PT96141A - METHOD FOR PREPARING DERIVATIVES OF N-SUBSTITUTED 1-ARYLOXY-2-PROPANOLAMINE AND PROPYLAMINE DERIVATIVES WITH HETEROARALKYL THAT HAVE CLASS III ANTIRHYTHMIC ACTIVITY - Google Patents

Description

DEPARTMENT OF DEVELOPMENT

Ay 16? The compounds of Formula (III) may be prepared by the following procedures: capac rity of ma rcad amen te j; The potency of the Purkinje fiber in terms of significant variations is high and unequal to maximal. Unlike Class 15 antiarrhythmic agents, a C1-alkaline agent causes no effect on the growth channels. The electrophysiological properties of a compound which defines the activity profile of Class III are observed in vivo as negligible effects on the H-v3 conduction lines while gus produce a marked (greater than percent) increase in both refractory periods attrxal and ventricular. 'In contrast, agents of Class I demonstrated an improvement in the rate of CCh id LI generally without va riation in the per VX' The reagents were refluxed for 1 hour and the reaction mixture was cooled to -78 ° C.

Piarsai. = Ther., 1./f. Pharmac .; ; 24, 95-108 (19:

(I.e. 3i5-00 (19fc-2) § Vaughan-yil 1 iams? The following works have described the. The activity of the compounds of the general formula (I) is in the range of from 1 to 10% by weight. 3h (1985 -6-56 (1985) and McQueen et al., 1997).

Wohl et al., 5 discloses the hydroxyl N- [2- [2- (diethylamino) ethyl] -4-methylphthalimide hydrochloride. 3 = 1, 4 = 544 = 654,

A compound according to claim 1, wherein the compound of formula (I)

Gross -st al =?. described examples of α-phenylethylamine N-heterocyclyl-methylsulfoxidyl-D-glucopyranosyl-D-glucopyranosyl; 0281254, September 7, 1988, as well as other alkyl sulphonamide compounds described in European Patent 0286277 1988 '0> 8 & 27S' as of October i

in which R 1 is alkyl ammonium sulphonamido of perfluoroalkylsulphonamido of 1 to perfluoroalkyl amido of 1 to 6 carbon atoms; alkylsulfonylamino, propylsulfonylmethylsulfonyl, cyclohexylmethylsulfonyl, cyclohexylmethyl, • j ΟΟΠ ΟΟΠ ΟΟΠ ΟΟΠ ΟΟΠ ΟΟΠ ΟΟΠ ΟΟΠ ΟΟΠ ΟΟΠ ΟΟΠ ΟΟΠ ΟΟΠ ΟΟΠ ΟΟΠ. Are you boozy? Tons of the carotids alkylsuccinate or 36 atoms of the carboxylic acid. alkylsulfonyl, aryl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, & H O Li LU! *! a o s d s i a. or ramifieads of 1 to. 6-carbon atoms is isolated CH.-, or UHOH κ Het

. in which H is -m-formyl (C1 to C6 alkyl) -NH- (C1-C4) alkyl; V-1. and Z is O, S, C1-4 alkyl or NR " H? C4 alkyl < d > L. < / RTI > 1 to 4 carbon atoms and salts thereof are reacted with SCSI 5. r

Examples of alkyl and alkylsulfonamidog are Examples of perfluoroalkyl as a trifluoromethyl group; or. part of the reaction is carried out in the presence of a compound of formula (I). A compound of formula (I) wherein X is H or Het of a group; and butyl. Preferred sulfonamido-

wherein R 1 is MO-, or methylsulfonamido;

DU is selected from the group consisting of

wherein R " 7 is H or me " x t v e s s «

• U J ÍU5 mac eutacamenis

A further object of the invention is the compounds N-4-C2-hydroxymethyl (η) -α (1-methyl-1-methanesulfonamide-1-methyl) amino-3-propoxy- . 13av

N- Γ. 4 'C 3 " quinolin-4-ylmethyl) amino] propionic acid (3-methanesulphonamide)

Im-E-C? 1-yl) -propionic acid (1-methylethyl) amide;

Jmet-amn I-. (1 H -benzimidazol-4-yl) methyl] -1-methylimidazo [1,2-a] pyrimidine; - L 4- [3 '" 1 (1H-benzoimidazol-2-yl) -3-methyl-1H-benzoimidazol-1-yl]

1-methyl-2-quinolinylmethyl-amino-4- (4-nitrophenyl) -2-propylalanyl] -1- [2-benzofuran- (2-benzofuranylmethyl) methylamino] -2-hydrazopyrazine-3-yl] imidanesulfonamide 1 H-NMR (DMSO-d 6) methylamino-3- (4-nitrophenyl) -2-propanol and 5% is pharmaceutically acceptable salts.

It will be understood that the definition of the compounds of formulas (I) and (II) encompasses all stereoisomers and mixtures thereof having the activity discussed below. In particular it encompasses racemic modifications and any optical isomers having the indicated activity.

Optical isomers can be obtained in pure form by separation techniques. For example? a racemic mixture may be converted to a mixture of optically active diastereomers by reaction with a single enantiomer of a resolving agent for example by salt formation or formation of a covalent bond. The resulting mixture of the optically active diastereoisomers may be separated by standard techniques > = crystallization or chromatography) and the individual optically active diastereoisomers may then be treated for removal of the resolving agent *, thereby liberating the single enantiomer of the compound of the invention . Chiral chromatography (using a chiral support, chiral eluent or ion pair agent) may be used for the separation of enantiomeric mixtures directly. Stereospecific synthesis using optically active starting materials and / or chiral catalyst and / or solvents may

For example, when the compound of formula (Cl) is prepared by an addition process creating an epic center then performing the scission using a chiral catalyst or a chiral reagent or in a chiral environment can give the product as a single enantiomer.

These physiologically acceptable salts may be formed with organic or inorganic acids, such as hydrochloric, bromic, phosphoric, sulfuric, sulfamic, nitric, methylsulfonic, methanesulfonic, ethanesulfonic and ethanesulfonic acids, acetic, maleic, succinic, fumaric, tartaric, citric, salicylic, lactic, naphthalenesulfonic and the like.

