~ot been a~mi~i~tered eo man nor ob~erved as metabGli~es of enc~inide in man or aD~als.
~Occurrence i~ pla~ma following o~al admini~tratlon of encainide to man has bee~ rare, and value has not been det~rminable.
The foregoing re~ults reflect approximately equl~ale~t a~tiarrhythmic activity for each of these sub~ances except for ~ompound No. 89 which is so~ewhat ~ore potent but al80 somewhat ~ore to~ic ln mice. Compou~d A dlffer3 ~r~m 2nd enJoys ehe advantages over each of Compound Nos. 89 and 107 of reduced toxicity and of a ~cre proloDged presence i~ the blood.

~escr~ptlon of Spec~fic Embodiments A. ~ract~o~ of ~olo~cal Fluid.~ To 1 ~1 of pl~s~ or

5 ur~e ln 8 screw-capped t~e these ~B added 0.2 SDl o~ 0.5 Pl. Tris-~lCl buff~r (2-~srt~ 2-hyd~o~ethyl-LJ3-propa:nedloY)3, p~ 8.5, a~d lû ml of ~butyl c)~oride containing 5~ by volume of '~50prS~pa~101. The ple 1~ the~ ~ha~ on a~ oscillati~ ;er foll~ed by ee~trlfu-~atlon to ~epa~ate the pha~es~ ~ 9 ~l a~l~t of ~he o~g~c layer O i8 r~nved and evaporated to dryne~ der a stream of sitro~e~ a~d the re~idue i5 re~tssolved i~ îO0 D~cl of cthanol. A 50 ~cl aliquot of th:Ls 801ut~0n i~ erted o~o ~he cDlumn for hlgh pr~sure liqu~d chromatography~
B. Eli~h Pres~ure Liquid _r~nato~raphy (I~LC) conditions.
~ ~ormal phase Rilicic acid cDlumn h~ving d~m~n5~0ns 3.9 mm b~r 30 cm in length equipped wi~h a v~iable ~velength ~I de~ector ~et at 254 Dm i3 u~ed. The bll pha5e e~ployed c~si~t~ of 500 ml of ethaDol, 30 ml of water~ d 0.1 ml of 1nethanesulfonic acid at a flow rate of 1 ml pe~ sinute. A ~eries of ~ea~dard~ conta~ g 0, 25, 100 and 500 ng/ml of each compound to be a~ayed ~as prepared u~ing pooled hu~an plasma. These ~tand&rds were treated as described a~ve. Quan~ification of ~he detector re~ponse was achi~ved by digital integration or mea~use~ent of peak heighe~. The 3tandard curve for each co~po~ent ~as co~structed by llne~r regresslon of the detector re~pon~e ver~us concentration fr~m the plasma standards.
The co~centraelo~ o compou~d ~ the sa~ple was then interpolsted fr~ these cu~ve~.

- 6 -~l8~
C. Result~.- The rel~tive order of elutiorl of encainide and its O-demethyl snd 3-methoxy 0-demethyl metabotlte~ from the colunm snd their r~t~ntlo~ time~ $s as follows: Compound No. 89, û. 3 minutes, Co~po~d A, 9.7 mi~ tes; Compo-md No. 107, 11.4 minu~e~.
5 The la~t e~doges~ou~ plasilDa cvmponent ~luted ro~ the colusnn hs~ a retes~tios tima of 3.6 ~utes a~d the bs~ellD.e i~ very sta~le ln the regiDn where the ~tabolite~ elute, 'rh~s, S~ ter~er~nce fr~m eDdogeIIous plass~a com~eD~ oc~urs. D~e to differ~nce~ trac~ion efficiencies, ~pec~lc molar aSsorpti~itiæ6~ a~d ~e~e~t~o~ t~ec for the individual componene39 ~he ~ensit:lv~ty of the asaay for each of the~e components i~ as follo~s: Compo~d No. 89, 10 ~gJ~l; Compound A, 20 ng~ml; Compound ~o. 107, 15 ng/ml.
E~ANPLE 2 Synthe3is of 4-~ydro~y 3-metho~y-~-[2-~2--(1-methyl-~
p~perld~nyl)ethyl~phe~yl]benzamide (Compou~d A 3~Methoxy ODE?
(1) lt With Mucic Acid.- A solutio~ of 7.3 8 tO 033 mole) of ~-(2-aminophenethyl)-1-methylpiper~dine in 65 ml of pyrid~ne i~ treated at ice bat~ tempesature with 9.3 g tO.034 ~ole) of 4-benzyloxy-3-~ethoxybenzoylchloride ~n 30 ~1 of tetrahydrofur~n. The resctio~
mlxture is stlrred for 1 hr a~ room ~e~perature a~d then ~olatile material~ re~oved by concentration ln vacuo ~o yield an oil. The latPe~ i8 di~olvet in chloroform, ~ashed ~ith dilu~e aqueou~ sodlum hydroxide water, brine, and then dried over ~agne~ium sulfate. The dried ~olutio~ i~ treated ~ith actlvated carbon and concentrated ~n va to ~u oll weighing 10.23 g ~hich is sho~n to co~tain only one compon~nt by thln layer chromatography. Thi~ materlal i8 then dissol~ed in 100 ~1 of ab601ute ethanol and catalytlcally reduced in 8 low pressure hydrogenation ~ppRratus over 2 g of 10~ p~lladi~ on .

