DERIVATIZED AL ANOLAMINES AS CARDIOVASCULAR AG NTS

Field of Invention

This invention relates to novel derivatized alkanol- a ines and their use as cardiovascular agents. More specifically, it deals with al anolamines derivatized by at least imidazol -1-yl phenyl or al yl sul fona nophenyl moieties, and their pharmaceutically acceptable salts. In the cardiovascular aspect compounds have been found especially to be antiarrhythmic agents possessing a combination Class II/Class III activity. The invention also relates to pharmaceutical compositions containing such compounds and their usefulness in cardiovascular therapy.

General Description of the Invention

Composition-of-Matter Aspect

In its composition-of-matter aspect this invention relates to novel derivatized a anol ami nes and their pharmaceutically acceptable salts. Particularly, this invention relates to the novel compounds defined by the following Formula I:

In the foregoing Formula I

Q is defined as ( C, -C _d ) -S0--NH- or

!=\ . >- x is the integer 0 or 1

0 I!

A is defined as -C-N-AI -NH- , S0--N-ALK-NH- ² I

R

-0-A -NH- -ALK-NH-

AL

R s y rogen, ower alkyl , 2-propenyl or lower- alkoxyloweral kyl . R- , R^, and R ₃ are the same or different and selected from hydrogen, lower alkyl , lower alkoxy,

2-propenyl , 2-propenyl oxy , 1 oweral koxyl oweral kyl , halogen.

■CF-., -CN \ ii

N-C-CH,

(C _Γ C ₄ )-SO ₂ NH* or (CH ₂ ) -0- CH (CH ₂ ) _t v

r is an integer of 1-4; w is an integer of 1-3; p is an integer of 1-3 and t is an integer of 2-5.

R ₄ is hydrogen or lower alkyl ; and the pharmaceutically acceptable salts thereof, with the provisos that:

0

II a) when A is -C-N-ALK-NH- or

I

R

■SO.N-ALK-NH- then Q cannot be ² |

(C ₁ -C ₄ )-S0 ₂ NH-

b) Q cannot be ortho to the "A" attachment and further when Q is (C _j -C^SOgNH- , it must be para to the A attachment;

c) when A is -N N- or -C- N N-

\ / then x must be the integer 1;

SUBSTITUTE SHEET

d) when A is -0-ALK-NH- , then r cannot be the nteger 1;

e) when x = 0 then B cannot be and f) when Q is (C _j -C _j -SOgNH- and A is ALK then x must be the integer 1.

As indicated, contemplated as part of this invention are the pharmaceutically acceptable salts of the compounds of Formula I. Useful acids for this purpose include both inorganic and organic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, propionic, benzoic, naphthoic, oxalic, succinic, maleic, malic, adipic, lactic, tartaric, citric, salicylic, methanesul fonic, and p-tol uenesul foπic acids.

It is to be understood that the definition- of the compounds of Formula I encompasses all possible stereoi so ers and mixtures thereof which possess the activity discussed below. In particular, it encompasses racemic modifications and any optical isomers which possess the indicated activity. In the above Formula I the term lower alkyl shall refer to a straight or branched chain of from 1 to 4 carbon atoms, lower alkoxy shall refer to a straight or branched chain of from 1 to 4 carbon atoms. The term loweralkoxy- loweralkyl shall be taken to mean a straight or branched chain alkoxy/alkyl of from 1 to 4 carbon atoms. The term halogen shall be taken to mean fluorine, chlorine, bromine or iodine.

Preferred classes of compounds embodied by this invention are those of the above general Formula I and having the following characteristics:

a) when A is -0-ALK-NH- and Q is (C,-C _Δ )-S0,NH- ;

b) when A is -0-ALK-NH- and Q is

and

c ) when A i s -

In addition to the compounds exemplified in the Examples section, the following are representati e of sti further aspects of the invention.

1. N-[4-[2-[[2-hydroxy-3-[4-(2-methoxyet yl )phenoxy]- propyl]amino]ethoxy]phenyl]methanesulfonamide.

2. N-[4-[3-[[2-hydroxy-3-[4-[(methylsulfonyl)amino]- phenoxy]propyl]amino]-3,3-dimeth lpropoxy]pheny1]- propanesul fonami e.

3. N-[4-[2-[[3-[[[bis(cyclopropyl )methyl ] mi no]oxy]-2- hydroxypropyl]amino]ethoxy]phenyl jethanesul fonamide.

4. N-[4-[2-[[-3-(5,6,7,8-tetrahydro-5-oxo-l-naphthaleny o )-2-hydroxypropyl ]amino]ethoxy]phenyl jbutane- sul f on a i de .

5. N-[4-[3-[[2- hydro xy-2-(l-naphthalenyl )eth l] am ino]- oropoxyjp enyl ]rnethanesul fonamide.

6. N-[4-[2-[[3-(3,4,5-tπ ^' ethoxyphenexy:-2-hydrcxyprcpy ] -ami no]ethoxy]phenyl]methanesul fonamide.

7. N-[2-[[3-[[[bis(cyclopropyl)methyl]imiπo]oxy]-2- hydroxypropy1]amino]et yl]-4-[(ethylsulfonyl )amino]- benzenesul fonamide.

8. N-[2-[[2-hydroxy-3-(l-naphtha1 eπyl oxy)propy! ]ami no]- ethy1 ]-4-[ (methy1 sulfon l) amino]benzeπesul fonamide.

9. N-[2-[[3-[4-(2-ethoxyethyl )phenoxy]-2-hydroxyprop l ]- a i no]ethyl 3-4- (IH-i idazol-l-yl)benzenesul fona ide.

10. N-[4-[[2-hydroxy-2-(l-naphthalenyl ) ethyl ]ami no]-4,4- dimethyl butyl ]-4- ( lH-imidazol -1-yl )-N-prop l- benzenesul fonamide.

11. N-C2-CC3-CC[bis (cyclopropy! ) ethyl ]imi no]oxy]-2- hydroxypropy1]ami πo]ethyl ]-4-[lH-imi dazol -1-yl ]- benzenesul fonami de.

Process Aspect

In general , the compounds of this invention may be prepared by various reactants and processes known in the art. Illustrative but not limiting as the reactants and processes utilized for the preparation of the compounds of the invention are the following Schemes A-H and J:

As depicted in Scheme A, treating methyl amino- benzoates 1 under typical Debus conditions (NH ₄ 0H, formaldehyde and glyoxal ) affords methyl imidazolyl- benzoates 2. Reaction of methyl ami nobenzoates 1 with various a vl sul onyl chlorides in pvrid ne and methyiene

chloride, usually at about 0°C, gives methyl al kyl sul fonyl aminobenzoates 2. Compounds 2, when treated with aqueous sodium hydroxide, give the sodium salts 3. Acid chloride formation follows when the sodium salt 3 is treated with thionyl chloride (neat) or in refluxing toluene. Amides 5 are prepared when acid chlorides 4 are treated with 1-benz lpiperazine in a solvent such as tetrahydrofuran . Hydrogenolysi s of the benzyl group occurs when the amides 5 are treated with hydrogen gas and a catalyst such as palladium on carbon. Common solvents for this hydrogenolysi s are water, ethanol , methanol and various mixtures thereof. Compounds 7 of this invention are prepared when amide 6 is mixed with known in the art epoxides in methanol . Compounds 9 are prepared by treating amides 6 with -hal oketones and Huenigs base in acetonitrile and subsequently reducing the ketone moiety of 8 under standard hydrogenati on conditions (H ₂ , Pd-C, Me0H/H ₂ 0) .

Scheme B summarizes the process for preparing compounds 13 and 15 where ALK=CH ₂ . Treatment of amino- benzoni tri 1 es 10 under typical Debus conditions give imidazolylbenzonitriles 11. Aminobenzonitriles 10 can be al kyl sul fonyl ated giving 11, using various al kyl sul fonyl - chlorides in pyridine and methyiene chloride. Reduction of the cyano moiety of 11 using hydrogen gas psi) and a Raney-Nickel catalyst in a moni a/methanol produces alkylamines 12. Treating 12 with known in the art epoxides n a solvent such as methanol gives compounds 13.

SUBSTITUTE SHEET

Compounds 15 are prepared by reacting 12 with α-halo ketones and Huenig's base in acetonitrile and subsequently reducing the ketone moiety of 14 under standard hydro- genation conditions (H ₂ , Pd-C, MeOH/H ₂ 0).

Scheme C summarizes the preparation of compounds 13 and 15 where ALK has the meaning described above in the specification and claims section of this invention. Generally ni trophenal kyl halides 16 are treated with sodium phthalimide in a solvent such as dimethyl formamide and give ni trophthal imides 17. Reduction of the nitro moiety by the method of Bellamy (SnCl ₂ , EtOH) gives amino- phthalimides 18 after work up. Imidazole formation via the Debus reaction (NH ₄ 0H, formaldehyde, glyoxal) follows to give 19. Al kyl sul fonyl ami no derivatives 19 are prepared by treatment of 18 with various al kyl sul fonyl chlorides in pyridine and methyiene chloride. Cleavage of the phthalimide moiety of 19 using hydrazine hydrate in refluxing ethanol yields alkylamines 12. Compounds 12 are employed to produce 13 and 15 using the general method outlined in Scheme B.

Preparations of compounds 24 and 26 of this invention are summarized in Scheme D. Treatment of 1-f1 uoro-4-ni tro- benzene and 1-benzyl pi perazi ne in acetonitrile with potassium carbonate affords ni trophenyl piperazi ne 20. Reduction of the nitro group using tin chloride in ethanol gives ami nophenyl pi perazi ne 21. When 21 is stirred with a mixture of ammonia, formaldehyde and glyoxal (Debus conditions) imidazole 22 is formed. Treating 21 with various al yl sul foni c anhydrides in a solvent such as acetonitrile produces al kyl sul fonyl ami des 22. Hydrogenolysi s of the benzyl group of 22 is carried out using standard conditions (H ₂ , Pd-C, EtOH/H ₂ 0) and yields 23. Reaction of 23 with known in the art epoxides in mixtures of methanol and water give compounds 24. Compounds 26 are prepared by treating 23 with -hal oketones and Huenig's base in acetonitrile and subsequently reducing the ketone moiety of 25 using standard reduction conditions (H ₂ , Pd-C, Me0H/H ₂ 0) .

The corresponding 3-imidazolyl derivatives 31 and 33 are prepared by analogous synthetic methods to those used for 24 and 26 via Scheme E. The only difference is that compound 27 is produced from the treatment of 3- nitroaπiline with N ,N-bi s ( 2-chl oroethyl ) benzyl ami ne hydrochl ori de in ethanol containing potassium carbonate. Compound 27 is carried through the same synthetic sequences as 20 (Scheme D) and provides compounds 31 and 33 of this invention.