This invention also provides processes for the preparation of compounds of the formula ## STR3 ## particularly the compounds of formula (I) can be prepared by one of the following processes: a) reacting a compound of formula

wherein Hapos; and Het are as defined hereinbefore, to give a compound of formula (I) wherein Y is CHOH or (a) reacting a compound of formula

O

Het (V)

J

= -3.0 coset precursor αβτιηαακ and t_ s a group ril- or. alkylsulphonyloni group with a compound of the formula wherein R " and

Is readily separable and a group such as p-tolyl- or methanesulfonyl (1), as defined above, to give a compound of formula (I) wherein Y is CHOp

J or a; The reaction of a compound (IV) above defined with a compound of formula

(VII) in which R 1, H 2 -t and L are as defined above, to give a compound (I) wherein Y is CH? or) " CCSD 08 "

wherein R1 is as hereinbefore defined A) a compound of formula

OR

D = CH-He}

Wherein L and Het are C--C--C 5.-C 5.-CÇ-CÇ-CÇ-CÇ-CÇ-CÇ-CÇ-CÇ-CÇ-CÇ-CÇ-CÇ-CÇ-C de-C de-C de-C de de; When creating a composite of reduction, a composite orthole

XV / Y > s / '' N > 'CQHet

(XD of the reaction of the compound of formula (I) wherein X5 is hydrogen; and Het are as previously defined to give a compound of formula (1) or

(ΧΙΠ) ΐΠ'i i | Ute? Κ ". Υ r. How to read it? ds? F iisldOS 5 CDiTs Uni

## STR1 ## in which R 1 is hydrogen; R 2 is hydrogen; i. Carbon monoxide and carbon dioxide | h) â! ... 1]. A compound of formula (I) wherein R 1 and R 2 are independently selected from the group consisting of C 1 -C 6 alkyl; SUMMARY OF THE INVENTION A compound of the formula: ## STR1 ## wherein R 1, R 2, R 3 and R 4 are as defined in formula (I). A compound of Formula C1 to provide an acid salt of the acid or salt of the acid addition salt of a compound of formula (I) to give a free base. (b) the reaction can be real times. at the same temperature or with an inert solvent such as acetone or ethanol in one portion. ac s t on i t ri 1 o =. The reaction may be carried out in the presence of a suitable base, diisopropylamine or triethylamine, or a carbonate or a carbonate. bicarbonate of an alkali metal in an inert polar solvent

In R " (B) and (g) the amination reduces the amount of ammonia in the body. 01 " In the presence of a catalyst. A suitable solvent such as palladium on carbon or sodium carboxylate according to standard procedures and using a solvent such as trifluoroacetic acid can be used in the preparation and straightening of an ag as well as the time of day or night of daylight hours, and the duration of the event, as well as the duration of the event. ac ac ions in the presence of a h / T; . .

The compounds of the invention in which Y is CHOH may be prepared by the reaction of an appropriately unsaturated sodium epoxide in the presence of acetone or acetonitriles in the presence of sulfuric acid, Het

CH 3 CN 25 - 80 ° C

Het

Y is Cf-i7 ,? the compounds may be prepared by the addition of appropriately substituted alkyl substituted with the required sequential amine at the appropriate pH of the appropriate sulfonylurea in SO2. such as acetone, or acetonitrile.

wherein R 2, R 3, chloro or bromo

The CsjihC are defined and W is

Known or otherwise known to be well-prepared or well-trained technicians by those who are familiar with it. chemistry optics

THE CHILDREN HAVE GIVEN ACTION. A compound of the formula: The animals were tested according to the method of the present invention. anthers. Q Γ á O O -B

Mongrel dogs of both sexes weighing 12 to 18 kg were anesthetized with sodium pentaharbital (35 mg / kg iv, supplemented at 5 mg / kg / hr) and artificially ventilated with ambient air (volume in minutes) / Kg >

A right thoracotomy was performed in the fifth intercostal space and the heart was suspended in a pericardium of origin. Bipolar pacing electrodes were sutured to the free wall of the right atrium and to the right ventricle *

Arterial blood pressure and Lead II ECG were measured on a map recorder and monitored on an oscilloscope. The heart of the heart was paced by a stimulus through the conduction of a constant current isolation unit.

Limit of ventricular fibrillation CLFV) was determined during an atrial pacemaker at 255 Hg. Sets of square wave pulses with duration of 4 ms (50 Hz * duration of 200 msec) were delivered to the right ventricle via the bipolar electrode of the epicardium (silver contacts 1 mm in diameter and 5 mm part embedded in a acrylic matrix). Pulse sets were delivered all 12Q paced beats and were timed to end with the end of the ECG T wave. Current intensity was increased progressively until ventricular fibrillation (CFV) occurs. The lowest current intensity producing PV was defined as the ventricular fibrillation threshold <LFV>. When fibrillation occurs the heart is defibrillated within 10 seconds from the fibrillation attack using a 10 J-loaded defibrillator. After defibrillation the animal was allowed to recover for at least 3 minutes or until the ECG returns to normal . LFV was measured twice before Auntie

X-7 administration of the drug for stable pre-drug '> tabelisation of a limit of CSs were mixed - randomly attempting to receive or drove the drug or a pure vehicle via IV. they do not show any significant effect of LFV = A: Appearance of the agents is typical for 8. elevation of the limiting factor in the range of Cs Dsp. iotential antifibrin 5 omo -3.Π XíBcí is tr 8t-Sd OS COfH VS x C Li i rv I &quot;epetidas; (a) a fraction of a substantial fraction C ΟΓΠ 8. (b) a test of the number of samples, to the winding step. Of vehicle-treated sfibrillation and a τ 'enomenon' attempts did not show completion is supported by the animals treated spontaneously and VENTRICULAR FIBRILLATION LIMITS IN CS.ES (n = 2 s κ + D 'Q' &gt;

UOMP

Pre-Drool Vehicle (the ma / kB): current fibrillation or 2 to 6 animals spontaneously defibrillated.

The compounds of this invention have an anti-arrhythmic profile of Class III. Class III antiarrhythmic activity was established in vitro and in vitro according to the following standard test procedures

In Vitro

Free Purkinje fibers with bound myocardium obtained from both adult dog ventricles were secured without twisting to the bottom of a 10 ml tissue chamber and continued to be superfused with oxygenated Tyrode's solution at a flow rate of 5 ml / minute. The composition of the Tyrode solution was (M) NaCl, 138 μl &lt; Cl 4 | C? dextrose, 5.5 = A

The solution was aerated with 95% CCl4.5% at 37 ° C. The bath temperature was maintained at 37 ± 0.5 ° C, due to the circulation of the preheated superfusate through a bath. thermostatically controlled water immediately before entering the tissue chamber,

The preparations were stimulated through bipolar Teflon coated silver wires, insulated at the ends, placed on the attached myocardial endocardial surface, using a digital stimulator prepared to deliver constant current pulses with 1.5 msec duration 30Θ to 1ΘΘ0 msec. The stimulus strength was established at approximately 2 x diastolic limit, and adjusted as necessary during the experiment. All preparations were allowed to equilibrate in the tissue chamber for at least one hour before measurements had begun. Subsequently, a minimum of 60 minutes were left to equilibrate with each superfusate containing the drug, before the dredge feet measurements were made.