~83437 ~arbon cataly~e at 60 p~tg un~ll one ~olecular proportion ~f hydrogen ha~ been ab~orbed. The cataly~t i~ remov~d b~ filtration and the ~olvent dlse~lled in ~acuo to yield the product ~n ~ree ba~e for~ ag a ~oam-like ~olld. Conver~ion to the m~cate salt i~ achi~ed b~
triturating the res~due ~lth hoe hexane to yleld 5.3 g of a gr~nular solid. The latter is dl~olved in warm ~b~oluts ~thanol and treated with 0.45 ~olec~ r equlv~lcntQ of mucic scid to yi~ld the hem~mocate salt whi~h is re~rystall~zed from 8 mi~ture of absolute ethanol and ethyl acet~ee, ~.p. llG-165D.
Ansl: C9 62,58; ~, 6.89; N, 5~75; H20, 2.18. The co~po-sltlo~ correspond~ to the ~nohydrate of ehe hemimucate s~lt.
IR: 760, ~290~ 1450~ 1505~ 1605, 1635, 1770, 2940, and 3400 cm-l.
~ N~R (DMS0-d6~: 1.55 (10, ~), 2.35 (3, 8), 2.65 t3, m~, 3.84 (3, ~), 4.12 (2, ~), 6.88 (1, d, ~.0 9z), ~.~i t53 m), 7.54 (1, ~), 9.80 (1, bs).
(2) Free Ba~e.- The foam-llke solid free ba~e above iB
di~solYed ln acetoue and deca~ted from lnsoluble material. The filtrate is diluted ~lth he~anP a~d concen~r~ted by boiling ~ff the solvent until a l~ght tan colored ~Dlid i~ formed whlch ~ collected.
Purlficatio~ of A portion of the tan colored solid by eolumn chroma-tography on alumlna us~ng chloroform cont~ining 52 by ~olume of methanol for development yielded materlal ~.p. 13S-136 which ~as indistingul~hable fro~ the orlgiDal by an~ly~isO
~5 Anal: C, 71,78; ~, 7.63; ~, 7.48.
rR: 760~ 1215, 1290, 1450, 1505, ~j85, 1640 and 2~40 cm 1.

~3343~
~R (CD~13): 1.20 (6, ~), 1.90 ~ ), 2.~ (3, ~), 2.70 (3~ m~, 3.90 (3, 9), 6.00 (1, b~), 6.89 (1, d, 8.2 ~Z), 7.22 (4, ~), `~.52 (1, d, 1.8 ~2), ~.OB ~ .4B ~, b~).
Tha ENMR BP8CtrU~ Of th~B ~ater~al w~3 1dent1C~1 ~ith th~
Of the ~etabO1ite i801ated frO~ P1~ = and Ur1ne ~amP1e9 bY th~ 8P~C
a~say PrOCedUre de~Cr1bed ~bOYe.
The COmYOU~d Of ehe PreBe~t inVentlon and lt3 pha~2ac~u~cally ~CCePtab1e ~a1tg ~ay ~ used fOr ther~PeUtiC PUrPOCea and PartiCU1a~1Y
~D~ the treatm~t Of CaSd~aC arSh~th~ n ~UCh the ~m~ ~ay and 1D
8~mi18S dO8aB2 ~mOU~t~ ~ eaCainid~o $03age 9e 10n~er ~nterval~ than 18 nece3sary ~th encainide i~ Yuitable ~ 15 1ndiC~ted by the relatl~Te pl8sma half-live8 o4 the two compounds. Dosage a~y be by the oral or pareDter~l routes lncludlDg ~tr~muRcular~ lnt~sperltonæ21, ~ubcutaneous and l~travenou~, the latter b~lng the pre~esred of the psre~teral routes. For ~Drmal therapeu~ic purposes 1~ the preventlo~
or treatme~t of asrhythmlsR~ oral ~dM~nistratlo~ ~8 preferred.
Generally, treatment ~8 o~menced wlth ~ umle do~e ~mall~ thsn anticlpated for opt~um co~tsol of the arrhythmia~ There~ft~r, the do~age i~ lucre3sed by ~mall iccre~entG until the opt~al e~fece 1 reached. Smsller do~age uDlt~ are ge~erall~ requi~ed far i~tra~enou~
treat~ent than are reqU1red fOr Ora1 treatm~. The dO~age amOUnt ~mtnistered i8 preferabl7 at D~ effeCt1Ve 1~Ve~ Wh1Ch 1~ wlthOut h~r~fU1 Or de1iterOU3 ~1de effect 0~ the Pati~Mt.
5he CVmPOUnd9 ~re Ordinar11Y ad~ini8teled i~ CO~binae10n with a PhBrmaCeUtiC81 Carrier. ~he ~eure 8nd Pr.OPOrtiOn Of Carr1er 1~ teter~1ned bY the ChOBe~ rOUte Of ~d~1D18~r~eiOn and bY th2 nOrm~1 Pr~Ct~Ce8 Of PhanmaCeUtiCa1 gCi~Ce. They ~y be ~d~ eered Ora11Y

....

