CA2196064A1 - 4-(4-methanesulfonamidophenyl)butylamine derivatives with antiarrhythmic activity - Google Patents

Abstract

Methanesulfonamides are structurally depicted by formula (I), or its pharmacologically acceptable salts where R3 is a C1-7 alkyl substituted with C3-7 cycloalkyl, or a C1-10 alkyl substituted with one to eight fluorine atoms, one to three hydroxy, one to three C1-5 acyloxy or one to three C1-4 alkoxy substituents. These compounds are useful as Class III antiarrhythmic agents and are stable against rapid metabolism. Methods for treating cardiac arrhythmias with the compounds of formula (I) as well as compositions thereof are also described.

Description

~ 1 ~60~i4 WO 96108471 PCT/~S95/J9424 4-(4-METHANESUL~ u~HENYL)BUTYLAMlNE DERIYATIVES
WITH ANTIARRHYTHMIC ACTIVITY
RA~.R.OU ND OF TElEirNn~E~qON
r The present invention iB directed toward ~ .l.v , l- having a butyl linkage 5 between a tertiary amine group having a ' ' ' ~ d aide chain and a mPthsnPAnl fonamide, l. ~ l phenyl. Preferably the amine side chain has a fluorine rvl 1 l ~4 ~ These novel mPth~nPclllf~n~m;~iPc prolong the effective refractory period of the ~I.~u~.cuLu..., have a reduced tendancy to cause ~rlLyLlllllir and are very potent and stable against L 1' A--Li~.LJ Lh l i-, drugs act upon the ele.Ll U~UL-,~ 1U~ properties of the Ill~u~r Lulllandconductivetissues. Typicallytherhythmic...,.1~ .,. ofthe heart are dependent upon the ability of the ~ u~Lu~l~ and conductive tissues to respond to electrical impulses. When the ~u~uiu.,li~;Ly of the heart's muscle and conductive tissue is altered by an occlusion of an artery or disease, a life Lhl~r Lc~g 15 I,r I Luv lAr d~i~.;ul r Liull is likely. It is therefore desirable to treat the el..l.u,ul.y~;ùlûgk,l properties of the l.lyu~,rul;~ and conductive tissue to restore rhythmic, 8 ._:: .,~c while not disrupting the o~ u,ul.~ 1 properties further which can have the ullde~ ~uu~ side effects.
One means for restoring rhythmic . .I .r .., is with an ~Li~lLyLllllllc 20 agent that selectively prolongs the action potential duration and ~ ~ ly increases the refractory period of heart cells without significant effect on cardiac r~n8llrti~lA. Such drugg are classified as Clasg III ~ Lir..LyLll~,,i., agents. Class III
r lliAIlllyl~l~.,~ which have good bioavailability and which do not affect othercirculatory p-~ such as blood pressure and heart rate are continually being25 sought. The subject - l u . ~1~ are Class III ~lLi~Lyl- which are suitable for the treatment of mammals suffering from AulhyLl~c disorders or disease.
Class III _ L;A~1LYII~C agents have been associated with the d~,._lu,u..._.lL
of a pulylllulyllic ~ ,ùdAu h~ i6 (PVI~ known as Torsades de Pointes. This ,ulurllllyLllllu~. potential has limited the 11 Al Ir utility of this class of 30 ; , ' for treating ~lLyi- In an animal model it has been found that ibutilide, a compound disclosed in U.S. 5,155,268, has a .li. .:"i..h.~.l potential for inducing PVT (L.V. Buchanan et al., J. GlLu~ ulr~ pl ~ E;Y 2;~Q:540 (1993)) although further h.l~.u._..._..l is desirous. Compounds of this invention have been found to have improved and greatly ~limini~hPd potential for producing35 PVT in this animal model. This invention thus provides . , l u .,~c which have _ _ _ _ _ _ _ . _ _ .. .. ....... .... , . _ .... .. .. ... .. . . . . .