J. : *. 4 · m

before and after exposure to drugs. Equivalent potentials were verified after each empathy. glass cells filled with KC1 neg high titanium and Ag / AgCl cell socks were used as reference wells = &gt; The first derivative of the potential upstream action (obtained using an analogue differentiating circuit, value iv) is coupled to a credit meter circuit which retains a value of 30 d. . Traces of potential action and max &quot; storage. P | T | pyrazin- Ii3 of paper r005.1 ti VO iTi editor of c x -

•: 5l. New drug stock inventories were used for each experiment. Compounds were added to a total concentration of 2 mg / mL and diluted to a final concentration of 3 to 1 μg in appropriate volumes of Tyrods solution evaluation of the in situ activi- ties.

Potential section parameters &lt; AP) of evacuation or volaqem (act) 5 beyond the limits of AO · (A) the time needed to repolar • i> C ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• and -80 mV <DAF 80 '• ve A maximum score in DAP .. Λ that OV;> s occurred without a significant change το2 considered as a function of

V-max active anti-arrhythmic activity of Class III &quot; xn vivo &quot; in vivo

J

12 to 15%. (35 mg / Kg and H V K with anesthetized with sodium pentaharfaita supplement of 5 mg / kg / hr) and artificially ventilated with room temperature (volume in minutes of 20 ml / kg). CDCl? TOi si -ípubtu a LUTí- a toracto; the real distance is in the fifth inter-temporal space and suspended ηι i / η ni »r ... ~. Ί Γ Γ Γ Γ Γ Γ Γ Γ;;;;;;;;;;;. J. Org. . It stimulates r ** iSi? i if sj n 1 · "- * w, =? is at for sAiíf suture to the free wall of the lower atrium, the birth of the venous cervix:

Each cell electrode contained air from the slides consisting of the electrode Ipo 1 i d f s on 2 region electrodes. s * c o o x po x a. Rigid acrylic acrylic resin. 0 ° C. .................. epicardium fiber lead were

Ff Arterial blood pressure and ri-Mimhr EUB

Measured in a logger and manipulated on an oscilloscope, conduction lesions and refractive periods; Measurements are measured dur ing the con. The temperature of the thermocouple conducting u is ϊΐ 3. unit dB. with the isolation of atrial-ventricles recorded by a given ante! in a double column, and will say Lu (f% h.RP and VfcPP) and a register after it. ---THE. A * "Da auri. . . &gt; U.S.A.

LntrcKiucao de

S. were of intensity (two vszss the limit) s of the action i ident / 2 msec). The range of S 2 O 2 s has been in the foregoing in Table 5. p * &quot; w gwlt &lt; L o o and κ t re-ss t i mu t io ns on induction of υ. rSS pQ 'BH.S ρ Γ * Q p -iri Q -S Cl 3 and interval 3, -HL · í · · I was considered for. to define the eriçai period

Time of systolic-to-ventricular conduction (LCA a! CV) is measured. The time intervals between the two distances and the distance between the distal and proximal sets of the electrodes are similar to that of the set of electrodes. The thermogravimetric complexes were considered as the moment the line crossed the line of the three-phase console, with the highest deflection peak drugs continued for ϊί · 3. JÉ. i minutes

An ima are given xj CuiTipQ '- 1.0 Lens μΟΓ xn section x = vAs ΐ ΐ a m ad ad ad ad ad ad ad ad ad ad ad ad ad ad ad ad ad ad ad ad ad ad ad ad ad ad s s s s a a. t; The title compound was prepared according to the procedure described in Example 1 wherein each of the compounds of formula (I) was prepared in the same manner as in Example 1. iuu

U.S.A. of the 15 minutes followed by the end of the COCO dog 3. Incremental doses

Variation animals mean increase in ERP which was considered antiarrhythmic in the case of non-spermatozoa. Non-spermatozoa showed a significant decrease in the number of pathogens. CT activity, without live &quot;.

Us test results were as indicated in the following table

&quot; 50 Β mse π i / 035, u0 Β 03 10 mg / kg bír urk inj © = ίν μη na

Biology of Biology! (5 mg / kg) (1 mg / kg) i. S ? 1 5 1 1 ϊ 1 ϊ E E K K K K K K K K K K K K K K K K K K K K K K K K K K K K K K K K. Br. i Ϊ! I i ! ! 1). A solution of the compound of formula (I) 1 H-NMR (CDCl3):? 1 {{f | (s, 1H); I-6 I I -20 s 1 J i 1 i 1 1 1 1 1 1 I? 3 i I 90 | • i Λ X -i *! ~ 5 1! ! - "ci! s f -25 \ s x .χ * 1 | 1 1 1 i i? t 1 7 1 S 1 I! I 1 1 1 1 1 1 I% I * | * r s 1 i i 6 l 1 | I 11! -8 j i! -I. i I | | W i 1! **** Ό f j í 1 1 \ 1? r (1). 7.11 (s, 1H). . 3 W 1 i! ϊ ϊ * * 1 1 1 1 ϊ. 2 j 51 | "· A-. * 1 ·: * | -Well! i. I / II 11! 1 Ϊ (n = 2) | 1 I% 1 1 Ah? Ϊ 1 1 I \ s I! s i FIG. ............ 1 30 I-A 1 \! (1H, s). 1, f 4! 1-yl] -1H-indol-1-yl]

Then, at 500 ° C, the reaction mixture is cooled to -78 ° C. r i 2 i a d os s 10 uri na

DOS-a.QO fiber ds Purkinge * V. ν < The activity profile of the compounds of this invention in the test models scientifically recognized as described herein, such compounds are considered to be anti-arrhythmic agents in the treatment of cardiac arrhythmia and d &gt; For this purpose, 5 arthralgia can be administered orally. The patient may be administered either orally or intravenously. or for the first time. : compatible with the administration of a compound of the formula I, in an anticoagulant, in an anticoagulant, in an anticoagulant Ccc »alkoxy, Ccc» alkyl, Ccc C alkyl, Ccc C alkyl, The models of the animals TO 3. e-e Laus 1 scxd-a dEsus zero-a of i ->. about 5 milligrams per kilogram of the host's choroidal bone (preferably from