©UB^B I-XJUT^SHEET

The synthetic sequences for preparing compounds 37 and 39 is summarized in Scheme F. Imi dazolyl -phenol s 34 can be alkylated with various chl oroal yl ami nes or chloroalkyl- benzylamines with sodium hydride in dimethyl formami de to give imi dazol e-ami nes 35 and 36, respectively. Treatment of 35 with various epoxides in methanol /water affords compounds 37. Reaction of imidazol e-ami nes 36 with α- haloketones and Huenigs base in acetonitrile yields imidazol e-ketones 38. Standard reduction of 38 (H _{2 >} Pd-C, MeOH/H ₂ 0) gives compound 39 of this invention.

Compounds 45 and 47 of this invention can be synthesized by the sequence shown in Scheme G. Nucleophilic aromatic substitution of 1-f1 uoro-4-ni tro- beπzene with various di benzyl ami noal cohol s using sodium hydride in dimethyl formami de and tetrahydrofuran affords n rodibenzyl ami nes 40. Reduction of the nitro group (SnCl ₂ , EtOH) followed by al kyl sul fonyl atioπ in acetonitrile yields di benzyl ami nes 42. Monodebenzyl ati on of 42 can be achieved under standard hydrogenolysi s conditions (H ₂ , Pd-C, EtOH/H ₂ 0) to give benzylamines 43. Complete debenzvl ati on of 42 can be accomplished under mor vigorous conditions (H* _2> Pd(0H) ₂ , HOAc, ^r - S Q psi) and affords amines 44. Amines 43 and 44 can be carried through the same synthetic sequences as amines 36 and 35 (Scheme F) to give compounds 45 and 47 of this invention.

SUBSTITUTE SHEET

Di benzyl ami nes 49 can be prepared by reacting various di benzyl i ami nes with either benzenesul fonyl chlorides or benzoyl chlorides 48 in a solvent such as tetrahydrofuran (Scheme H). Compounds 49 can be carried through the same sequences as compounds 42 (Scheme G) to produce compounds 52 and 54 of this invention.

An alternate way of preparing 52 follows from Scheme J. Methyl imi dazol l benzoates 55 can be heated with various al kanedi ami nes to give amines 50. Treating 50 with epoxides known in the art yields compounds 52 of this invention.

In general the methods for preparing the optically active enantio ers of the compounds of Formula I follow standard procedures. For instance, to produce the compounds of Formula I wherein x is the integer 1, the corresponding epoxides are formed from the optically active epi chol orohydri ns or tosylates. In the instance where x is the integer 0 the compounds, via one procedure, are prepared from the corresponding racemates by classical resolution procedures i .e., optically active acids forming di astereomeri c salts which are separated then converted to the free bases to produce the corresponding enantiomers.

TTUTE SHEET

SCHEME A

SCHEME B

SUBSTITUTE SHEET

SCHEME C

Z=Cl,Br

10 16 17

SnCl ₂

(C^C^SO _j Cl EtOH pyr,CH ₂ Cl ₂

A K-NH_,

25 12

30

SCHEME D

κ ₂ co ₃

°2 ^» -©- * HN ^/ ~\ NCH, Λ0

NCH _2T <

CH,CN ^■* ®-G

20

26

24

SUBSTITUTE SHEET

SCHEME E

27

SnCl ₂ EtOH

NH ₄ OH

H ₂

CH ₂ OB 10% Pd-C MeθH/H ₂ θ MeOH/H ₂ 0

SCHEME F

36

Q=

N' N

Cl-ALK-NH, -HC1 XCHjCB

NaH CH ₃ CN X=Cl,Br

DMF Et(iPr) ₂ N

37 39

suBsiriτϋ g

SCHEME 6

SnCl, EtOH

45

SCHEME H

O X=Cl,Br

XCH ₂ CB CH ₃ CN

CH ₂ 0B

Et(iPr) ₂ N MeOH/NaOH

54

SCHEME J

J& Y-N-ALK-N- CH ₂ PCHCH ₂ OB H

52

ethod-of-Use and Pharmaceutical Composi ? on Aspect

The novel alkanol a ines of th s invention derivatized by at least a imidazol -1-yl phenyl or al kyl sul fonyl ami no- phenyl moiety and their pharmaceutically acceptable salts are cardiovascular agents. Most especially within the aegis of cardiovascular pharmacology, these compounds have been specifically designed to provide a combination beta- adrenergic blockade with el ectrophysiol ogi c activity to selectively prolong cellular refractoriness. According to the Vaughan Williams classification, such agents would have Class II/Class III ant arrhythmic effect. Such combination contains those therapeutic effects attributed to Class II and Class III antiarrhythmic agents singly.

In the Vaughan Williams classification of anti¬ arrhythmic agents, Class II agents are the β-adrenergic blocking agents, which so called β-blockers decrease the sensitivity of the cardiac tissue to catechol ami nes . The catechol ami nes in excess can increase the electrical instability of the heart. Class II agents are exemplified by propranolol , metoprolol , nadolol , timolol , atenolol , sotalol, acebutolol and nipradilol. The Class III agents prolong the action potential duration of the heart thus increasing the time interval in which the heart is unexcitable (refractory period) without slowing conduction or changing the excitability of the cardiac cells. These agents have little or no effect on conduction, in fact, they are quite independent of conduction. Such agents are exemplified in the literature by bretylium, amiodarone, clofilium, melperone and se atϊlide (the latter compound developed in these laboratories) .

SUBSTITUTE SHEET

Several investigators have demonscrated tnat the arrhythmia responsible for sudden cardiac deat is ventricular fibrillation (VF). VF has been shown to occur via a reentrant mechanism. Reentrant ventricular arrhythmias can occur as a result of abnormalities in conduction and/or refractoriness. In a reentrant arrhythmia, a single cardiac impulse follows a circular pathway, allowing repeated excitation of the same tissue. One approach to the abolition of such reentrant arrhythmias is to further prolong the refractory period of cardiac cells, such that the impulse, upon returning to its point of origin, is met with refractory tissue and propagation of the impulse is stopped. This is clearly the therapeutic rationale behind the development of agents possessing Class III activity.

Reentrant arrhythmias often are initiated or "triggered" by an appropriately timed premature impulse. In patients following myocardial infarction, excessive catechol ami ne levels may be responsible for triggering many arrhythmias which may be associated with sudden cardiac death. In fact, the results of several large, multi-center trials have shown that beta-adrenergic blockers can reduce mortality from sudden cardiac death in post-infarction patients. Presumably, beta-blockers work by decreasing the sensitivity of the heart to catechol amines, and thereby decrease the potential "triggering" event which leads to reentrant ventricular arrhythmias. The overall decrease in mortality from these studies is approximately 25%, suggesting that beta-adrenergic blockade when used alone offers no beneficial antiarrhythmic effect in the remainin majority of post-infarction patients. Clinical data such

g g e mu p e et o ogies present in patients dying of sudden cardiac death ana the need for a more "broad spectrum" approach. One broad spectrum approach is to produce an agent with both Class II and Class III properties. Several investigators have shown that an increase in sympathetic tone to the heart will shorten refractoriness, an action which can be blocked by beta-adrenergic antagonists. Preliminary data using the selective Class III agent clofiliu have shown that its Class III actions are blunted in the setting of enhanced sympathetic tone (Sullivan and Steinberg, 1981). Furthermore preliminary studies performed in conscious dogs in these laboratories suggest a synergistic effect between inhibition of beta-receptors and prolongation of refractoriness. In pilot studies utilizing programmed electrical stimulation (PES) techniques to induce reentrant arrhythmias, a sub-therapeutic dose of sematilide was administered and shown not to be efficacious. Subsequent administration of a beta-blocking dose of propranolol (0.5 g/kg, i .v.) was shown to protect the heart from PES-induced arrhythmias. Previous studies in these laboratories have demonstrated that propranolol when used alone is not efficacious in this model. In animals receiving the combination therapy, ventricular refractory period increased 8% following sematilide and 18% with the addition of propranolol. Propranolol, when used alone at this dose, had no effect on refractoriness. These data suggest a synergistic action between Class III and Class II agents and that modulation of beta-adrenergic tone can enhance the Class III properties of certain agents.

Sotalol can be considered the prototype drug for an agent with both Class II and Class III activity. Experimental and clinical data suggest that the beta-blocking effect of sotalol begins at doses lower or equivalent to doses which produce its Class III actions. Thus, the compounds of this invention are designed to have a more potent Class III action relative to their Class II potency in order to demonstrate a distinct advantage in the setting of reentrant ventricular arrhythmias.

The compounds of this invention have been tested for their Class III activity via in vitro el ectrophysiologic testing utilizing standard intracel 1 ul ar microelectrode techniques in the canine cardiac Purkinje fiber. They were then tested for reasonable β-adrenergic blocking activity as measured in the in vitro screens of isolated papillary muscle (inhibition of the inotropic response to epinephrine) and the beta-adrenergic binding screen (displacement of radi olabel 1 ed dihydroalprenolol ) . They were then assessed in the in vivo model of the pentobarbi tal anesthetized dog in which the compound was administered intraduodenally and Its Class III (increase in functional refractory period) and Class II (inhibition of i soproterenol response) effects were monitored.

SUBSTITUTESHEET

Compounds were assayed for Class III βleetrophysioiogical activity in isolated canine cardiac Purkinje fibers using standard icroalactrode techniques. To be considered active as a Class III agent, the compound must have increased action potential duration at 95% full rβpolarixation (APO„) by at least 20%. Reported is the concentration of test compound which increased action potential duration by 20% <C _lβ APD„) .

Affinity for β-receptors was determined versus 'H- dihydroalprenolol in partially purified membrane fractions

SUBSTITUTE SHEET

of canine ventricular muscle (βi-affinity) and in partially purified membrane fractions of canine lung tissue (β ₂ - affinity) . Reported is the concentration of test compound which inhibited the binding of Η-dihydroalprenolol <4.5 nM) by 50% (IC„) .

Compounds were studied for effects on contractility in isolated ferret papillary muscles. Compounds were considered to show β-blocking activity if they inhibited the positive inotropic response of the muscle to the β-agonist, N-isopropyl actopamine.

Sematilide (selective Class III agent), sotalol (Class II/III agent) and propranolol (selective Class II agent, i.e., β-blocker) are included as reference compounds.