2 1,q60G4 improved safety for treating .~rLl.yl.lllias.
Bioavailability is another important ~ of any drug.
uurul ' 1!/, with r- ~ similar to ~ .I.uu, l- disclosed in U.S. 5,155,268, L;ua~a;lalv;l;iy is hampered by a rapid ' ' of the amine side chain. Thus, 5 the subject invention alsû seeks to solve this problem by ' _ the side chain to prevent rapid ' ~' and thereby increase L;uavail&b;l;iy. SUI~ Y~ the subject . ' have achieved this important bioavailability property and are potent tLuLa lLy11~ ~ as well.

10 I~ORr'ATTtlN DISCLOSURE STATEMENT
The subject ~ ' are structurally related to those ~ ~l~u ~k described in European Patent No. 0164865, and PCT PuuL~aLvll US90/03960, which discloses L . useful for the ~.~, " of the subject '-European Patent ArrlirAtir~n EP 0134424 discloses ~l ~aL~ y r. i~
15 salts of l v ~ which are isomers of the subject AIL Al .. 3 ~
T. K Morgan, Jr. et &1., J. Med Chem., 29, 1398 (1986) reports tertiary amine U.S. Patents 3,341,584 and 3,478,149 disclose ~ u~ rl4 some of which can be used as; " I .. l: - ' .. for the ~ u aLiv~ of the subject ~
Other U.S. Patents having ex~nples of ~ lf --.- .. ;.lr containing ~ I v l_ and ~Liar-l-yUIlui- activity are DeMarinis et al. 4,507,320, Molloy et al. 4,569,801 and 4,596,827, and Gould et al. 3,574,741.

.SI~'r'ARY OF THE INVENTION : ~ ~
In one aspect the subject invention is directed toward a compound of Formula I, its ~ .,-. l . ... or r~ g;. Ally acceptable salts thereo~
C~H5 CH3S02-~lH~CH2-CH2-CH2'CH2 ~

Formula I is defined where R3 is a C1 7 alkyl ' ' with C3 7 cycloalkyl, or a C1 1û alkyl, t ' with from one to eight fluorine atoms, or one to three hydroxy, one to three C1 sacyloxy or one to three C1 4alkoxy ~ ' ' :' .. ' Preferred ~ ~ l v l- are where R3 is a C1 7 alkyl having one or more 2 t ~61~4 wo 96/08471 ~I/U.. ,3.C ~~

Preferred ~ ' are fiuorine atoms. Rc~ Lr~L._ examples are N~4-(4-(Ethyl(7-ll....l,. ~.yl~amino)butyl)phenyl) ~i.-. ~r _ 1 N{4{4{Ethyl(6-nuuluL-l~Lyl)amino)butyl)phenyl)m~Ati --- ~r _ ~ and N{4{4-(Etbyl(6-fluoro,6 ' ~lhe"~yl)amino)butyl)pheny~ lr.. ~
In another aspect the subject invention is directed toward a method for treating cardisc cu Ihy LL.. iu in msmmals UUl~l,v.i-~b the c.l . . .; ~ .n of a Il~- - -1~ -.1 A~IY effective amount of a compound of Formula I including ri,~ rl.~ i. _lly acceptable salts thereo~ An effective amount i5 from about 0.01 to about 300 mg. Preferably, the compound ia - ' ' .1 in a unit dosage form 10 for oral, allh~in~lsi I .,...~.i. _l or parenteral ad~QLI~Liuu.
The Formula I cAnnrolln iQ are generally prepared into ~ i..g;. ~l ' Lu..s or ~ A for 1..~ ;-L,' tû patients auffering from cardiac culL~Llul ia. The (.. l u ~ l- are classified aa Clasa III ~ILi~uli.yLLl. ic which are agents that selectively prolong the action potential duration and ~ . .. 1~. ~l~y increase the refractory period of _eart cells without serious side effects or significant effects on cardiac rnn~in~;rn DETAILED DESCRIPTION OF THE SUEJECT INVENTION
Alt~nsAlllr~ rA which prolong tbe effective refractory period of the 20 ~uyu~.~diul~ and are useful for treating cardiac cu~LJ~' in mammala are disclosed. The ' of the present invention are l.~ VI by the structural Formula I, or its rh-~ - lly acceptable salt6. Formula I iB defined where R3ia a Cl 7 alkyl 1 ~ :l l d with a C3 7 cycloaL~yl, or a Cl 10 aL~yl, ' ' with from one to eight fluorine atom_, or one to three hydroxy, one to three Cl 5 acyloxy 25 or one to three Cl 4aL~oxy ~"l. l :l ., ~
Typically, ~- l v l~ similar to those described herein suffer from a bioavailabiLty problem associated with rapid ~ l of the amine side chain (herein, R3). It has been discovered that ' on this side chain can &I~_..t " u~ y prevent rapid ~ l and thereby increage the 1.1...,.1....I:
30 utiLty of the cAmrolln~iQ It has been discovered that the subject ~ .I v ~ have reduced aide effecta, such as ~lucu~LyLluuic potential and, therefore, are 11~. .nl.~ .11 lly preferred.
An "alkyl" is a straight or branched carbon chain containing the number of carbon atoms designated such as Cl 4, Cl ~;, Cl 10, etc. A ".,..l ' :1 ,.l-.l alkyl is a 35 straight or branched carbon chain having a hydrogen atom replaced by another _ _ _ _ _ _ _ . . . .. .... . _ ... . . . . . _ _ _ _ _ _ , . . ..