Pr .0 mg / Kg / g / x hv a, and from spermatozoa. to l 10 to 10 mg / kg) to be administered in a single dose in a number of doses as necessary for the administration of the drug. the arrhythmic process. The dosage is specific for a diluted dose. The oral administration is a liquid dosage form or only in the form of an oral dosage form. The oral dosage form is a liquid or a liquid dosage form. realizada realizada realizada realizada realizada realizada realizada realizada realizada realizada realizada realizada realizada realizada realizada realizada realizada realizada realizada realizada realizada realizada or or or or or or or or or or or or or or or or or or or or or or or or or or or. ad j Livan tas needed - for the. In conventional manner such as tablets, solutions, solutions, which comprises a conventional coating, coating or color coating. Parenteral administration with liquid unit dosage forms may be via sterile solutions or suspensions in aqueous or oleaginous medium. Isotonic aqueous vehicle for injection is preferred with or without stabilizers, preservatives and emulsifying agents.

Accordingly, this invention also provides a pharmaceutical composition comprising a compound of formula &lt; I &gt; or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable salt thereof.

A representative number of compounds of this invention are disclosed in US Pat.

EXAMPLE 1 1,1-Dimethylethyl 1-cyclohexylamine hydrochloride. (4-nitrophenoxy) -2-oro-1

J

Step I) Preparation of l-

STΠ \ -i ώ · r. &gt; ' p Γ Ú p * · Π M

In the same manner as in Example 1, the reaction mixture was stirred at -78øC for 1 hour and then cooled to -78 ° C. The reaction mixture was stirred at room temperature for 3 hours and the combined organic compound was dried (MgSO 4) and washed with ethyl acetate. The combined organic extracts were dried (MgSO 4) 'Γ Γ C C Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ. 3. Q cri φ f * ÇT; Γ (3 to 10 mL) = A τ rac T 01. d 1 LU. He watched as it began. ri 8a nn χ 3 J 3 3 ¾ 5 5 5 with water C 2 κ 1 ΘΘ mL) p rada rada para para para para para para para 27 27 27 27 27 27 27 27 27 27. ) form of a red oil of sufficient purity to be used next step in the following formula: ## STR1 ## ) 5 6 rt V / 5 4p65 Cdp 2H? , Â € ‡ â € ‡ â € ‡ â € ‡

To a solution of 1-p-nitrophenoxy-2 κ C3 ρΓυρδΠΟ19 p 20 gp in methylene chloride (30 ml) was added dropwise. The reaction mixture was stirred under a nitrogen atmosphere for 48 hours. The mixture was filtered and the filtrate filtered. The residue was purified by flash chromatography (silica gel) and extracted with dichloromethane. Yielding a yellow residue. Trituration of the crude yellow solid gave the crude product as a crude product. Flash chromatography (flash chromatography) mp 75-6 ° C (56%) of the product in the form of a yellow solid, mp 218-151 ° C. 1 H NMR (CDCl3) δ 8.15 Hz, 2 ArH), 3.80 (d, J = 8.2

Hs, 2 ArH) ρ 4.36 and 3.98 &lt; 2m, -OCH3 -CH3 = 36 Cm, 1H, methine of ωράκίοο ρ 2.92 and 2.76 &lt; 2m, 2H, methylene of the epoxide ) »

Calc'd; C 59.19; H, 5.8; N, 6.27 Found: C, 59.51; 5.84; N, 6.31 =

Step 3) Preparation of 2-methylaminomethyl) -benzimidazole 2-Chloromethylbenzimidazole (3.1 g, 18.1 mmol) was dissolved in aqueous mecicilamine <5 ml 4% w / w at Η ° C) at 1 ° C under 3 minutes, the reaction mixture was warmed. The organic phase was dried (MgSOâ, ") and concentrated to give crude product which was purified by HPLC (methanol / chlorite gradient of methylene) to give pure product as a brown solid.1 H NMR (CDCl3): δ 7.56 (m, 2H, ArH); 7.22 (m, 2H, ArH), 4.57 (s, 3H, 2.51 (m, 2H),

Step 4) Preparation of 1-E (1H-Benzimidazol-2-ylmethyl) methyl] -3- (4-nitrophenoxy) -2-propanol 2-methylaminomethyl) benzimidazole dihydrochloride (3.0 g, 1.7 mmol) was added to a solution of 1,2-epoxy-3- (p-nitrophenoxy) propane (®, 6®) in acetonitrile &lt; The reaction mixture was stirred at reflux for 18 hours, cooled and concentrated in vacuo. The residue was purified by chromatography (1% w / w) and then treated with ethanolic HCl and ether to give , 45% g &lt; 34%) the product as a light yellow solid hydrochloride salt, ρ =

J

1 H-NMR (DMSO-d 6): δ = 9.22 (1H, 2H, ArH), 7.73 (1H, 2H, ArH), 7.59 (1H, ArH), 7.13 (d, J = 9 = 32H, ArH), 2.74 / c. 4.45 g long? 1H, CHOH), 4.55 (m, 2H, J = 9 Hz), 3.34 (s, 3H), 3.85 (t, 2H). (3H, t, J = 9Hz); "2 YesS / f..iM + i - · v *. (M / e) 5 357 (n-T 94%), 1333 (100%) = An Analysis Ua 1 cua% - ** c ./'. 1 H-NMR (CDCl3): δ 5.16; M 13.05 In embodiments C 50.09 P H 5.02 S U 13, Θ 4 =

Preparation of 3 - [(4-Amino-3-methoxy-1-

3-yl (4-nitro) phenoxy] -3-i-propenes prepared by the procedure of Step 1; (85 mL) at 0 ° C was added stannous chloride (20.4 g, 212 mmole). After stirring for 2 minutes at 55 ° C the mixture was cooled to 0 ° C C and carefully basified with 50% MaOH. The nubellose mixture was extracted with dichloromethane.

(MnRO-1) was added as a yellow oil which was used directly in the next step.

(M, 4H, ArH), 5.45 (d, 2H, CH3), 5.45 (d, 2H) ? OCH?

Step 1: Preparation of N- [4- (2-Propenoyl) phenyl] imethanesulfonamide

Methanesulfonyl chloride (5.06 mL: added to a solution of 4-amino-4-methoxyphenyl) propene stirred in pyridine (50 mL) at 0 DEG C. The mixture was stirred for several hours. then slowly poured into ice-water for 2 hours. The reaction mixture was stirred for 24 hours at 0 ° C. was 13. v &amp; The reaction mixture was stirred at room temperature for 1 hour and then cooled to 0 ° C. (c) The product (9.05 g, 73%) was precipitated. gives. f * iw, Τι.-ΐί '~ * {Π <5. QS.