NR = not reached NT - not tested

The compounds of this invention exemplified by N-[4-[4-[2-ιydroxy-3-(2-methylphenoxy)propyl ]piperazin-l- yl]phenyl jmethanesul fonamide, N-[4-[2-hydroxy-3-[[2-[4- (lH-imidazol-1-yl )phenoxy]ami no] ropoxy]phenyl jmet ane- sulfonamide and N-[4-[l-hydroxy-2-[[2-[4-(lH-imidazol _ _ yl)phenoxy]ethyl]amino]ethyl]phenyl jmethanesul fonamide have been analyzed in the foregoing biological procedures and provide the combination Class II/III antiarrhythmic

e ec s. n essence, e p ys c an as een prov e w a simple chemical entity providing c ' effects tnereby mitigating the problems of multiple drug therapy, e.g. side effects, metabolic problems, drug interactions, etc. and the problems in patient compliance - different drugs, different therapeutic regimens.

The compounds whilst preferably utilized in the treatment of mammalian arrhythmias and most specifically used in the treatment of mammalian arrhythmias in need of combination Class II/III effects, possess some general cardiovascular properties. Some of the compounds may, due to the level of Class II effects, exhibit an anti- hypertensive effect. In general , the compounds of this invention may be administered orally or parenteral l . The dosage administered will depend on the subject being treated, the route of administration and the type and severity of the arrhythmias being prevented or reduced.

The compound to be administered can be formulated by admixing with any of a number of suitable pharmaceutical diluents and carriers such as lactose, sucrose, starch powder, cellulose, calcium sulfate, sodium benzoate and the like. Such formulations can be compressed into tablets or can be encapsulated into gelatin capsules for convenient oral administration. Such a capsule may contain one of the compounds of this invention for example, N-[4-[4-[2- hydroxy-3-(2-methylphenoxy)propyl]pi perazi n-l-]phenyl]- methanesul fonamide, N-[4-[2-hydroxy-3-[[2-[4-( lH-i i dazol -

SUBSTITUTE SHEET

1-yl )phenoxy]et l ]a ino]propoxy]phc.nyl Jmethanesul fona ide or N-[4-[l-hydroxy-2-[[2-[4-(lH-imidazol-l-yl )phenoxyJ- ethyl ]amino]ethyl ]phenyl jmethanesul fonamide in the amount of about 1 to about 500 mg. Such formulation can be administered orally at the rate of about 1 to 4 capsules per day or more often as needed, depending upon the particular condition and sub.iect being treated.

For parenteral administration a compound of this invention can be formulated as an intramuscular or intravenous medicament but is not limited thereto. In the case of treatment of a patient suffering from severe cardiac arrhythmias, it may be desirable to administer a compound of the invention by intravenous slow bolus in order to effect a rapid conversion to a normal sinus rhythm. The normalized condition can then be maintained by oral administration.

The compounds of this invention can be formulated for parenteral administration with any of a number of pharmaceutically acceptable carriers and diluents to constitute an injectable liquid solution. Commonly used diluents and carriers include water or a saline solution, buffered aqueous solutions as well as dispersing and surface active agents if necessary. A typical formulation suited to intravenous or intramuscular administration may contain one of the compounds of this invention such as N-[4-[4-[2-hydrox -3- (2- ethy! phenoxy)propy! ]pi perazi n-1-1- pheny jmethanesul fonamide in the amount of about 50 to 150 mg and a solubiliziπg agent and sufficient sterile water to bring the volume to about 5ml-100ml . Such formulation can

be infused at a constant rate or injected one to four time? per day or more often depending upon the particular condition of the subject being treated.

It is further contemplated that the compounds of this invention may be formulated into sublingual lozenges or impregnated into fabric appliques for a type of transdermal application.

The invention described hereinabove is illustrated below in the Preparations and Examples, which, however, are not to be construed as limiting the scope of this invention.

PREPARATIONS

Preparation 1

N-[2-[4-(lH-Imidazol -1-yl )phenoxyjethyljpropiona ide To 25 g (0.25 mol ) of 2-ethyl -4 ,5-di hydrooxazol e add 10.0 g (62 mol ) of 4- ( lH-i idazol -1-yl )phenol . Reflux the reaction mixture. Monitor the progress of the reaction by thin-layer chro atography on silica gel (9:1, CHgCl ₂ :Me0H) . Upon completion of the reaction remove the excess starting material by distillation, add ethyl acetate, and wash the solution with 2N NaOH. Dry the organic layer over anhydrous Na ₂ S0.. Remove the drying agent by filtration and remove the solvent in vacuo. Recrystal 1 i zati on from ethyl acetate-hexane affords the title compound.

NMR (DMS0-d ₆ ) δ = 1.01(t,3) , 2.12(q,2), 3.44(q,2) , 4.04(t,2), 7.09(d,2), 7.09(s,l), 7.57(d,2), 7.67(s,l), 8.08(brt,l) and 8.16 ( s , 1 ) pp .

SUBSTITUTE SHEET

Preparation 2

2-[4-(lH-Imidazol-l-yl )phenoxy]ethaπamine di hydrochl oride To 40 mL of 2M aqueous hydrochloric acid add 10.3 g (39 mmol) of N-[2-[4- ( lH-imi dazol -1-yl )phenoxyjethyl j- propionami de. Reflux the reaction mixture. Monitor the progress of the reaction by thin-layer chromatography on silica gel (9:1, CH ₂ C1 ₂ :Me0H) . Upon completion of the reaction, remove the solvent in vacuo and triturate with isopropanol . Recrystall i zation of the resulting solid from ethanol affords the title compound.

NMR (DMS0-d ₆ ) δ = 3.21(q,2), 3.6(br,l + H ₂ 0), 4.32 (t,2), 7.23(d,2), 7.79(d,2), 7.92(s,l), 8.26(s,l), 8.54 (br,3) and 9.74(s,l) ppm.

Preparation 3

N-(4-Cyaπophenyl)methanesul fonamide Dissolve 50.3 g (0.426 mol ) 4-ami πobeπzonitri 1 e in 250 mL CH ₂ C1 ₂ with 36 mL (0.445 mol) pyridine. Chill the solution with an ice/MeOH bath and add 34 L (0.42 mol) methanesul fonyl chloride dropwise, maintaining the reaction temperature below 0 ^β C. Stir the reaction mixture under ₂ for 20 h at ambient temperature. After this time, filter the reaction mixture and extract with 3 X 250 mL IN NaOH. Acidify the aqueous layer with concentrated HC1 to pH=7. Filter the precipitate to provide the title compound.

NMR (CDC1 ₃ ): δ =3.03(s,3), 7.37(d,2), 7.58(d,2) and 10.1(s,l) ppm. SUBSTITUTE SHEET

Preparation 4

N-(4-Ami πo ethyl phenyl )methanesul fonamide hydrochloride Saturate 450 mL methanol with ammonia gas and add 45 g

(0.229 mol) N- (4-cyanophenyl )methanesul fonamide and 4 g Raney Nickel catalyst. Hydrogenate the mixture at 52 psi for 2 h. After this time, filter the catalyst and evaporate the solvents. The resultant oil is dissolved in methanolic HC1. Remove the solvents to provide the title compound .

NMR (DMS0-d ₆ ): δ = 3.00(s,3), 3.95(s,2), 7.24(d,2), 7.46 ( d , 2 ) and 8.51(br s,4) ppm.

Preparation 5

N-(2-Aminoethyl)-4-(lH-imidazol -1-yl )benza ide hydrochl oride

Reflux 150 mL (2.25 mol) ethyl enedi ami ne , and 21.0 g (0.097 mol ) 4-( lH-i idazol -1-yl )benzoic acid methyl ester for about 24 h. The excess ethyl enedi ami ne is removed in vacuo and the residue is triturated with H ₂ 0, filtered, and the water evaporated. The residue is dissolved in ethanol and treated with excess HC1 gas to provide the title compound .

NMR (DMS0-d ₆ ): 6- 3.02(t,2), 3.57(quar ,2) , 7.15(s,l), 7.81(d,2), 7.88(s,l), 8.11(d,2), 8.42(s,l), 8.99(t,l), 7.95-8.80(br s,3) ppm.

SUBSTITUTE SHEET

Preparation 6

N- (2-Aminoethyl)-4-(lH-imidazol -1-yl )benzamide

Dissolve N-(2-a inoethyl ) -4- ( 1H-imidazol-1-yl )- benzamide hydrochloride in 50 mL H ₂ 0 and pour onto a column of hydroxide anion exchange resin. Flush the column with H ₂ 0 and collect fractions with pH>8. Combine the basic fractions and remove the solvents in vacuo to obtain the free base.

Preparation 7

4-(4-Nitrophenyl )-!-(phenylmethyl )piperazi ne Reflux a mixture of 53.5 L (0.504 mol) of 1-fluoro- 4-ni trobenzene, 99.14 g (0.555 mol) of 1-benzyl piperazi ne, and 76.7 g (0.555 mol) potassium carbonate in acetonitrile for about 17 h. Cool the mixture to room temperature and dilute with methyiene chloride and filter. Concentrate the filtrate in vacuo. Dissolve the residue in methyiene chloride and wash with water. Dry the organic layer with anhydrous sodium sulfate and concentrate in vacuo to give the title compound.

NMR (DMS0-d ₆ ): - = 2.59(t,4), 3.42(t,4), 3.57(s,2), 6.80(d,2), 7.34(m,5) and 8.11(d,2) ppm.

Preparation 8

4-[4-(Phenylmethy1 )piperazin-l-yl benzenamine Add 474 g (2.10 mol) tin chloride dihydrate to a refluxing solution of 125 g (0.420 mol) 4-(4-nitrophenyl )- l-(phenylmethyl )piperazine in ethanol . Reflux the solution for about 15 h then cool to room temperature and remove the solvent. Dissolve the residue in water and adjust to pH 12 with sodium hydroxide. Extract the aqueous solution with methyiene chloride and dry the organic layer with anhydrous sodium sulfate. Concentration at reduced pressure gives the title compound.

NMR (DMS0-d ₆ ): = 2.61(t,4) , 3.05(t,4), 3.41(br s,2), 3.56(s,2), 6.63(d,2), 6.81(d,2) and 7.25-7.36 (m,5 ) ppm.

_S TITUTE SHEET

Preparation 9

N-[4-[4-(Phenylmeth l )piperaz n-1-yl jphcnyl] _' - methanesul foπami de 1.2 hydrochloride To a chilled solution of 9.50 g (35.5 mmol ) of 4-[4-

(phenylmethyl )piperazi n-l-yl jbenzena ine in 100 mL of acetoni tri 1 e , ^" add 6.49 g (37 mmol) of methanesul foni c anhydride in 50 L of acetonitrile. Allow the reaction mixture to stir at room temperature for 5 h. After this time, filter the resulting precipitate, add 100 mL of saturated aqueous sodium bicarbonate solution and extract this solution with 2 X 100 mL of methyiene chloride. Wash the combined methyiene chloride layers with 100 mL of saturated aqueous sodium chloride solution. Remove the solvent in vacuo. Dissolve the residue in 100 mL of methanol and acidify to pH=l solution with hydrogen chloride gas. The solution is cooled and the resulting solid filtered to obtain the title compound.