2 ~ ~60.6~
W096/08471 .~ .,,J~lr chemical group such as a cycloalkyl.
An "alkoxy" is an alcohol in which the hydrogen attached to the oxygen is replaced with 8 straight or branched carbon chain having one to four carbons.
A "~ ~ loall.yl is a cyclic ring structure formed from three to seven carbon 5 atoms. The cyclic structure may also contain an alkyl I ' wherein the total carbons are calculated to include thig cnh~ t;rn "Acyloxy" is an ester of a alcohol with a carboxylic acid having from one to five carbon atoms.
~ pl._... ..l.,~8 _lly acceptable salts" are acid addition salts which can be 10 prepared by any of the art recognized means. I~pical, acid addition salts include 11YULU~I1U.;~ y~ h~ hyd~u;uLdc~ sulfate, phosphate, acetate, rror;-not~
lactate, maleate, malate, succinate, tartrate, ~. 1.~l,.. .Ir_.. ~., ~"p'l, .. ~lF.. --~. " eth_nPc1llr ~ I lfrn ~ 1............. 1..... ,. .Ir.. -8 r, fumarates and other r~ h - ... - ~ lly acceptable counter ions for amines.
The Formula I l v . l are used for the treatment of -"LyUIl.. - wherever a Class m ~uL_~hy;llllllc drug is indicated. The .. l.u . I_ and ~ .P of Formula I are ' ' ev. in a 11.. . ~ .8-r effective amount which is an amount sufficient to control arrhythmia in the host being treated such as mammals whichincludes humans. Typically, the Formula I - lL- lLyUIllli~ agents are used in unit 20 dosages of from 0.01 to 300 mg in oral or irdectable ,ul~ 1: c Preferably, the Formula I .. l v.. l~ are used in unit dosages of 0.001 to 10 mg/kg for by routes either oral, ~ in~r~ l or parenteral such as by _.. 1,~"1_".. _ ;~1._.. 1-., or hlL~ v~.o irdection.
The particular dose of compound f ~ ' ' ' ed according to this invention will 25 of course be ,1~ ~. ...;..nd by the particular ~ .. ou~ v~dll.g the case, including the compound ~ ' l, the route of -~' the particular ~.IFllyl~llllia being treated, and similar .. ; l.. ,.~: .c The Formula I ' " l~u"l .k can be frrmnlotorl into typical rhA~ ~. -..1 ,.1 LullD for either oral or parenteral G'h.. l- _1 ~ For example, the Formula 30 I compound can be f~.rn~.lotod into a ... r "' by admixing with any of a number of suitable ~ diluents and carriers such as lactose, sucrose, starch powder, cellulose, calcium sulfate, sodium benzoate and the like. Such frrrn~ nccan be ~,U~Ul~ d into tablets or can be Pnrnp~ l into gelation capsules for convenient oral ~.l ...: ,.; . _ l :. , A gelatin capsule suited to oral ' " .~ : . may contain, for example, a wo sfilus47l 2 1 9 6 0 6 4 PCT/US95/10424 Formula I compolmd in the amount of about 0.1 to sbout 100 mg. Such r." .,..,1-I: .
can be - ' ~1 orally as of ~en as needed depending upon the particular condition and patient being treated.
For parenteral o.l~ . a Formula I compound can be frrmnlo~od for j l l Ll A ~ lor or il l LAA~ UllS ~~ ' ' I ' In the case of treatment of a patient suffering from a severe cardiac ~u~l~yU~ ia, it may be desirable to administer the Formula I compound by i-lL~ VUO infusion in order to effect a speedy conversion to a normPl cardiac rhythm. Such normal condition can then be ~,,A8~ d by oral p.~ , ..
The u~ -- A of the present invention may also include sustained release oral dosage forms and controDed release dosage forms by which the effect of the dosage is through the skin. Such ~ are those known to an ordinary ski4ed artisan or can be C~ . i, d4Od by ordinary ~ . . I l: .., from known~ '""I"'' ~ ...A such as creams, gels, pastes or liquids. ~ypical I . _ _ 1~ . .. -l 15 - l-v~ are pvl~ ..-_ glycol, triacetin, ,u~u,u,~ ., ethanol and isopropyl myristate The Formula I rrmpollnAAA can be combined with other ~.4LiA lLyU4lliù agents having the same or different ,.. l.-";_r. of action. For example, ....~.1.;l._~;....A may include, Class I AAAuLi u.L~LL44c agents, such as quinidine, tocainide, lidocaine or the 20 like; Class II AUL,. ,l.~U.4d. agents, such as, ~.uu.A~olol, soWol, atenolol or the like; Class III L.ILiAAu~llyU~ i. agents such as clofilium, sotalol, ~4dvv_lu.._ and ". .1 .I ..r; and Class IV anti u.L~LL~c agents such as verapamil or diltiazem.