J

1 H NMR (CDCl 3):? 7 318? D = d = 63/0 Hz 3? d 3 d-8? 94 Hz, 3 H, A rH): 63.3 (ms 1H, CH3 CH3), 5.40 (w) and 530 (<2m) (CHCl3). . Analysis for C 24 H 35 N 3 O 4 S: * | In the present invention, the present invention relates to a process for the preparation of a compound of formula (I): (s, 3H), 7.42 (d, J = 8 Hz,

Step 3) Preparation of 2,3-Propenoylated

(12 g, 16 g, 0.04 mole) was added to a solution of the compound of general formula (II): (a) N- [4- (2-methoxyphenyl) ethenyl] ethanesulfonamide. (S, O), 5.359 mmol) was dissolved in methylene chloride (120 mL) and the mixture stirred for 4 hours. gave the crude product which was purified by flash chromatography using

1 H NMR (CDCl3): Î'7.17 (3H, s); Hz? J "d 2H ArH 5, 9, and. d, Q. 5 / Γ1 2H = ArH) δ 6.4 (broad s, NHSO3 CH3); 4? 2? Cdd? 2 = 98 Hz? H? CH? H C m s 1H 3 C-H of the epoxide) g 2 ' 1 H-NMR (CDCl 3): 2.90 and 2 = 763 (MH): 324 (MH) e) s 24-5 (60% w / w) = 164 (100%)

Hnalise LsiLUifios; C = 49.0 / ¾ H = -0. N = 5,

L. · a * 17 - 57 5 | - {. Kl εζ Ο -J * SJ

2- (Methylaminomethyl) benzenesulfonate prepared by (0.993 g, 6.16 mmol)

To a solution of 1,2-epoxy-3-Cp-isethanesulfonamidophenylsulfonyl chloride (1.0 g, 10.0 mmol) in dichloromethane (10 ml) was added dropwise. The reaction mixture was stirred at &lt; RTI ID = 0.0 &gt; acetonitrile (12 mL) and cooled to &lt; RTI ID = 0.0 &gt; C, &lt; / RTI &gt; P. dried and dried on an analogous reaction with 1% methanol. Î'9.33 (s, 2H, CH3), 5.9 (d, J = 9 Hz, 2H, ArH), 3.09 (2H, ArH) 5 L · OQ f a ♦. J = 8.6 Hz, 2H, ArW). ã 9 &quot; 1 ei U * *? 3. :? . long 1H), 3.95 (m, 2H, n-yl, Î's), 3.00 (3H, m), 3.35 (3H, s) ) t H (m, 2H, CHOCH 2, NCH3, 2.27 &lt; 5, 3H, NCH2): IR (KBr cm-1: 3290 cm -1) (10%), 13% (100%) and (1%) of the title compound were prepared as described in Example 1, sj A /? awaqg H, 5.94? it 4 &quot;

EXEM

(1-Ethyl-2-quinolinylmethyl) amino) -3-3- (4-methoxyphenyl) -1- Preparation of (R) 1-quinolinecarboxylic acid hydrazide hydrochloride QS-CI-O-methyl Liinoline (3: 1), suspended in aqueous methylamine (4: 1), were weighed at 0 ° C under a Si After 2 minutes, the reaction mixture was warmed to room temperature and stirred for 5 minutes. The reaction mixture was cooled to 0 ° C. The extracts were dried (MgSOâ, ") and extracted with methylene chloride. The organic extracts were dried (MgSOâ,") and evaporated to yield 2.22 g (0.02%) of the gold in the form of Lu ff ò 1 bd> _ as L an ho. /? 44 (d, CH-r4HCH3 ·) • DCI s & 8 δ 8, 2H, ηγΒ &gt; (m, 1H, ArH) δ 7.52 (d, J = 8.3 Hz, 1H = ArH) ρ J = 8.72 Hz, 1H, H-quinoline); H - (CH2) n H; .

Step 2) Preparation of β-methyl-2β-quinoline dihydrochloride 4-nitroisnosyl) -2'-propanoyl-2-methylcyclohexyl) amide; (1) B is the amount of 1, prep arated by the pr o edin g of the plant (1) (1: 6 gp 10.22 mmol) was 2-epoxy-3 (&quot; p-nitrophenane &lt; / RTI &gt;) propane. The crude product was purified by chromatography (MeOH-C) and treated (yield: 51.5 g) in dichloromethane (100 ml), and evaporated to dryness. In a preferred embodiment of the present invention the present invention relates to the use of ethanolic HCl in flash chromatography with ethanolic HCl and to provide for the preparation of dihydro- â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ1 H-1 H: Hz, LH, (DMSO-dâ, †);

10? 27 π and 3. Π 01 X Π S) S

JC Lr 5 J-6589 Hi 5 ΣΗ 5 ηγΗ) 3 /, 82 CMp 1H? ArH) 5 7 r. / Hz, H of quinoline)% 7.67 (m, 1H, ArH) 57, <57 Cd, 3 HCM # 5 7 '/ 8; J = 55.4 Hz, 2 H), 7.84 (d, J = 8.43 Hz, ArH), 8503, J = 8.54 (br s, 1 H, CHOH) = 12 Cd-35.50 and -5.33 (m, 2H, CHOH-CH 2 -N); &lt; s. IR (KBr) cm-1: 3260 (MH +) 3560 CNH) MS m / e: 360 ° (MH +): Found: C, 59.5; H, 5.55; H, 5.58; M at 9.1 δ a *

ΕΧΕΗΡ Μ- r s $ - s_q- ι \ ζ ~ y u χ π ο 11 η 1 χ me r ι ι ι meti ι agi inoJ-r-ηϊα r ο; ρ r ο ρο

β-methylaminomethyl-β-quinolinecarboxylate prepared by the procedure described above. X O j. Osisture. To a stirred solution of 1% propane, prepared by the procedure of &gt; 33 (2500 g, 822 mmol) in acetonitrile (1.2 mL, The mixture reacts. The reaction mixture was heated at reflux for 18 hours in vacuo and the residue was purified on a 10% strength column. The reaction mixture was cooled to -78 ° C. r-s d e. SPC-3. SOb heated to give 15 g g 44c; the analytically pure amorphous salt, m.p. 118-202 ° C, as a tan solid.