~3~
:LD the form of tablets, coated tablets, or capsules cont~1nlng excipleat~ ~uch aEI atnrch, lacto~e, ~ugar, v~rlo~t~ ph~ ce~ltlcal clay~g gela~n, atearic acld or ualts ~hereof ~ ve%etable fEIt~ or oils, g~ms, ~lycol~ and other Icnown ~7~c~pien~s. For parellt~r~
5 ~dministration ~terlle ~olut~ nn0 are pref erred .
The nonnal dosage r~nge i~ from 0. 01 to 20 mg/kg of body elgh~ of the mammal ~der tre~t~ne~t. Fixed dosage ~ 0 containi~g fro~n 1 to 500 mg an~l prefer~bly from 5 to 100 ~g of the acti~Je i~gredien~ Bre pref erred .
E~AMPL~ 3 The compouIlds of ~he prese~t lnve~tio~ are fon~lated wieh pharmacologically ~cceptable carrier~g to pro~ride co~npo~itlon eful in the preaent invention. ~ypi cal of the ph3r~aceutical composit~ On5 are ehe followi~g:
A. Tablet~
~erial Amount __ Compound A (~ample 2), as the ba~e 50.0 g ~a~nesiu~ 3tearat~ 1.3 g Cor~ s~srch 12.4 g Corn ~tarch pregelatinized 1.3 g Lacto~e 185.0 8 The foregoin8 ~aterlals are blended in a twin-shell blender Rnd th~n granulated snd pre3~ed l~to tablets wei~hing 250 mg. each.
Each tablet c~nt~ 50 mllllgrams of active ingredient. The tablet may be scored in quar~ers ~o thst a do~e of 1~.5 mg. of ac~ive lngredlent $ay b~ conveDiently obtained.

~33~

B. C~PBU:1eB
M~t~rial Amount Co~pou~d A SExa~ple 2)~ a~ the b~ae 125.0 mg Lac~o~e 146.0 ~g M~g~e~ium ~ear~te 4.0 mg The foregoin8 ~aterial~ are bl~nded in 8 twln-sh~ll blender a~d then ~illed i~to ~o. 1 hard gelat~n cap~ule~ Ea~h c~p~ule contaiD~ 125 Mg of ac~lve in8rcdient~
C. Solution for l~trav~nous Admini~tra~ion A s~er~le solut~on ~b~e for ~v~ us i~Jectiou i~
prepared by dl~olving 10.0 g of Compou~d A (Exa~pl~ 2) a~ the ba3e in a mlnlmal smount of 0.5 N hydrochloric acid. Thi~ solueio~ is ad~usted to p~ 4.3 wlth 0~1 ~ sodium hydroxlde asd diluted to 1000 ~1 tot~1 so1ume with physio1Ogic Bal~n~ ~olution. The ~o1uSion i~
s~eri1ized by pa~sage t~rough ~ bac~erlologic81 f11ter ~nd ssept1cal1y fi11ed 1~to 10 ~1 ~terlle ~mpoule30 ~ach ~i11111ter of ~olu~io~
contain8 10 mg of ~he actlve in~red~e~t.
The invention, in its broadest aspect, contemplates a process for preparing 4-hydroxyl-3-methoxy-N-[2-[2-(l-methyl-2-piperidinyl)ethyl]
phenyl]benzamide having ~t~ f I a and a pharmaceutically acceptable acid addition salt thereof which comprises contacting 2-(2-amino-phenethyl-l-methylpiperidine with 4-benzyloxy-3-methoxybenzoylchloride, then catalytically debenzylating the resulting product and, if desired, forming a pharmaceutically acceptable acid addition salt thereof.
In a Eurther embodiment, the invention contemplates a process for the quantitative determination of encainide and the 0-demethyl and 3-methoxy-0-demethy:L metabolites thereof in a biological fluid involving extractiOn thereof from the fluid and separation thereof by high pressure liquid chromatography on a silicic acid column using an organic solvent as mobil phase, wherein the mobil phase is the mi~ture ethanol:wdter:
methanesulfonic acid 500:30:0.1.

Claims

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

1. In a process for the quantitative determination of encainide and the 0-demethyl and 3-methoxy-0-demethyl metabolites thereof in a biological fluid involving extraction thereof from said fluid and separation thereof by high pressure liquid chromatography on a silicic acid column using an organic solvent as mobil phase, the improvement wherein said mobil phase is the mixture ethanol:water:methanesulfonic acid 500:30:0.1.