Formula I U'" -1~U " 1A as shown in Examples 1 and 2 are prepared as described. Other for_s can be prepared by starting with suitable starting materials 25 as described in PCT p. I.li _1: - US90/03960, European Patents 0 164 865 and 0 233 051, U.S. Patents 3,341,584, 3,478,149, all herein i4~u~pu~Abv by reference.
The Formula I u l v 1~ were evaluated for Cle LIU1/L~ ~ O 1 activity in an isolated, perfused rabbit cardiac tissue system. Ihe method used was as follows:
New Zealand White rabbits of either sex (1.5-2.0 kg) were r- '~ - " 1 and 30 their hearts removed. The heart was immersed in ice cold perfusate while the right atria (RA), papillary muscles (PAP), and right ventricular muscle strips (RV) were isolated. The perfusate was, .~ UA~ bv with 95% oxygen and 5%
csrbon dioxide and contained the fo4Owing in mM .. 1. Al: .. c NaCl 118.0; KCl 5.4; NaHCO~ 25.0; MgC12 1.2; KEI2P04 1.0; CaC12 2.4; glucose 110.0 and pyruvic 35 acid 2Ø During hypoxic conditions the perfusate was eAposed to a mixture of 83~o .. . ... ... . . _ _ . . . _ _ _ 2 1 q6064 .
wo 96/0847~ PCTIUS95110424 nitrogen, 10% corbon dioxide and 7% oxygen. The pH during normoxia was U~lt~ ly 7.4 and dropped to ~.IJ,ulu~al~ 'y 7.2 dur~ng hypoxic cûnditions.
The tissues were individually mounted on a plexiglass holder containing platinum st;r~lnlsting electrodes and suspended in a 100 ml bath ~ 1 at 30~C5 by a circulating heat pump. All tissues were attached by silk suture to a force-c~ and a I ~ d~ 1 preload of 500-1000 mg was applied. RA were allowed to contract Rl...i~.... ~ly RV and PAP were stimulated at 2X threshold with 4 msec rP~on~llsr pulses at a frequency of 1 and 3 Hz.
OEffective refractory period percent increment over control are ERPl~0 and ERP3, conduction time l.._.._ 'I~...I_.liD are CTl and CT3). Between those tiOsues were stimulated at a resting pace of 2 Hz. Each tissue served as its own baseline control and was allowed an ~qn;lihrrl;~rl period of two hours prior to ~ During this period the perfusate wa~ changed every 10-15 minutes.
Working solutions of the drugs were prepared by dissolving the drugs in distilled water and one drop of NaOH/ml to aid in dissolutiûn (pH 9.4).
r~ 0 were made on each set of tissues after exposure to 10-7, 10-6, or lO~M drug for 15 minutes; and 10-5M drug under hypoxic conditions for 15 minutes.
20A.... ~ iy (RATE), force of . L,~ ~: .. (FOC) and threshold were measured directly on a polygraph. The ERP of cardiac tissues by definition is the longest coupling interval between the basic drive (Sl) and the premature impulse(S2) that fails to propagate through the tissue. The S2 stimulus was introduced after every eighth Sl which allowed time for ~ishili7st;rm of ~~
25 Refractory period ~ ..._..LD were made via a digital timing circuit. The limit of resûlution for these refractory period ~,..._.l~D was ~,u,u~u~ hllo.Lt~ly 6 msec.
C ' " time (CT) were recorded directly in msec by gently placing a teflon-coated silver bipolar electrode against tho C..IG~diA1 surface of the RV strip with the resulting ele_LIu~ c.ldiq;.~u.. displayed on an r.R~ An 30 increase in CT is equivalent to a decrease in conduction velocity.
Examples of Formula I . .I.v ~. l evaluated in this mamner are collected in Table I. A measure of the class III u~ y ll.. activity of these ~.. l u ,.. 1~ is indicated by the percent increase in the effective refractory period of rabbit papillary muscle ~ d at pacing rates of 1 and 3 Hz (ERPl and ERP3). The 35 ~ u. .. ~I~u.. li..g data for ibutilide, a structurally similar compound of U.S. Patent WO 96108471 2 1 ~ 6 0 6 4 . ~ e -~