NMR (DMS0-d ₆ ): δ » 2.87(s,3), 3.03-3.25(m,4) , 3.33 (d,2), 3.63-3.81(m,2) , 4.37(d,2), 6.96(d,2), 7.12(d,2),

7.47(m,3), 7-.66(m,2), 9.37(br s,l) and 11.38(br s,l) ppm.

Preparation 10

N-[4-(Piperazin-l-yl)pheπyl jmethanesulfonamide hydrochloride Hydrogenolyze a suspension of 7.03 g (18.2 mmol) of N- [4-[4-(phenylmethyl )pi perazi n-l-yl jphenyljmethane- sulfonamide in 400 mL of 50% aqueous ethanol over 0.35 g of 10% palladium on activated carbon catalyst at 50 psi. At the completion of the reaction remove the catalyst by filtration and evaporate the solvent in vacuo. Recrystal- lize the residue from ethanol to obtain the title compound.

NMR (D ₂ 0): δ ^■ = 3.08(s,3), 3.48(m,8), 7.16(d,2) and 7.31 ( d ,2 ) ppm.

Preparation 11

l-[4-[(Methyl sul fonyl)aminojbenzoyl j-4-(phenylmethyl )- piperazine hydrochloride To a cold solution of 29.8 g (0.169 mol) N-benzyl- piperazine in 200 mL THF, slowly add a solution of 39.5 g (0.169 mol ) 4-[(methyl sul fonyl ) ami nojbenzoyl chloride in 200 mL THF, maintaining the reaction temperature below 0°C. When the addition is complete, stir the reaction at ambient temperature for 24 h. After this time, evaporate the solvents to give a dark oil. Dissolve the residue in 6M NaOH (pH=14) and wash 3 X 200 mL ether. Acidify the aqueous layer with concentrated hydrochloric acid to pH=8. Collect the resulting solid via suction filtration to give the title compound as the free base. Dissolve the solid in methanol and acidify with HC1 gas. Remove the solvents to give the ΗC1 salt which can be recrystal 1 ized from 95% ethanol .

NMR (DMS0-d ₆ ): δ = 3.06(s,3), 3.10-4.20(m,8) , 4.33 (m,2), 7.2S(d,2), 7.44(d,2), 7.46(br s,3), 7.59(br s,2), 10.13(s,l) and 11.10(br s,l) ppm.

SUBSTITUTE SHEET

Preparation 12

l-[4-[[(Methyl sul fonyl) aminojbeπzoyljpiperazine hydrochl oride Dissolve 26.97 g (0.071 mol) l-[4-[(methyl sul fonyl ) - ami nojbenzoyl ]-4-(phenylmethyl )piperazine hydrochloride in 500 mL water with 2.75 g 10% palladium on carbon. Hydrogeπate at 52 psi in a Parr shaker for 18 h. After this time, filter the catalyst and remove the solvents to give the title compound which can be recrystal 1 i zed from EtOH.

NMR (DMSO-dg): δ = 3.06(s,3), 3.12(m,4), 3.7l(m,4), 7.27(d,2), 7.44(d,2) and 9.82(br s,3) ppm.

Preparation 13

N-[ -[bis(Phenylmeth l) ami nojethyljpropanamide To a chilled solution of 5.0 g (21 mmol) N,N-dibenzyl - ethylenedi amine and 30 mL (21 mmol) tri ethyl ami ne in 20 mL THF is added 1.8 mL (21 mmol) propionyl chloride, dropwise. The temperature of the reaction mixture is maintained below 0°C during addition. The reaction mixture is stirred for 30 m nutes at 0°C. After this time, the reaction mixture is filtered and the solvents are evaporated to give the product which can be purified via column chromatograph .

NMR (CDC1 ₃ ): δ = 1.10(t,3), 2.12(quar,2) , 2.58(t,2), 3.30(m,2), 3.60(s,4), 5.78(br s,l) and 7.30(m,10) ppm.

Preparation 14

N,N-bis(Pheny1methyl)-N'-propy1-l,2-ethanediamine To a chilled solution of 4.12 g (0.109 mol) lithium aluminum hydride in 200 mL THF is added a solution of 32.44 g (0.109 mol) N-[2-[bi s(phenyl ethyl )ami nojethyl jpropan- amide in 50 THF. The temperature during addition is maintained below 0°C. The reaction mixture is stirred at room temperature for 18 h, then is refluxed for 4 h. After this time, the reaction mixture is cooled and is quenched with H ₂ 0. The quenched solution is stirred at room temperature for 18 h. After this time, the salts are removed by filtration and the solvents are evaporated to give the title compound.

NMR (CDC1 ₃ ) : 6 = 0.86(t,3), 1.42(qui nt ,2) , 1.76 (br s,l), 2.36(t,2), 2.64(m,2), 4.60(s,4) and 7.30(m,10) ppm.

Preparation 15

N-[2-[[bi s( henylmethyl) ami nojet l jj-N-propyl- 4-[(methyl sul fonyl )amiπojbenzamide To a cold solution of 24.10 g (0.085 mol) N,N-bis- (phenylmethyl ) -N ' -propyl -1 ,2-ethanedi ami ne in 250 mL THF with 12.5 L (0.089 mol) tri ethyl ami ne is added dropwise to a solution of 20.0 (0.085 mol) 4-[ (methyl sul fonyl )ami noj- benzoyl chloride in 50 mL THF. The temperature is

_SU BSTITUTE SHEET

maintained below 0°C during addition. The reaction mixture is stirred at room temperature for 18 h. After this time, the solution is filtered and the solvents are evaporated to give the crude product which is purified via column chromatography on silica gel [petroleum ether : acetone, 9 :lj.

NMR (DMSO-dg, 110°C): δ - 0.65(t,3), 1.38(quint,2) , 2.62(t,2), 2.98(s,3), 3.12(t,2), 3.40(t,2), 3.58(s,4), 7.15(m,14) and 9.50(br s,l) ppm.

Preparation 16

N-[-2-[(Phenylmethy!)amiπojethylj-N-propyl-4- [(methyl sul fonyl)aminojbenzamide hydrochloride

To a solution of 13.09 g (27.3 mmol) N-[2-[bis- (phenylmethyl ) ami no ethyl j-N-propyl -4-[(methyl sul fonyl )- aminojbenzamide in 75 mL 80% aqueous methanol is added 27.3 mL IN HC1 and 1. ^' 6 g 10% palladium on charcoal. The solution is hydrogenated at 50 psi for 75 minutes. After this time, the reaction mixture is diluted with 100 mL methanol , filtered and the solvents are evaporated to yield the title compound.

NMR (DMS0-d ₆ , 100°C): = 0.74(t,3), 1.51(qui nt ,2) , 3.01(5,3), 3.12(t,2), 3.26(t,2), 3.76(t ,2) ,.4.15( s ,2) , 7.28(m,2), 7.39(m,5) , 7.59(m,2) and 9.60(br s,2) ppm.

SUBSTITUTE SHEET

Preparation 17

N-[2-[[2-H _. ydroxy-3-phenyloxypropy1 j (phenyl methyl ) ami noJ- et 1 j-N-propyl-4-[(methyl sul fonyl ) ami nojbenza ide To a solution of 7.95 g (20 mmol ) N-[2-(pheπyl - methyl ) ami no) ethyl j-N-propyl-4-[ (meth l sul fonyl) ami noj- benzamide in 20 mL 10% aqueous methanol is added 2.89 mL (21 mmol ) 1 ,2-epoxy-3-phenoxypropane . The solution is stirred at room temperature for 24 h. After this time, the solvents are evaporated and the title compound .is obtained as a foamy solid via column chro atography on silica gel (hexane racetone , 9:1) .

NMR (DMS ^' 0-dg, 100°C): δ = 0.72(t,3), 1.43(qui nt ,2) , 2.49-2.63(m,2) , 2.69(t,2), 2.96(s,3) , 3.17(t,2), 3.38(t,2), 3.63(d,2) , 3.81-3.92(m,3) , 4.42(br s,l) , 6.87(m,3) , 7.21(m,ll) and 9.56(br s,l) ppm.

SUBSTITUTE SHEET

Preparation 18

2-[4-(lH- Imidazol -1-yl )phenoxy]-N- (phenyl methyl )ethanamιne di hydrochl pride

To a suspension of 39.5 g (0.82 mol ) sodium hydride in

500 mL DMF add 37.3 g (0.233 mol) 4-( IH-imidazol -yl )phenol portioπwise. Chill the reaction mixture on an ice/MeOH bath during the addition. After addition, stir the reaction mixture at room temperature until gas evolution ceases. After this time, return the reaction mixture to the ice bath and add 50.2 g (0.29 g) N-benzyl -2-chl oro- ethylamine hydrochloride portionwise. After addition is complete, heat the stirring suspension to 65°C. Follow the progress of the reaction by thin-layer chromatography on silica gel (methyiene chl oride :methanol , 9:1). At the completion of the reaction, cool to room temperature and slowly add 20 L H ₂ 0. Remove the solids by suction filtration and evaporate the solvents. Chromatograph the resulting oil on silica gel using (CHgCl ₂ :Me0H, 98:2), to isolate the title compound as the free base. Dissolve the free base in excess 3M methanolic HC1 and evaporate the solvents to give the title compound.

NMR (DMSO-dg) δ = 3.25(m,2) , 3.42(br, 2 + H ₂ 0), 4.25

(s,2) , 4.44(t,2) , 7.23(d,2), 7.43(m,3), 7.64(m,2), 7.78

(d,2) , 7.91(m,l) , 8.24(m,l), 9.70(s,l) and lO.O(m.l) ppm.

2HC1 + H ₂ 0 at 3.35 ppm.

Preparation 19

l-[[2-[4-(lH-Imidazol-l-yl )phenoxy]ethyl j(pheπy1- methyl)amino]-3-phenoxy-2-propanol

To a solution of 3.2 mL (23.9 mmol) 1 ,2-epoxy-3- phenoxypropane in 20 mL MeOH, add 6.99 g (23.9 mmol) 2-[4- ( IH-imidazol -1- l )phenoxy]-N- (phenylmethyl )ethanamine as the free base described above. Stir at room temperature under a nitrogen atmosphere. Follow the progress of the reaction by thin-layer chromatography on silica gel (methyiene chl ori de:methanol , 9:1). At the completion of the reaction, evaporate the solvents. The resulting oil is chromatographed on a silica gel column using (petroleum ether :acetone, 8:2). Collect the appropriate fractions and remove the solvents to give the title compound.