1 H-NMR (DMSO-d 6):? ; R @ 24 1H, H of the quinazoline v. , 94%; 21-ArH) -7 * T / <m? (ti U U U 8 8 8 ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti (((((((((((((((((((* * * * * * * * * * * * * * (ArH) 4 Î "Î ± 4 Cd 5 J = 8.93 æm. 2H), ArH) ρ 5, δ (broad d, 1H, OH), 3.96 (m, 2H, OCR-,)? 35.82 (m, 3H), 2.61 (s, 3H, NH), 2.61 and 249 (CHOHCH3 NCH-y), 2.28 (s, 3H, NC1-R) IR (CKBr, cm -quot; 345 &lt; 0H), 318 (NH)

Analysis Calc'd: C, 60.59; H, 6.9; N, 10.11. Found: C, 64.51; . M. 9.85.

EXAMPLE 5

(2-Benzoxazolidylmethyl) methyl] amino] -N- (4-nitrophenyl) -1-

J

J

The title compound was prepared from the title compound as a white solid (0.98 g, 0.6 mmol) in tetrahydrofuran (0.8 g, 0.6 mmol) in CH2 Cl2 5.98 mmole), 331 (ethanol C (g)). to reflux. The mixture was stirred at room temperature for 18 hours. The mixture was evaporated to dryness. The. The reaction mixture was dried (MgSOâ, ") and concentrated to give the product as a brown oil which was purified by chromatography on silica gel. : and in the next step (1: 5 / »': ϊ Ϊ: TXH == ArH) i 7? 56 <m? 1H); ArH), 4.76 (5), filtered under vacuum. The filtrate was concentrated in vacuo. NMR: Η ξCDC1 j,> 2H "CH" C1>. 2) Preparation of 2- (heptylaminomethylbenzosulfoxy

X-ray diffraction pattern. I CT: ifi 1.Π -PT; The title compound was prepared from the title compound as a white solid (40 mL, 4% w / w) in dichloromethane at 40 ° C under a nitrogen atmosphere. After 20 minutes, the reaction mixture was warmed to room temperature and quenched.

The precipitate was dried over magnesium chloride and concentrated in vacuo. The precipitate was dried over magnesium chloride, and concentrated in vacuo. τ · '· - D X pLí Γ * X Τ X i_. Sj and IOH / t) for the reaction of an oil at φ -3. r s 1 or -

1-ylmethyl) amino] -3- (4-methylphenyl) -2-propanol hydrochloride

J

(1.36 g, 11.53 mmol) was added to a solution of 1,2-epoxy-3-p-nitrophenoxy. propane, prepared by the procedure of Example 1, Step 2, C 17, 7.68 mmol) in acetonitrile (25 mL). The reaction mixture was heated at reflux for 24 hours and then quenched at ambient temperature for an additional 24 hours The residue was purified by chrom; then treated with pure ethanolic HCl in the form of a salt, m.p. 214-216Â ° C. toluene concentration in vacuo, 0% MeOH). The title compound was prepared as a white solid (2.12 g) as a pale yellow solid (2.12 g) as a white solid (2.12 g). 7.84 (d, J = 7.67 Hz, J = 7, 7 Hz, 1H), 7.8 (d, 1H, J = (1H, ArH) ε 7.45 (m, 1H, ArH), 7.14 (m, 1H), 7.50 (m, 1H, ArH)

Calc'd: C, 54.96; H. 5.12 = N. 10.67

CHOH-CH,, Ν Li OR 1 ΐώ π Â!!  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ (A = H); J = 4.77 Hz, 2 H, OCR-); 1 H-NMR (DMSO-d 6):?  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ3.54 (m, 2H,

IV

31 (OH

NH 3, 5,535; H, 5; ils Hu 10.68;

hXhnPL-O &lt; 2-Benzofuranylmethyl &lt; / RTI &gt; methyl-2-hydroxyprop- milfgpil 3.metan, psul, fOTamidq

J

Step 1: Preparation of Benzofuran-2-ene I

J

Diborane 1 Molar in tetrahydrofuran &lt; 61.6 ml, 61.6 ml) was added dropwise. was added dropwise over 10 minutes to a stirred solution of benzofuran-2-carhoxylic acid (5.0 g, 30.0 mmol) in tetrahydrofuran (50 ml) at 0 ° C. Stirring was continued at 0 ° C The reaction mixture was carefully quenched by slow addition of THF / Hâ,,Oâ,, and extracted with ether. The organic extracts were dried (MgSOâ, ") and concentrated to give 3- , 58 g (78%) of product as a colorless oil, NMR δ CDMSO-d6): δ 7.57 (m, 2H). ArH) p 7a27 &lt; mf 2H, ArH) p 6.75 &lt; s, 1H, CH = C-) b4.5bis, 2H, CH3 OH).

Step 2) Preparation of 2- [&lt; / RTI &gt; Chloromethane) benzofuran

Thionyl chloride (14 ml, 70.46 mmol) was added dropwise to a solution of benzofuran-2-methanol (3.58 g, 23.48%) and pyridine (10 drops) in methylene chloride The mixture was carefully diluted with water and extracted with methylene chloride. The organic extracts were washed with aqueous sodium bicarbonate, dried (MgSOâ, ") and concentrated to give the crude product which was purified by flash column chromatography &lt; 10% EtOAc / hexanes) to afford 2.77 g (69%) of pure product as a yellow oil.1 H NMR (CDCl3) δ

(CH2) m, CH3).

j. v / vm, 2 r "ArH) a

Step 3) Preparation of 2-Methyl-1-aminomethyl) -thiophene in 77 g (16.6-3 mmol) in 40 minutes in 10 minutes in dichloromethane 1-yl) -furan dissolved in aqueous methylamine. (40 ml at 10 ° C under a nitrogen atmosphere). The reaction was warmed to room temperature and the stirring was continued for 72 hours. The reaction was cooled to 0 ° C. for ori. (10% MeOH / CH2 Cl2) to provide 1: 00 (37%) of product as a yellow oil â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ H, CH = C-), 3.89 (2H, CH, NHCH2), 2.47 (s, 3H, NHCH3).