5,155,268 i~ shown f~r '""l'~ CULl.,..,JollLllg data for a w ,u~lLiv~ compound ~where the l~Ul~ UIlUillg R3 position is (CH2)6CH3) disclosed in U.S. Patent 4,569,801 as ~ ... 1- ... 5, Col. 15 is shown as Formula M (Molloy). Corresponding data for another culll,u~Liv~ compound (where R~ is a fluorine ~ul- ''1 1_,1 alkyl, 5 (CH2)5CH(F)CH3), but contains an alkenyl linksge between the amine and P~lPqlllf~n~nni-lP ~ 1 phenyl) digcloged in PCT US90/03960 is shown as Formula H (Hester).

2~ 961~6~q WO 96/08471 r~ ~
.

E~1~ E~3 Exam~le # ;~3 ~E~
1 (CH2)7F 29.5 (5.4) 30.4 (1.3) 2 (CH2)5CH(F)CH3 50.1 (9.4)3 29.2 (8.5)3 Formula H2 (CH2)sCH(F)CH3 35.5 (7.02) 19.2 (2.9) Ibutilide2 ~CH2)6GH9 18.0 (4.1) 15.8 (2.0) Formula M2 (CH2)6CH3 28.3 (14.1) 19.2 (2.9) percent increase in the effective refractory period over control value~ mea~uredat a drug . ... I.. _I; of 10-5M and a pacing rate of 1 Hz i~ percent increase in the effective refractory period over control value~ mea~ured at a drug . - ~ of 10-5M and a pacing rate of 3 Hz Standard error of the mean 2 Not a compound of the invention 3 Data for a drug .. ~ - - of 104M

2 1 ~6064 WO 96108471 A ~,1/1)~. 1 '1 Exam~le # E~3 PV(%) In Vitro ~ v (CH2)7F 6 2 (CH2)sCH(F)CH3 13 3.1 3 (CH.,)5CF(CH3)CH3 0 3.2 Formula H2 (CH2)5CH(F)CH3 75 3,0 Formula M2 (cH2)6cH3 6 0.12 Table 2 shows dah collected from Examples of the invention as compared to 10 structurally close . l u ~ H (Hester) and M (Molloy), The PVT data is the percentage of rabbits that d--- - ' pul~ u~l/Li~i ventricular i~-~LJ.,~L~i following exposure to the drug, In vitro stability i9 a measure of the metabolicstability of the drug when exposed to pooled human L.._.~ The value represents the ratio of .P~ u~ of a control (an ~ ..-.,1: .... of Ibutilide) from a 15 microsome incubation relative to the rate of L~ u_~.,c of the drug, The value is inversely ,u. upu~ iiu.l&l to stabilit,v, therefore a small number indicates that the drug is rapidly ' 'i7Pd and is unstable.
Formulas 1, 2 and 3 show good to excellent resistance to PVT with ver,v good stability. "H" shows poor resistancc to PVT but good stability and "M" shows good 20 resistance to PVT but poor stability.