NMR (CDC1 ₃ : δ = .81-3.18(m,4 ) , 3.85(br s,l), 3.74 (d,l), 3.90(d,l), 3.96-4.20(m,5), 6.86-6.97(m,6) , 7.18- 7.33(m,10) and 7.44(s,l) ppm.

Preparation 20

2-[[2-[4-(lH-Imidazol-l-yl )phenoxyjethyl j(phenylmethyl )- a i no -1-( -methoxypheπyl )ethaπone Dissolve 5.06 g (17.2 mmol) 2-[4-( lH-i i dazol -1-yl ) - phenoxyj-N-(p ^' henylmethyl )ethanamine in 20 mL acetonitrile with 3.0 mL (17.2 mmol) ethyl di i sopropyl amine. Chill the solution in an ice/methanol bath and add 3.93 g (17.2 mmol) α-bromo-2-methoxyacetophenone dropwise. Allow the reaction to warm to room temperature and stir for 24 h. After this time, remove the solvents in vacuo. Chromatograph the residue on silica gel using 3% methanol in methyiene chloride. Collect the appropriate fractions and remove the solvents to give the title compound. NMR (DMS0-d ₆ ): δ = 3.00(t,2), 3.78(s,3), 3.84(s,2),

4.02(s,2), 4.10(t,2), 6.96-7.18(m,5), 7.32(m,5), 7.52(m,4),

7.66(s,l) and 8.14(s,l) ppm.

Preparation 21

N-[4-[2-[[2-[4-( 1H-Imidazol -1-yl )pheπoxyjethyl j(phenyl- methyl ) ami noj-l-oxoethyl jphenyl methanesul fonamide

Add 5.87 g (16 mmol) 2-[4-(lH-imi dazol-1-yl )phenox j-

N-(phenylmethyl )ethanamine di hydrochloride to a solution of 1.8 g (32 mmol ) ^" potassi urn hydroxide in 50 mL water.

Extract the solution with 3 X 100 mL CH ₂ C1 ₂ and dry the organic layers with sodium sulfate. Evaporation of the solvents gives 2-[4-(lH-imidazol-l-yl )phenoxyj-N-(phenyl - methyl )ethanami ne as a pasty solid. Add the free base to a solution of 2.8 mL (16 mmol) ethyl di i sopropyl ami ne in 10 mL acetonitrile. Chill the solution in an ice/methanol bath and add N-[4-(2-bromo-l-oxoethyl )phenyl methane-

sulfonamide dropwise. Allow to warm to room temperature and stir for 18 h. After this time, remove the solvents in vacuo and dissolve the residue in 50 mL 6N NaOH. Wash the basic solution 1 X 25 mL diethyl ether. Adjust the pH of the aqueous layer to pH=6 with concentrated HCl and extract with CH^Cl ₂ • Dry the methyiene chloride layers with anhydrous sodium sulfate and evaporate the solvents to give the title compound.

NMR (CDC1 ₃ ) : 6 = 3.04(s,3), 3.12(t,2) , 3.92(s,2), 4.04(s,2), 4.12(t,2) , 6.78(d,2), 7.3(m,12), 7.84(s,l), 7.92(s,l) and 7.96(s,l) ppm.

Preparation 22

l-[[2-[4(lH-Imidazol -1-yl )phenoxyjethyl ] (phenylmethyl )- aminoj-3-[4-(2-methoxyethyl )phenoxyj-2-propanol Combine 7.3 g (25 mmol) 2-[4- ( lH-imidazol -1-yl ) - phenoxy -N-(phenyl methyl ) ethanami ne di hydrochl ori de and 5.2 g (25 mmol) 1 ,2-epoxy-3-[4-( 2-methoxyethyl Jphenoxyjpropaπe in 75 mL methanol and heat to-50°C. Follow the progress of the reaction" by thin-layer chromatography on silica gel (acetonitri 1 e: ammonia, 9:1). At the completion of the reaction, evaporate the solvents. Chromatograph the resulting oil on silica gel using 3% methanol in methyiene chloride to give the title compound.

Preparation 23

1-[[2-r -(lH-Im dazol -1-yl )phenox ethyl (phenylmethyl )- am no -3-(3-methyl phenox )-2-propanol To a solution of 2.75 g (17 mmol) 2,3-epoxypropyl 3-methylphenyl ether in 50 L methanol add 4.4 g (15 mmol) 2-[4-(lH-imidazol-l-yl )phenoxyj-N-(phenylmethyl )ethanamine and heat to 50°C for 24 h. Follow the progress of the reaction by thin-layer chromatography on silica gel (methyiene chl oride.-methanol , 9:1). At the completion of the reaction, evaporate the solvents. The resulting oil is chromatographed on a silica gel column using 2% methanol in methyiene chloride to provide the title compound.

NMR (CDC1 ₃ ): ^■ - = 2.31(s,3), 2.75-3.10(n,4) 3.80 (br s,l), 3.75(d,l), 3.90(d,l), 3.94-4.10(m,5) , 6.85-7.00 (m,6), 7.20-7.30(m,10) and 7.50(s,l) ppm.

Preparation 24

2-[4-( lH-Imidazol -1-yl )phenoxyj-l ,1-dimeth l ethanami ne di hydrochl ori de Dissolve 27.0 g (0.106 mol) of N-[-2-[4-( lH-imi dazol - 1-yl )phenoxyj-l ,1-dimethyl ethyl jacetamide in 270 mL of 2N of hydrochloric acid and heat to reflux for 18 h. After this time, remove the water on the rotary evaporator and redissolve the residue in 50 mL of isopropanol. Remove the isopropanol on a rotary evaporator and suspend the resulting solid in diethyl ether. Filter off the solid to provide the title compound.

NMR (DMSO-dg): δ ■ 1.40(s,6), 3.6(br,l), 4.12(s,2), 7.24(d,2), 7.80(m,2), 7.92(m,l), 8.26(m,l), 8.60(br s,3) and 9.74(m, 1 ) ppm.

Preparation 25

l-[4-(2-Met yl -2-propenyl ox )phenylj-!H-imidazole Suspend 40 g (0.25 mol) of 4- ( IH-imidazol -1-yl ) phenol in 280 mL of THF and treat with 15 g (0.375 mol ) of a 60% dispersion of sodium hydride in mineral oil . Stir this suspension for 20 min and then add 27.1 mL (0.25 mol ) of 3-

SUBSTITU

chloro-2-methylpropene. Heat this mixture to 100°C for 3 h. After thi-s time, add 250 mL of water and 250 mL of diethyl ether and separate the layers. Re-extract the aqueous layer with 2 X 250 mL of diethyl ether. Evaporate the combined ether extracts on a rotary evaporator. Triturate with 300 mL of hexanes and filter off the resulting solid to provide the title compound.

NMR (CDC1 ₃ ): δ = 1.84(s,3), 4.48(s,2), 5.03(s,l), 5.11 (s,l), 7.00(d,2), 7.20(d,2) , 7.30(m,2) and 7.76(s,l) ppm.

Preparation 26

N-[-2-[4- (1H- Imi dazol -1-yl)phenoxyj-1 ,1-dimethyl- ethyl jacetami de

Dissolve 27 g (0.126 mol) of l-[4-(2-methyl -2-pro¬ penyl oxy)phenyl j-lH-imidazol e in a solution of 78 mL of glacial acetic acid and 29 mL of acetonitrile. Cool this solution to 0°C over an ice bath and add 29.0 mL of 95% sulfuric acid dropwise at a rate to keep temperature below 15°C. Upon completion of the addition, stir overnight at room temperature. After this time, make basic (pH=12-14) with 4N sodium hydroxide. Dilute with 400 mL of water and extract with 3 X 400 mL of diethyl ether. Concentrate the combined ether extracts to 350 L on the rotary evaporator and cool in the refrigerator for 1 h. Filter off the resulting precipitate to provide the title compound.

NMR (DMSO-dg): δ = 1.33(s,6), 1.78(s,3), 4.10(s,2), 7.04(d,2) 7.07(s,l) , 7.54(d,2), 7.62(s,l) , 7.64(s,l) and 8.13(s,l) ppm.

Preparation 27

2-[4-(lH-Imidazol-l-y1 )phenoxyj-l,l-di methylethanamine Partial ly dissolve 30.69 g (0.1 mol ) of 2-[4-( IH-

imidazol -1-yl )phenox j-l,l-dimethylethanamine dihydro- chloride in 50 mL of water and make basic with 70 mL 4N NaOH. Extract this mixture with 2 X 100 mL of methyiene chloride. Remove the solvent on a rotary evaporator to provide the title compound.

NMR (CDC13) : δ = 1.22(s,6), 1.59(br s,2), 3.71(s,2), 7.00(d,2) , 7.18(s,l) , 7.20(s,l), 7.27(d,2) and 7.77 ( s , 1) ppm.

EXAMPLES

Example I

N-[4-[[2-Hydroxy-3-(3-methy1phenoxy)propyljam nomethy1j- phenyl jmethanesul fonamide hydrochl oride Heat a mixture of N-[4-( ami no ethyl )phenyl jmethane- sulfonamide hydrochloride (15.0 g, 63.4 mmol ) and 1,2- epoxy-3-phenoxypropane (10.41 g, 63.4 mmol) in 63.4 mL of IN K0H in methanol and 10 L of water for about 3.5 h. Remove the solvent to afford crystals of the title compound.

NMR (DMS0-dg) : δ = 2.27(s,3) , 2.85-3.15 (m,2) , 3.02 (s,3), 3.93(s,2), 4.14(s,2), 4.23(br s,l), 5.90(br s,l), 6.74(m,3), 7.19(m,l), 7.24(d,2), 7.53(d,2), ca. 9.35 (br s,2) and 9.97 ( s ,1 ) ppm.

^S UB ^STI TUTESHEE _T

Examp l e I I

N-[4-[[2-Hydroxy-3-[4-( 2-methox ethyl )phenoxyjpropyl j- a inomethyljphenyl jmethanesul fonamide hyd ochloride l,2-epoxy-3-[4-(2-methoxyethyl )phenox jpropane (63.7 mmol) in 15 L of MeOH is added dropwise to a solution of

N-[4- (aminomethyl )phenyl jmethanesul fonamide hydrochl oride

(62.4 mmol) in 1M KOH in MeOH (65 mL) at room temperature, H ₂ 0 (5 L) is added ad the mixture is refluxed overnight. Methanol is removed from the cooled mixture under reduced pressure, and the residue is partitioned between H _? 0 and CH ₂ C1 _2> and the combined organic portions are washed with brine and dried with anhydrous a ₂ S0 ₄ . After removal of the solvent under reduced pressure the hydrochloride salt is formed and recrystal 1 i zed with CH ₃ CN/Me0H to yield the title compound.