Step 4) Preparation of N-C4-1,3-C (2-Benzofuranylmethyl) -methoxyimino-2-hydroxy-3-isopropyl-2-methylmethoxy) bentufurane (W, v2 / g, 6.16 (1H, 1 H) was added to a solution of 1,2-epichloro-3-pyridinylaminophenyl) propanoic acid (1.0 g) in acetonitrile (12 g, mixture

Mnatotron is sometimes used to give a compound of the formula D3.CB. urinating 0.640 qi 25% rsacciona! was heated to reflux for 4 hours, concentrated in vacuo. The residue was purified by ethanolic HCl and the crude product was the salt of white solid hydrochloride, m.p. F

Hz, 2H, ArH &gt; s), 6.88 (d, 93 Hz, 2H, ΑγΗ) η 3 6 6 2 2 2 wide,

J

(OH), 4565 Cs broad, 2H, -C (CH), 4.41 (CH3), 3.91 (d, J = 4.98 Hz, 1H); 3 5 34 Cs? : &lt; m, 2H, CHOH-CH? N). IR (KBr): Calculated for CΓΓHΓ ·FN aO a: Calcd. For CΠ "H, ,ClN iO a: Calcd. (i.e. H. 5 ' 71% N. 6.35 Found: C, 40 ° C. 1 H-NMR (DMSO-d6):?  € ƒâ € ƒâ € ƒâ € ƒâ € ƒ (3H)

EXAMPLE

2-Benzofuran-3-ylmethyl) -3-methyl-1H-benzofuran, prepared by the compound of the formula: h. &gt; in μ 1 or 6.! Step 3? Λ V W 5 99 i g s 6 p 1 4 HIT 1 1! USX addition to the solubility of 1S-2-epoxy (O -? prepared by the praxis of the E X in Fig. 1, Pas 50 2. (I.e. 6 &lt; 3 g, 3 &lt; / RTI &gt; (1) and the title compound was obtained as a white solid. 0. (C) i &quot; The residue was concentrated in vacuo and the residue purified by flash chromatography on EtOAc and treated with ethanolic HCl (1: 1) and v 66% of pure hydrohalide salt The yellow oil was evaporated in vacuo to give the title compound as a yellow oil, mp = 208-209Â °.

(DMSO-d6): Î'1.344 (br s, 1H), 4.42 (d, J = 2.2 Hz, (D, -3-8.28 Hz, 5 ArH) = 7.39 (1H, ArH), 7.30 (m, 5H) 1H, ArH), 7.25 (br s, 1H), 7.12 (d, J = 9, and A Hz, 2; _ Ap, ís. 4 * 13

J = 8 Hz); 4. 3-yl) -1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (3-chlorophenyl) IR (KBr): 322 (M + H) +. ), 11.51 (1%) =

Calc'd for C 20 H 13 N 3 O 3:

"Ys-MPi-ri-U-M-4-C-5-Methoxy-2-gt; &lt; / RTI &gt;

Step 1) Preparation 2-EN-E3- (4-Nitrophenoxy) propyl] methyl] amino] -1-quinoline

A suspension of 2- (methylsulfonyl) quinolin-3-one of the title compound of Example 33 Step 13 C3567 gn 21 iodide of sodium &lt; 2.78 g / l. (1), and (2) (13.3 g) in acetonitrile (8.8 mL) was refluxed for 2 hours at room temperature.

orop ropi. 1-4-n-trophsn i. 1 o C 400 g = at 80 ° C overnight, with W B and divided by 1 ° C. silyl acetate. The organic phase was washed with dichloromethane. sec a. The title compound was prepared as a white solid (0.9 g, 36%) as a pale yellow oil. The product was purified by chromatography on silica gel (MgSO 4) Π-5. δ (CDCl3) δ 8.2-2.39 (m, 4H); Η »H da. (M, 4H), 7.50 (m, 1H). H of quindins): Î'7.15 (c = 3 Hz, 2H, β, β); 1, 2, 3, 4, 4, 8, 8, 8, 8, 8, 9, ) 1 2 3 35 C 3 H 5 O 5 - (CH 2) 3 - (CH 3) 3 - (CH 2)

Step j ~ f f &quot; t: 1 'Ο Θ. re.C -ão

methylaminomethyl] quinoline

A mixture of Nâ € ²- (4-nitrophenoxy) -β-PKK-methyl-aminoline- (¹² eC) ¹H-NMR (CDCl e) δ (CDCl e) δ (CDCl e) δ was req ad i dsix ada duran te a. night. The mixture was then concentrated through Solka-Floc to give 1, 1) of amine in the form of a yellow oil which was used directly in the next step: 1 H NMR. ww · - · I ~ S 8? 1 (2H, t, J = 7.4 Hz); r Γ Γ t t t ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ W? X S.R * LfO Λ »f t is l Η Γ ri / t; Qir (t = j = 1), where n is 1, 2, 3, 4, 5, 6, 1, 3, 4, 3, 4, 5, 6, 8, 9, 10, 12, 13, 1 and -HCbU> 1.97 (ϊΤ q ϊΤ «« μ μ μ μ μ μ μ μ μ μ)

Step 3) Preparation of N-L4 -C3 -Methoxy-2-quinolylmethyl) amino] propoxy] phenyl] methanesulfonamide

Methanesuifanyl sulfide (0.5 g, 2mls, 6.5 mmol) was added dropwise to a stirred solution of N - (4-aminophenyl) pyrrolo [3,2,1- SiFi X-dimethylquinoline &lt; 1.8 &gt; &lt; / RTI &gt; &lt; / RTI &gt; The composition of the present invention comprises the steps of: A (nuSOj)? the crude product which was purified by flash chromatography (5% CH 3 Cl 2 / KBr) was added to give the crude product which was purified by chromatography on silica gel. triethyl ether with ether / hexane to form a solid

Ur.

J

N-E4-E3-Eheethyl &lt; 2-guinoxalinylmethyl] Amino-pyrrosin-3-yl] methanesulfonamide

A solution of 2-methylquinoxaline (2: 1, &quot; 155 mmol) and benzoyl peroxide &lt; 3 g ;; 12 mmol) in carbon tetrachloride (80 ml) was added 1β-dibromino-5β-dimethyl hydantoin (22Âμl, 77 mmol). The resulting mixture was irradiated with a C2â, ... watt lamp) for 1.5 hours. The mixture was cooled, filtered, concentrated to give the crude product which was purified by HPLC (hexane / EtOAc 4: 1) to give 14.0 g of &quot; monobromomethyl product &lt; 40%) as a gray solid

(S, 1H, ArH), 8.11 (m, 2H, ArH), 7.8 (m, 2H, ArH), 4.72 (s, 2H, BrCHu -Ar), 15 g of dibromo-4-methyl-

(35%) as a brown solid.1 H NMR (CDCl3); S &gt; 9339 (s, 1H, Ar H); 8.15 (m, 2H, ArH); 7.90 (1H, t, 2H, ArH), 6.76 (s, 1H, Br BrCH2-Ar).