2 1 ~606~
W O 96/08471 P ClnUS95/10424 Exam~le 1 N~4-(UEthyl(7-11.. u.vl._"~yl)amino)butyl)phenyl) .. .~ ., I__ . A mixture of 34.32 g (0.133 mol) of 4~(.". l, ,. .lF~ -yl)amino)-k- - ~ acid (U.S. 5,155,268) and 24.74 ml (0.1775 mol) of Ll;_U.yl. .ule in 5 1500 ml of THF was stirred, under nitrogen for 5 minutes, cooled in an ice-2-propanol bath (-10~C) and treated dropwise during 10 minutes witb 24.24 ml (0.1775 mol) of isobutyl chlvlvrv IllG~G. This mixture was stirred at 0~C for 2 hours and then treated, dropwise during 25 minutes, with a solution of ll;_:llyl_llhlc (27.74 ml, 0.1775 mol) in 100 ml of 2.0 M L~ IGII11IIC (0.2 mol) in THF. The mixture was kept 10 at 5~C for 3.5 hours and ~ 1 in vacuo. The residue amounted to 40.8 g of an oil which crystallized on standing. It was recrystallized from EtOAc to give 2.68 g, mp 122-123~C and 12.71 g, mp 118-120~C of N-ethyl-4-_ " l r~ yl)amino)~

15 hlaLCalc~dforC13H20N2O3S: C, 54.90; H, 7.09; N, 9.85, S, 11.28. Found: C,54.85; H, 7.03; N, 9.84; S, 11.30.

~L To a 6tirred, ice cold sll~rPn~;"n of 2.9 g (76.3 mmol) of lithium aluminum hydride in 68 ml of THF, under nitrogen, was added, dropwise during 70 minutes, a 20 solution of 9.88 g (34.7 mmol) of the product from Step I in 200 ml of THF. The mixture was warmed to ambient L -- ~ and kept for 1 hour; it was then refluxed for 4.5 hours and kept at ambient 1....~ e for 18 hours. The mixture was cooled in an ice bath and treated, dropwise with 125 ml of a saturated aqueous solution of potassium sodium tartrate. This mixture was stirred 1 hour at ambient 25 i e and extracted with EtOAc. The extracts were washed with water and brine, dried (MgSO4) and .. ~ -d to give 7.07 g of crude product which was el.~_ '1;7Pd from - _'.. I.-;li to give 6.03 g (64.2%) of N (4{4~GLLY~ ~ )butyl)-phenyl)mPth~nPo llr ', mp 110-111~C.

30 ~IL A stirred mixture of 3.51 g (0.013 mol) of the product from Step II, 3.0 g (0.0152 mol) of a 1-bromo-7-nuu.uL_~l~e (see, PCTIUS90/03960, Ex. 32) and 2.71 g(0.0323 mol) of sodium l - A ~ b~ ~. ~ in 120 mi of AAAPtr~nitrilP was refluxed, under nitrogen for 24 hours and kept at ambient ~ -- l~ -' . ~ for 48 hours. Additional 1-bromo-7-nuu.ul._"k~e (0.4 g) was added and the mixture was refluxed for 3 hours 35 and kept at 75~C for 18 hours. It was then ~,UIl.~ lGLeV ~Z~Q. The residue was WO 96108471 ~ 1 9 6 ~ 6 4 PCT/US9S110424 m~xed with ice water ant extracted with CH2C12; the extracb were wached with water and brine and ~ 1 to give 3.18 g of crude product. This was .l on silica gel with 5% MeOH - 0.25% NH40H - CHC13 to give 2.38 g of the titled product, an oil. The high resolution maas spectrum had M+ at m/z5 386. Theory for C20H35FN2O2S: 386.2403; Measured: 386.2395. (Formula I where B3 is -(CH2)6CH2F)-~!v~ 2 N-~4~4~Ethyl(6-nuu. uh~ptyl)amino)butyl)phenyl)-10 ~LL A solution of 6-hydroxy heptanoic acid, E lactone (see, PCT/US90103960, Ex.
5) (18.94 g, 0.148 mol) in 66 mL of absolute EtOH was treated with 0.8 mL of conc.
H2SO4, stirred at room; . ~UI~: for 7 hours and ~.. _..:-,.1~.1 in vacuo. The residue was treated with ice and n~ntr~li7~d with dilute NaHCO3. The aqueous mixture was extracted with Et2O and the extracts were washed with water and thenbrine. The pooled extract was dried (MgSO4) and .. ~ l to give 24.38 g of crude product. This was combined with tbe product from a previous reaction and distilled to give 18.45 g, bp 96~C (2.2 mm Hg) and 6.73 g, bp 91~C (0.8 mm Hg) of etbyl 6-hydlu.yl.. l~