E x amp l e I I I

N-[4-[(2-Hydroxy-3-phenoxypropyl)aminomethy1jphenylj- methanesul fona i de hydrochloride To a solution of 18.0 g (0.76 mmol) of N-[4-(ami no- methyl )phenyl jmethanesul fonamide hydrochloride in 200 mL of methanol , add a solution of 3.04 g of sodium hydroxide in 10 mL of water. Stir for fifteen minutes. Add 11.14 g (0.076 mmol) of 1 , 2-epoxy-3-phenoxy propane and reflux for 4.5 h. Monitor the progress of the reaction by thin-layer chromatography on silica gel (acetoni tri 1 e:ammoni urn hydroxide, 9:1). Remove the solvent in vacuo. Chromatograph the oil on 800 g of silica gel using a mixture of methyiene chl oride:methanol :triethyl ami ne (97:2:1) initially and changing to methyiene chloride, methanol, triethyl ami ne (95:4:1). Combine the fractions containing product and remove the solvent in vacuo. Dissolve the product in methanol and add a solution of hydrogen chloride in methanol. Remove the solvent in vacuo. Recrystal 1 i ze the salt from acetonitri 1 e:methanol to obtain the title compound.

NMR (DMS0-d ₆ ): δ = 2.94(t,l), 3.08(s,3), 3.12(m,l), 4.01(d,2), 4.20(s,2) , 4.23(m,l) , 5.88(d,l), 6.94(m,3), 7.27(m,4) , 7.52(d,2), 9.97(br s,2) and 10.10(br s,l) ppm.

SUBST cut

Example IV

N-[2-[[2-H_ydroxy-3-(4-methoxyphenox )propy! jaminojethyl - - 4-(lH-imidazol-l-yl)benzamide

To a solution of 2.39 g (13.2 mmol) 1 , 2-epoxy-3-(4- mιiethoxyphenoxy)propane in 25 L methanol is added 3.05 g (13.2 g) N-(2-aminoethyl )-4-(lH-imidazol-l-yl )benzamide. The reaction mixture is stirred under a nitrogen atmosphere for 24 h. After this time, the precipitate is collected and recrystal 1 i zed from ethanol to provide the title compound .

NMR (DMS0-dg, 60°C): δ- 2.58-2.75(m,2) , 2.75(t,2), 3.15(bp s,l + H ₂ 0), 3.37(quar,2), 3.67(s,3), 3.80-3.98 (m,3), 4.72(br s,l), 6.83(m,4), 7.12(s,l), 7.72(d,2), 7.77 (s,l), 7.97(d,2), 8.29(s,l) and 8.32(br s,l) ppm.

SUBSTITUTE SHEET

E x amp l e V

N-[2-[[2-Hydroxy-3-(l-naphthalenyloxy)propylja iπoj- ethylj-4-(!H-imi dazol -1-yl )benzamide (Z)-butenedioic acid salt (1:1) To a solution of 34.45 g (0.172 mol) 1 ,2-epoxy-3-( 1- naphthal enyl oxy)propane in 275 mL methanol add 39.62 g (0.172 mol) N-(2-aminoethyl ) -4- ( IH-imidazol -1-yl )benzamide . Stir the reaction mixture under a nitrogen atmosphere for 24 h. After this time, remove the solvents in vacuo to obtain an oil . Chromatograph the oil on a silica gel column using acetonitrile then acetoni tri 1 e:methanol , 4:1 as eluent. Combine the appropriate fractions and remove the solvents. Dissolve the residue in hot ethanol with one equivalent of maleic acid. Chill the solution and filter the solid to αive the t tle compound.

NMR (DMSO-dg): δ - 3.08-3.52(m,6 ) , 3.52-3.76(m,2) , 4.08-4.24(m,2), 4.08-4.46(br s,l), 6.03(s,3), 6.98(d,2), 7.15(s,l), 7.40-7.62(m,4), 7.76-7.96(m,3 maleic acid), 8.02(d,2), 8.27(d,2), 8.41(s,l), 8.66(br s,l) and 8.78(t,l) ppm.

SUBSTITUTE S

Ex amp l e V I

N-[2-[[2-Hydroxy-3-(4-(2-methoxyethyl )phenoxy)propyl j- aminojethylj-4-(lH-i idazol-l-yl)benzamide To a solution of 10 g (37.5 mmol) N-(2-ami noethyl )-4- ( IH-imi dazol -1-yl )benzami de hydrochloride in 50 mL methanol and 5 mL water with 1.69 g (42 mmol) sodium hydroxide, add 8.59 g (41.2 mmol) 1 ,2-epoxy-3-[4-(2-methoxyethyl )phenyl j- propane. Heat the mixture to 60°C for about 18 h. Cool the reaction mixture to room temperature and remove the solvents in vacuo. The resulting oil is chromatograph¬ ed on alumina (activity III) using CH ₂ Cl ₂ :Me0H, 98:2. Combine the appropriate fractions and remove the solvents to give the title compound which can be recrystal 1 i zed from ethyl acetate.

NMR (CDCl _j ): δ » 2.85(t,2), 2.90(m,2), 2.95(t,2), 3.78 (s,3), 3.59(t,2), 3.62(m,2), 4.00(m,2), 4.15(m,l), 6.85(d,3), 7.16(d,2), 7.28(d,2), 7.29(s,l), 7.35(s,l), 7.45 (d,2) and 7.93(d,3) ppm.

E x amp l e V I I

N-[4-[4-(2-Hydroxy-3-pheπox prop l )p iperazi n-l-yl jphenyl j- ethanesul fonamide Suspend a mixture of 20.0 g (56.9 mmol) of N-[4- (piperazi n-l- l Jphen l jmethanesul fonamide methanesul fonate, 7.68 mL (56,9 mmol ) of 1 , 2-epoxy-3-phenoxypropane and 3.07g

(56.9 mmol) of sodium methoxide in 800 mL of 90% aqueous methanol and warm to 60°C for 18 h. After 18 h, filter the precipitate and wash this precipitate with 100 L of water and 100 L of methanol. Suspend this solid precipitate in 500 L of methanol and reflux for 1 h. After 1 h, cool the suspension to room temperature and filter to obtain the title compound.

NMR (DMSO-dg): δ = 2.57(dd,2), 2.6(m,4), 2.85(s,3), 3.0(br s,l), 3.12(t,4), 3.93(m,l), 3.97(m,2), 6.88(m,3), 6.94(d,2), 7.09(d,2), 7.25(m,2) and 8.9(br s,l) ppm.

SUBSTITUTE SHEET

Example VIII

N-[4-[-4-[3-[[[b s(Cyclopropyl )methyl jiminojoxyj-2- hydroxypropyljpi peraz n-l-yl jphenyl jmethanesul fonamide

N-[ -(Piperazin-l-yl )phenyl jmethanesul fonamide (25 mmol) in 50 mL of 9:1, MeOH:H ₂ 0 is heated to 50°C. A solution of di cycl opropylmethanone-O- (oxi ranylmethyl )oxime (28 mmol) in 50 mL of 9:1 Me0H:H ₂ 0 is added to the hot solution and heated at reflux for two days. The solvent i removed from the reaction mixture under reduced pressure, and the residue is partitioned between CH ₂ C1 ₂ and H ₂ 0. Th aqueous portion is extracted with CH-Cl-t ^{i n <} - the combined organic portion are washed with brine and dried with Na-SO.. Removal of the solvent under reduced pressure yields the product which is recrystal 1 i zed from.ethyl acetate .

NMR (DMSO-dg) : δ= 0.46-0.60(m,4) , 0.78-0.86(m,2) , 0.86-0.95(m,2), 0.95-1.08(m, 1 ) , 2.25-2.45 (m,3) , 2.52-2.60 (m,4 + DMSO) , 2.85(s,3), 3.02-3.10(m,4) , 3.80-3.90(m,3) , 4.59-4.61(m,l), 6.88(d,2), 7.08(d,2) and 9.22(br s,l) ppm Ethyl acetate present at 1.18, 2.00 and 4.01 ppm.

Ex amp l e I X

N-[4-[4-[2-Hydroxy-3-( 3-methyl phenoxy)propy! jpiperazin- 1-yljphenyl jmethanesul fonamide dihydrochloride Heat a mixture of 5.0 g (19.6 mmol) N-[4-(piperazi n-

1-yl )phenyl jmethanesul fonami de and 3.22 g (19.6 mmol) 1,2- epoxy-3-( 3-methyl phenoxy)propane in 50 mL of methanol and 2 mL of water at reflux for about 8 h. Cool the reaction to room temperature and collect the precipitate. Dissolve the solid in ethanol and bubble hydrochloric acid gas through the solution until the pH is 2.0. Concentrate the solution in vacuo to give the title compound.

NMR (DMSO-dg) : δ=2.29(s,3) , 2.89(s,3), 3.09-3.39(m,6) , 3.60-3.80(m,4) , 3.94-4.01 ( ,2 ) , 4.42(m,l), ca. 5.25(br s,2), 6.75-6.79(m,3), 7.00(d,2), 7.12-7.21(m,3) , 9.37(s,l) and 10.27(br s,l) ppm.

^■ i J-T "c < ^~~ ~ -..~*_" ^~ " ^*

E x a p l e X

N-[4-[4-[2-Hydroxy-3- (2-methyl phenox )propy! jpiperazi n- 1-yljphenyl jmethanesul fonamide hydrochloride Heat a mixture of 5.0 g (19 mmol) N-[4-(piperazi n- 1-yl )phenyl methanesul fonamide and 3.5 g (21.3 mmol) 1,2- epoxy-3-(2-methylphenoxy)propaπe in 50 mL MeOH and 5 mL water. Reflux for 6 h. After this time, allow the reaction mixture to cool to room temperature and filter the resulting precipitate. Dissolve the precipitate in excess methanolic HCl and concentrate in vacuo to provide the title compound which can be recrystal 1 i zed from ethanol. NMR (DMSO-dg): _s = 2.20(s,3), 2.88(s,3), 3.29(m,7), 3.85(m,3), 3.97(t,2), 4.22(br s,l), 6.0(s,l) 6.86-7.00(m,4), 7.13(m,4), 9.37(s,l) and 10.2(br s,l) ppm.

Example XI

N-[4-C4-[2-Hydroxy-3-(5.6,7,8-tetrahydro-5-oxo-l- πaphtha! enyl oxy)propyl -1-piperazi nyl jphenyl j- methanesul fonamide di hydrochl oride

Heat a mixture of 5.5 g (21.6 mmol) N-[4-piperazi n-l- yl )phenyl jmethanesul fonamide and 4.7 g (21.6 mmol) 1,2- epoxy-3-(5,6,7 ,8-tetrahydro-5-oxo-l-napht al enyl ox )propane in 75 mL methanol and 5 mL water at 60°X for about 17 h. Cool the reaction mixture and remove the solvents to give an off white solid. Suspend the solid in 100 mL methanol and acidify with 4 mL of 12M hydrochloric acid. Remove the solvents to give a white solid which is recrystal 1 ized from ethanol to give the title compound.