20 ~ILIL A solution of the product from Step I (18.4 g, 0.106 mol) in 200 mL of CH2C12, under nitrogen, was cooled to -72~C in a dry ice-acetone bath and treated dropwise with a solution of 30 mL (0.225 mol) of Et2NSF3 (DAST) in CH2C12 (195 ml) over 1 hour. The mixture was stirred at -72~C for 1 hour and then for 2 hours while the mixture was allowed to warm to 5~C (by periodic uddition of acetone to the 25 bath). The mixture was ' at 5~C for 15 minutes then poured into a mixture of 600 mL of 10% Na2CO3 and 200 mL of ice with vigorous swirling (foaming). The pH of the resulting aqueous mixture was 7. This was extracted with Et2O; the extracts were washed with water and brine, dried (MgSO4) and The residue was distilled to give 7.16 g (38.5~o) of ethyl 6-30 nU~ , bp 76-78~ (5.8 mm Hg): NMB (CDC13) ~ 1.26 (m, 4.5H), 1.35 (d, 1.5H), 1.57 (m, 6H), 2.32 (t, 2H), 4.13 (q, 2H), 4.57, 4.72 (m's, lH).

~L To a mixture of 3.46 g (0.096 mol) of LiAlH4 in 200 mL of Et20, under N2, at 4~C was added a solution of the product from Step II (10.4 g, 0.059 mol) in 35 mL
35 of Et20 over 45 minutes. The mixture was stirred in the cold for 15 minutes and 2 ~ 5~64 .

allowed to warm to room 1~ . G over 100 minutes. The mixture was cooled in an ice bath and treated dropwise during 40 minutes with 35 mL of saturated aqueous Na2SO4; 200 mL more Et2O was added and after stirring at ambient for 16 minutes tbe mixture was filtered through a pad of Na2SO4. The 5 filter cake was washed well with Et20 and the filtrate was ~ in vacuo.The residue was distilled to give 4.8 g (60.7%) of product, bp 85-87~C (9.2 mm Hg), which by NMR was slightly .. ~ l by an alkene, and 0.58 g (7.3% of clean product, 6-fluoro-1-heptanol): bp 85-87~C (9.2 mm Hg); NMR (CDC13) o L27, 1.35 (d's, 3H), 1.55 (m, 9H), 3.65 (t, 2H), 4.58, 4.73 (m's, lH).
~!. A solution of L;~L~ ' . ' ( 10.32 g, 0.0393 mol) and the product from Step III (4.8 g, 0.0358 mol) in 75 mL of benzene, under nitrogen, was cooled in an ice batb and treated, in portions over 40 minutes, with 7.0 g (0.0393 mol) of N-1,.. ' The mLxture was stirred in the cold for 20 minutes and at 15 ambient l~ .., for 2.5 hours. This mixture was poured into 250 mL of pentane, a precipitate was filtered off and the filtrate was ... ...1 ,_l-l at ambient G ia~aL. The residue was treated with 300 mL of pentane, tbe mixture was cooled, a solid was filtered off and the filtrate was ... .,~ 1 to 100 mL. This was cooled and a solid was filtered off. The filtrate was ~ d at 20 ambient ~ in vacuo. The residue was treated with 200 mL of Et2O and the solution was washed with 5% Na2S2O3, 0.5N NaOH and then brine, dried (MgSO4) and _ ,~ Q at ambient i . G to givo 6.6 g (93.6%) of l-bromo-6-nu~, ul~ --c: NMR (CDC13) o 1.22, 1.28 (d's, 3H), 1.57 (m, 6H), 1.88(m, 2H), 3.42 (t, 2H), 4.57, 4.73 (m's, lH).
3teD V. To a stirred mixture of 1.11 g (4.11 mmol) of N~4~4-.yl.. iuo)butyl)phenyl).,,-ll.- Ifrn~ n~ (as prepared in Example 1, Step II) in ~r~fnnitril~ (35 ml), under nitrogen was added 0.9 g (4.57 mmol) of 1-bromo-6-~e, the product from Step IV, and 0.77 g (9.14 mmol) of sodium 30 1: ~ The mixture was refluxed for 22 hours, cooled and < ~ l d in The residue was mixed with water and extracted with EtOAc. The extracts were washed with water and brine, dried (MgSO4) and .... ,. _ .. l . ~ 1 ~3L to give L59 g of crude product. This was .L~ .1 on silica gel with 5% MeOH -0.25% NH40H-CHC13 to give 0.94 g of the titled product. The high resolution FAB
35 mass spectrum had M+H~ at m/z 387. Theory for C20H36FN2O2S: 387.2481;