NMR (DMSO-dg): δ - 2.04(m,2), 2.59(t,2), 2.89(s,3), 2.90(m,2), 3.14-3.43(m,6), 3.63-3.79(m,4) , 4.04(m,2), 4.49 (br s,l), 5.25(br s,2 + H ₂ 0), 7.00(d,2), 7.13(d,2), 7.26 (d,2), 7.32(t,l), 7.50(d,l), 9.38(s,l) and 10.50(br s,l) ppm.

Example XII

N-[4-[4-[2-Hydroxy-3-[4-(2-methoxyethyl )phenoxyj- propyl jpiperazi n-l-yl jphenyl jmethanesul fonamide di hydrochl oride

Heat a mixture of 5.0 g (19.6 mmol) N-[4-(piperazi n- 1-yl )phenyl jmethanesul fonamide and 4.08 g (19.6 mmol) 1,2- epoxy-3-[4-(2-methoxyethyl )phenox propane in 75 mL of methanol and 5 mL of water at 60°C for about 17 h. Cool the reaction to room temperature and collect the precipitate. Dissolve the solid in ethanol and bubble hydrochloric acid gas through the solut on until the pH is

2.0. Concentrate the solution in vacuo to give the title compound.

NMR (DMSO-dg): δ = 2.74(t,2), 2,88(s,3), 3.10-3.50 (m,8), 3.23(s,3) , 3.48(t,2), 3.66(t,2), 3.76(t,2), 3.95(m,2), 4.45(m,l), 6.88(d,2), 6.99(d,2), 7.13(d,2), 7.16(d,2), 9.37(s,l) and 10.32(br s,l) ppm.

SUBSTITUTE SHEE-

Example Xlϊl

4-[2-H_ydroxy-3-[4-[4-[(methyl sul fonyl ) aminojphenyl j- piperazin-1-yl jpropox jbenzeneacetamide hydrochloride Heat a mixture of 5.0 g (19.6 mmol) N-[4-(piperazi n- 1-yl )phenyl jmethanesul fonamide and 4.06 g (19.6 mmol) 4-(oxi raπylmethoxy)benzeneacetamide in 50 mL of methanol and 50 mL of water at 65°C for about 28 h. Cool the reaction to room temperature and collect the precipitate. Dissolve the solid in hot methanol and bubble hydrochloric acid gas through the solution until the pH is 2.0. Concentrate the solution in vacuo to give the title compound.

NMR (DMS0-d ₆ ): δ = 2.88(s,3), 3. ll-3.35(m,8) , 3.60- 3.75(m,4), 3.94(m,2), 4.46(br s,l), 6.01 (br s,l), 6.83(s,l), 6.90(d,2), 6.99(d,2), 7.13(d,2), 7.19(d,2), 7.44(s,l), 9.38(s,l) and 10.46(br s,l) ppm.

Example XIV

l-[2-Hydroxy-3-(l-naphthalenyloxy)propyl j-4-[4-[(methyl - sul fonyl) ami nojbenzoyl jpiperazi ne

Add 7.89 g (42.4 mmol) of 1 ,2-epoxy-3-(l-naphtha-

1 enyl oxy)propane to a solution of 12.0 g (42.4 mmol) of l-[4-[(methyl sulfonyl )ami nojbenzoyl jpiperazi ne in methanol.

Heat the resultant solution at reflux for about 46 h. Cool

the solution to room temperature and evaporate the solvent Triturate the residue with ether to obtain crystals of the title compound.

NMR (DMSO-dg): δ = 2.40-2.70(m,6) , 3.04(s,3), 3.28-3.76(m,4), 4.04-4.22(m,3) , 5.04(d,l), 6.95(d,l), 7.23 (d,2), 7.37(d,2), 7.39-7.57(m,4) , 7.86(dd,l), 8.24(dd,l) and 10.03 (s,l) ppm.

Example XV

l-[2-Hydroxy-3-phenoxypropyl]-4-[4-[(methy1sulfonyl ) ami noj¬ benzoyl jpiperazi ne phosphoric acid salt (1:1) To a solution of 13.31 g (47 mmol) l-[4-[(methyl - sul fonyl )ami nojbenzoyl jpiperazi ne in 50 mL methanol add 6.4 mL (47 .mmol) 1 ,2-epoxy-3-phenoxypropane. Stir the reaction mixture at room temperature under a nitrogen atmosphere. Follow the progress of the reaction by thin-layer chromatography on silica gel (methyiene chloride: MeOH, 9:1). When the reaction is complete, remove the solvents in vacuo to obtain an oil . Dissolve the oil in ethanol with one equivalent of H ₃ P0. and remove the solvents to obtain the title compound.

NMR (DMSO-dg): δ = 2.53-2.65(m,6) , 3.05(s,3), 3.52 (br s,4), 3.87-4.02(m,4), 6.93(m,3), 7.26(m,4), 7.38(d,2), 8.5(br s,3), 10.05(br s,l) ppm.

_β UBsrπτtιτεsιH€E

E x amp l e X V I

l-[2-Hydroxy-3-[4-(2-methoxyethyl )phenoxyjpropyl j-4- [4-[(methyl sul fonyl )amino benzoyl piperazine phosphoric acid salt (1:1) Add 2.64 g (.013 mol) of 1 ,2-epoxy-3-[4-( 2-methoxy- ethyl )ρhenoxyjpropane to a solution of 3.86 (12 mmol) l-[4-

[(methyl sul fonyl )aminojbenzoyl jpiperazine hydrochloride in

50 L MeOH and 13 mL IN NaOH. Heat the resultant solution at 50°C for about 24 h. Cool the solution to room temperature and evaporate the solvents. Dissolve the resultant oil in ethanol and acidify with one equivalent of phosphoric acid. Remove the solvents to obtain the title compound.

Example XVII

l-[[2-[4-(lH-Imidazol -l-yl)phenoxyjethyl jaminoj-3-p enoxy-

2-propanol To a solution of 5.5 g (12.4 mmol) l-[[2-[4-(lH- imi dazol -1-yl )phenox jethyl ( henylmethyl )arai no -3-phenoxy- 2-propanol in 25 mL methanol is suspended 1.0 g 10% palladium on carbon. The reaction mixture is hydrogenated at 50 psi in a Parr Hydrogenator. Follow the progress of the reaction by thin-layer chromatography on silica gel (methyiene chl oride:methanol , 9:1). At the completion of the reaction, the catalyst is filtered and the solvents are

re oved in vacuo. The isolated oil is taken up in methyiene chloride, dried over anhydrous Na ₂ S0 ₄ , filtered and the solvents are removed to give the title compound.

NMR (CDCI3): δ = 1.24(br s,2), 2.93(m,2), 3.10(t,2), 4.00(d,2), 4.13(t,3) , 6.89-6.99(m,5) , 7.18(m,2), 7.27 (m,4), and 7.75(s,l) ppm.

Example XVIII

a-[[[2-[4-(lH-Imi dazol -1-yl )phenoxyjethyl jaminojmethylj-

2-methoxybenzenemethanol Dissolve 3.8 g 2-[[2-[4-( IH-imi dazol -1-yl )phenoxyj- eth l j (phen l eth l) ami no]-l-( 2-methox phenyl )ethaπone in

50 L 5M HCl in methanol and remove the solvents in vacuo. Dissolve the residue in 50 mL H ₂ 0 with 0.85 g 10% palladium hydroxide on charcoal. Hydrogenate the solution under 52 psi hydrogen for 20 h. After this time, filter the catalyst and remove the solvents to give the crude product. Recrystal 1 ize the solid from ethanol to give the title compound .

NMR (DMSO + D ₂ 0, 100°C): δ = 3.09(m,l), 3.47(t,2), 3.82(s,3) , 4.41(t,2) , 2.27(m,l) , 7.01(d,2) , 7.18(d,2), 7.30(m,l) , 7.47(d,l), 7.56(s,l), 7.66(d,2) , 7.89(s,l), and 8.09(s,l) ppm.

TITUTE SH

Examp l e X I X

N-[4-[1-Hydroxy-2-[[2-[4-(IH-imidazol -1-yl )phenoxy ethyl ]- ami nojethyl jphenyl jmethanesul fonamide

Dissolve 4.0 g (0.7 mmol) of Preparation 21 in excess 4.0 M methanolic HCl and remove the solvents in vacuo. Dissolve the residue in 30 mL H ₂ 0 with 0.6 g palladium hydroxide on carbon. Hydrogenate the aqueous solution under 52 psi hydrogen gas. Follow the progress of the reaction by thin-layer chromatography (silica gel: acetonitri le:ammoni a, 9:1); visualize via UV and iodoplatmate. When the reaction is complete, filter the catalyst and remove the solvents in vacuo. Recrystal! i ze the residue from ethanol to obtain the title compound.

NMR (DMSO-dg): δ = 2.98(s,3), 3.21(m,2), 3.44(t,2), 4.42(t,2), 5.03(d,l), 6.24(br s,l), 7.23(d,4), 7.37(d,2), 7.76(d,2), 7.87(s,l), 8.21(5,1), 9.12(br s,l), 9.50(br s,l), 9.60(s,l) and 9.84(s,l) ppm.

Example XX

1-[[2-[4- (1H-Imi dazol -1-yl )phenoxyjethyl jami noj-3-[4- (2-methoxyethyl)phenoxyj-2-propanol Dissolve 6.36 g (.013 mol) l-[[2-[4-( IH-imidazol -1- yl)phenox jethyl j (phenylmethyl ) aminoj-3-[4-( 2-methoxy- ethyl )phenoxyj-2-propanol in 50 mL 5M methanolic HCl and remove the solvents in vacuo. Dissolve the residue in glacial acetic acid with 0.86 g 10% palladium hydroxide on carbon. The reaction mixture is hydrogeπated under 52 psi H ₂ on a Parr Hydrogenator. Follow the progress of the

reaction by thin-layer chromatography en silic? o e l (acetoni tri le:ammoni a, 9:1). At the completion of the reaction, the catalyst is filtered and the solvents are removed n vacuo. The resulting oil is chromatographed on alumina (activity III) using 2% methanol in methyiene chloride to provide the title compound.

NMR (CDC1 ₃ ): 6 = 2.8-3.4(br s,2) , 2.89(t,2), 2.90- 3.10(m,2), 3.200t,2) , 3.42(s,3) , 3.63(t,2), 4.06(d,2) , 4.25(m,3), 6.92(d,2) , 7.05(d,2), 7.19(d,2), 7.25(m,2), 7.35(d,2) and 7.85(s,l) ppm.

Example XXI

1-[[2-[4- (1H- Imi dazol -1-y1 ) phenoxyjethyl a i no]-3-( 3- ethyl -phenox ) -2-propanol phosphoric acid salt (1:1) Dissolve 4.1 g (8.9 mmol) l-[[2-[4-( IH-imidazol -1-yl ) - phenoxyjethylj(phenylmethyl ) ami no -3- ( 3-methyl henoxy) -2- propanol in 25 mL 4M methanolic HCl and remove the solvents on a rotary evaporator. Dissolve the resulting oil in 40 mL glacial acetic acid and add 0.5 g 10% palladium hydroxide on carbon. The reaction mixture is hydrogenated at 50 psi H ₂ in a Parr Hydrogenator . Follow the progress of the reaction by thin-layer chromatography on silica gel (methyiene chl oride :methanol , 9:1). At the completion of the reaction, the catalyst is filtered and the solvents are removed in vacuo. Chromatograph the resulting oil on silica using 2% methanol in methyiene chloride to give the

title compound as a free base. Dissolve the f ree base in 50 mL ethanol with 1 equivalent phosporic acid and remove the solvents on the rotary evaporator to give the title compound .

NMR (DMSO-dg): δ . 2.31(s,3), 2.95(dd,2) , 3.17(t,2) , 3.99(d,2), 4.05(m,l), 4.24(t,2) , 6.33(br s, ca. 5), 7.09 (m,3) , 7.13(m,4) , 7.53(m,3) and 8.04(s,l) ppm. Trace ethanol at 1.05 ppm.

Example XXII

4-[2-Hydroxy-3-[[2-[4- (IH-i i azol -1-yl )phenoxy -1 , 1- dimethyl ethyl jaminojpropyljbenzeneacetamide di hydrochl or de

Dissolve 7.0 g (30.1 mmol) of 2-[4-( lH-imidazol-1- yl )phenox j-1 ,1-dimethyl ethanami ne and 7.64 g (39.2 mmol) of 4-(oxi raήylmethox )benzeneacetami de in 100 mL of 90% aq. DMS0 and heat to 115°C for 18 h. After this time, add 100 L water and extract with 3 X 100 mL of methyiene chloride: methanol , 90:10. Combine the organic extracts and wash with 100 mL of water. Remove the solvent on the rotary evaporator and purify the residue by flash chromatography using flash silica gel (Baker) and eluting with acetoπitri 1 e:ammoni a (aq.), 93:7. Combine the pure fractions and remove the solvent on the rotary evaporator. Dissolve this residue in 100 mL of isopropanol and remove the solvent on the rotary evaporator. Dissolve this residue in isopropanol and add 1.2N methanolic hydrochloric acid to pH=l. Crystallize by cooling in the freezer for 24 h to provide the title compound.

^ ^• l_s»'_-_,—— -.

NMR (DMSO-dg) : δ= 1.46(s,6), 2.9-4.2(br,l + H ₂ 0), 2.98-3.4(m,2) , 3.29(s,2) , 3.99(m,2), 4.24(m,3) , 5.96 (br s,l), 6.83(br s,l), 6.85(d,2) , 7.16(d,2), 7.25(d,2), 7.48(br s,l), 7.78(d,2), 7.89(s,l), 8.23(s,l), 8.96 (br t,l), 9.5(br t,l) and 9.68(s,l) ppm.

Example XXIII

l-[[[4-( 1H-Imidazol -1-yl )pheπyl jmethyl jami noj-3- (2-methyl - phenoxy)-2-propanol dihydrochloride Dissolve 1.74 g (10.04 mmol) of 4- ( IH-imidazol -1-yl ) - benzenemethanami ne in 20 mL of dry DMSO under nitrogen. Add 2.44 mL (11.55 mmol) of hexamethyl di si 1 azane and stir at room temperature for 30 min. After this time, add a solution of 1.73 g (10.54 mmol) of 1 ,2-epoxy-3-( 2-methyl - phenoxy)propane in 10 mL of DMSO and heat in an oil bath at 60°C for 42 h. Follow the progress of the reaction by thin-layer chromatography on silica gel (acetonitrile: ammonia (aq), 90:10). At the completion of the reaction, add 6N hydrochloric acid to pH=l and then add 4N sodium hydroxide to pH=12. Dilute this basic mixture with 20 mL of water and extract with 3 X 75 L of methyiene chloride. Remove the solvent on the rotary evaporator. Purify this residue by flash chromatography using flash silica gel (Baker) and eluting with a solution of acetoni tri 1 e: ammoni a hydroxide 98:2. Combine pure fractions and remove the solvent on the rotary evaporator. Dissolve this residue in 50 mL of acetonitrile and remove the solvent on the rotary evaporator. Dissolve this residue in 10 mL of methanol and

«ϊBST1TUTE3SeEεT

bubble hydrogen chloride through the solution until pK ^* =l reached. Remove the solvent on the rotary evaporator and recrystallize the solid from 20 mL of isopropanol to provide the title compound.

NMR (DMSO-dg): δ = 2.11(s,3), 3.0(m,l), 3.5(br s,2 + H ₂ 0), 3.97(m,2), 4.32(m,3), 6.66(t,l), 6.72(d,l), 7.13(m,2), 7.90(s,4) _f 7.93(s,l), 8.33(s,l), 9.5(br s,l), 9.78(s,l) and 9.88(br s,l) ppm.

Example XXIV

N-[4-[2-Hydroxy-3-[[2-[4-( IH-imidazol -1-yl )phenoxyj-1 ,1- di ethylethyljaminojpropox jpheπyl jmethanesul fonamide dihydrochloride Dissolve 6.21 g (26.7 mmol) of 2-[4-( IH-imidazol -1- yl )phenoxyj-l , 1-dimethyl ethanami ne and 6.62 g (27.21 mmol) of N-[4-(oxi ranylmethoxy)phenyl jmethanesul fonamide in 70 mL of 25% aq. DMSO and heat to 115°C for 48 h. After this time, add 200 mL of water and 20 L 2N NaOH. Neutralize the aqueous layer to pH=8.5 with IN hydrochloric acid and extract into 3 X 300 mL of methyiene chl oride:methanol , 90:10. Wash the combined organic extracts with 100 mL of water and remove the solvent on the rotary evaporator. Purify this residue by flash chromatography using flash silica gel (Baker) and eluting with an acetonitrile: ammonia (aq.) gradient (98:2 —*95:5). Combine the pure fractions and remove the solvent on the rotary evaporator. Dissolve the resulting residue in 50 L of isopropanol and then remove the solvent on the rotary evaporator. Dissolve

this residue in methanol and acidify to pH I wich 2N methanolic hydrochloric acid. Remove the solvent on the rotary evaporator to provide a foamy residue. Stir this residue in 50 mL of diethyl ether for 2 h and filter to provide the title compound.

NMR (DMSO-dg) : δ - 1.46(s,6), 2.88(s,3), 2.92-3.45 (m,2) , 3.45(br,l + H ₂ 0) , 3.99(m,2) , 4.22(m,3) , 6.0(br s,l), 6.92(d,2), 7.15(d,2) , 7.26(d,2) , 7.78(d,2), 7.90(s,l) , 8.23(s,l) , 8.9(br t,l) , 9.46(m,l), 9.47(s,l) and 9.66(s,l) ppm.

Example XXV

Di cycl opropyl methanone-0-[2-hydroxy-3-[[2-[4-(lH-imi dazol - 1-yl )-phenoxyjethyljaminojpropyljoxime sulfuric acid salt (1:1) To 60 mL of methanol under nitrogen atmosphere add 3.14 g (17.3 mmol ) of di cycl opropylmethanone-0-(oxi ranyl - methyl )oxime, 4.58 g (16.7 mmol ) of 2-[4-( IH-imi dazol -1- l )phenoxyjethanamine di hydrochloride and 20 L of 2N NaOH. Stir the mixture at 62°C. Monitor the progress of the reaction by thin-layer chromatography on silica gel CH ₂ Cl ₂ :MeOH, 9:1) . Upon completion of the reaction remove the solvent in vacuo, add water, and extract with methyiene chloride. Dry the organic layer over anhydrous Na ₂ S0 ₄ . Remove the drying agent by filtration and remove solvent in vacuo. Chromatograph the resulting oil on 90 g of silica gel with CH ₂ Cl ₂ : eOH, 9:1. Dissolve the resulting oil in methanol and add an equivalent of concentrated H ₂ S0 ₄ . The solid material is removed by suction filtration to afford the title compound.

_S UBSTITUTE SHEET

NMR (DMSO-dg): δ = 0.59(m,* . n .8-1.1 ⁽ m,5) , 2-30 (m,l), 2.98(m,l), 3.20(d,l), 3.42(br t,2), 3.88(dd,l), 3.97(dd,l), 4.10(br s,l), 4.34(br t,2), 5.88(br s,l), 7.10(s,l), 7.11(d,2), 7.60(d,2), 7.66(s,l), 8.15(s,l), 8.9(br,3) .

Example XXVI N-[4-[2-Hydroxy-3-[[2-[4- (IH-imi dazol -1-yl )phenox j- ethyljaminojpropox jphenyl jmethanesul fonamide hydrochl oride To a solution of 2.3 g (0.008 mol) of 2-[4-(lH- imidazol -1-yl )phenox jethanami ne di hydrochlori de in 100 mL of methanol add a solution of 0.66 g of sodium hydroxide in 5 mL of water. Stir for 15 minutes. Add 2.0 g (0.008 mol) of N-[4-(oxiranylmethoxy)phenyl jmethanesul fonamide and reflux for 16 h. Monitor the progress of the reaction by thin-layer chromatography on silica gel (methyiene chloride, methanol , tri ethyl ami ne, 84:15:1). Remove the solvent in vacuo. Chromatograph the oil on 350 g of silica gel using a mixture of methyiene chl ori de:methanol :tri - ethylamine (94:5:1). Combine the fractions containing residue and remove the solvent in vacuo. Dissolve the residue in methanol and add a solution of hydrogen chloride in methanol . Remove the solvent in vacuo. Recrystal 1 i ze the salt from acetoni tri 1 e:methanol to obtain the title compound .

NM ^" R (DMSO-dg) : δ = 2.88(s,3), 3.l(m,l ) , ^~ 3.25-3.4 ^~ 0

(m,l), 3.42(m,2), 3.95(d,2) , 4.20(br m,l), 4.31(t,2),

5.88(m,l), 6.95(d,2), 7.09(s,l), 7.12(d,2), 7.17(d,2),

7.60(d,2), 7.67(s,l), 8.16(s,l) , ca. 8.8(br,2) and

9.42(s,l).