~ 1 960~4 wo 96108471 P~ I / u..,~ A C471 mea6ured 387.Z483. (Formula I, where R3 ia -(CH2)5CH(F~CH3.

Example 3 N.(4-(4-(Ethyl(6-fluoro-6-methylheptyl)amino)butyl)phenyl) A stirred solution of 2.0 g (0.0074 mol) of N~4{4{eul.~l~o)butyl)phenyl)-,.. ;1. -.. llf:.. .-.~F (ag prepared in Example 1, step II) in ~lF~tr~ trilF~ (64 ml) was treated with 1.72 g (0.00814 mol) of 1-bromo-6-fluoro-6 ._Ulylll.,"l~, (see EAsample 3, Step V) and 1.24 g (0.0148 mol) of sodium 1 A Ib . -~ ~ and refiuxed ~
for 17.5 hours. The mixture waa cooled, filt~red and . u ~ _.8 Al- d in vacuo. The residue was ~ on silica gel with 4% MeOH-0.4% NH40H - CH2Cl2.
A solution of the resulting product in ETOAc was washed with dilute NaHCO3 and brine, dried (17g SO4) and . . -..1. Al ~d to give 2.33 g (78.6~o) of the titled product.
The high resolution FAB mas6 spectrum had 17 + H+ at m/z 401. Theory for C21H38FN2O2S:401.2638; mea6ured 401.2645. (Formula I, where R3 i6 -15 (CH2)sC(CH3)2F) , ~ ,

Claims (6)

1. A compound of Formula I

or pharmacologically acceptable salts thereof wherein:
R3 is a C1-7 alkyl substituted with a C3-7 cycloalkyl, or a C1-10 alkyl substituted with one to eight fluorine atoms, one to three hydroxy, one to three C1-5 acyloxy or one to three C1-4 alkoxy substituents.

2. The compound of Claim 1 where R3 is a C1-10 alkyl substituted with one to eight fluorine atoms.

3. The compound of Claim 1 which is:
a) N-(4-(4-(Ethyl(7-fluoroheptyl)amino)butyl)phenyl)methanesulfonamide;
b) N-(4-(4-(Ethyl(6-fluoroheptyl)amino)butyl)phenyl)methanesulfonamide; and c) N-(4-(4-(Ethyl(6-fluoro,6-methylheptyl)amino)butyl)phenyl)methanesulfonamide.

4. The use of a compound of Claim 1 for preparing a medicament for treating cardiac arrhythmia in patients by administering a therapeutically effective amount of a compound of Formula I or pharmacologically acceptable salts thereof.

5. The use of Claim 4 where said effective amount is from about 0.01 to about 300 mg.

6. The use of Claim 4 where said compound is in a unit dosage form for oral, sublingual, transdermal or parenteral administration.