Step 2) Preparation of 2- (2-methylaminomethyl) quinoline 2- (bromomethyl) quinazoline <3, 13.4 mmol) was added in portions to a stirred solution of methylamine <3%) in ethanol (100 mL) at 0 ° C. The reaction was stirred at 0 ° C for 2 hours, concentrated, and partitioned between 50% aqueous potassium carbonate / ethyl acetate. The organic phase was dried (MgSO 4), decolorized (mineral coal), and concentrated. Purification was achieved by elution of the sample through a small silica cap to give 1.80 g (78%) of a brown oil. Î ± S 8.85 Î "S, 1B, ArH> 8.10 ~ Η Η Α Α Α Α Α ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ? 4.15 &lt; s, 2θ, NCH2 Ar)? 2.60 (s, 3H, NCH3).

Step 3) Preparation of 3-methoxyphenyl ether To a solution of 4-nitropropane &lt; tb &gt; 1 g, 71.94 mmol) in tetrahydrofuran (1 ml) at & 5C fax added triphenylphosphine (22.0 g, 86.33 mmol), 3-iodopropanol (16.73 g ρ 89 , 93 mmol), and distilazodicarboxylate &lt; 14.3 mL, 86.33 mmol). The resulting mixture was stirred at 25 ° C overnight. The mixture was partitioned between brine and ethyl acetate. The organic phase was dried and concentrated. The residue was triturated with 8/1 ethyl ether / ethyl acetate to induce the precipitation of 22 g of phenyltriphosphine oxide which was filtered off. The filtrate was pre-absorbed on silica gel and flash chromatographed Chexane / EtOAc (5: 1) to give 7.5 g (79%) of white solid product. NMR Î'(CDClâ,ƒ): Î'8.22 (d, 3 -8.2 Hz, 2H, ArH) Î'6.96 (d, J = 9 Hz, 2H, ArH) t, J = 5.8Hz, 2H, OCH3), 3.37 (t, d = 7.6

Hz, 2 H, 2.31 (m, 2H, CH 2 CH 2 CH 3).

To a stirred suspension of 2- (methylaminomethyl) quinoline (1.1 g, 6.35 mmol) was added to potassium carbonate (0.6 g, 0.6 mmol) in dichloromethane , 1.88 g, 6.35 mmol) in acetonitrile / ethanol (4 ml) was added 3-iodopropyl-4-nitrophenyl ether (1.95 g, 6.35 mmol) .The resulting mixture was heated to 85øC The organic phase was dried (MgSO 4), decolorized, and dried (MgSO 4), and concentrated to give 1.86 g (83%) of product as a colorless oil. form of a yellow semi-solid which was of sufficient purity for

be used in the next step. NMR (CDClâ,ƒ): δ 8.95 (s, 1H, ArH), 5.11 (d, J = 9.4 Hz, 2H,

ArH); 8, Cm, 2H, ArH), 7.72 (m, 2H, ArH), 6.76 (d, J = 9.8 Hz, 2H, ArH), 4.09, J = 5.4 Hz, 2H, O): 2.67 (t, d = 5.2 Hz, 2H, CH3 N); 2.41 (s, 3H, CH3); 2, 5 5, Cm, 2 H, CH 2 CH 2).

Step 5) Preparation of 2-CN-β-3- (4-Aminophenyl) -pyridinylaminomethyl] quinoline

A mixture of N-1-C4-nitrophenoxy) propyl] methyl ammonium methylmethyloxaline (1.75 g, 4.97 mmol) and PtO, in ethanol (17 ml) was charged with 1 H 2 Cl 2). After 30 minutes the mixture was filtered through Solka-Floc and concentrated to give the crude product which was purified by HPLC to give 1.18 (CDClâ,ƒ, Hâ,ƒCS, 1H, ArH), 5.8 (m, 2H, ArH), 7.73 (m, 2H, ArH), 6 ,  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ3 H, 3.4 &quot; Wide Cs, 2H, NH &gt; 2.68 (t, t, J = 6.6 Hz, 2H, CH2 NH); 2.33 (s, 3H, NCHâ,ƒ); 1.99 (m, 2H, 8â¼20â¼8â¼2â Ν); .

To a stirred solution of N - (4-aminophenyl) propoxy-4-methyl-3-methyl-3-propoxy-3-methyl- 33 Âμmethylquinoxaline C®, 93 g, 2.89 mmol) and pyridine C®, 47mL. 5.78 mmol) in dichloromethane (2 mL) at -80 ° C under N 2 was added portionwise methanesulfonyl chloride (25 mL, 3.21 mmol). The mixture was warmed to 25 ° C, stirred for 2.5 hours, and then partitioned between 10% aq. NaHCO 3 and ethyl acetate. The organic phase was washed with brine, dried (MgSO 4),

(8%) of the product as a yellow oil (an inane π-a by UCF). The compound was treated with methylene chloride. Ethanolic hexane / ether to give 1 g of hydrochloride as a gray powder, mp 70 DEG C. (1: 1): 1 H NMR (DMSO-d6, Î') ; &gt; p &lt; / RTI &gt;

(2H, ArH), 7.91 (s, 1H). 2H, ArH) .delta. = 14 (d-J = V).

ArH 5 | &amp; 87 (d 3 d-9, ξ, s 2H 3 ArH); 4.84 (m, 2H, H-ChL · Ar)

Iim &lt; (M, 2H, -CH₂CH₂CH₂CH₂NH), 2.39 (s, 3H, NCH3); 2 p Θ 7 (Mw 3 H 2 OCH 3) 2H2O, CH3. (NH4) 4 (CH3) 2 (CH3) 3 (CH3) 2 (CH3) 2 (CH3) • ΐϊ J. J. J. ΐ ΐ J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J. J.. H = 5.87 M. 12.560

Claims (2)

A process for the preparation of compounds of formula (lys wherein R1 is alkylsulfonamido of 1 to L · carbon atoms. arylsulfonamido of 6 to 10 carbon atoms, perfluoroalkylsulfonamido of 1 to 6 carbon atoms, perfluoroalkylamido of 1 to 6 carbon atoms, alkylsulfone or alkylsulfoxide of 1 to 6 carbon atoms, N0 ,.? CM, or 1-imidazolyl: R "is a branched or straight chain alkyl of 1 to & carbon atoms X is O, S ,; or NR '&quot;' where R &quot; ' is H or a branched or straight chain alkyl of from 1 to 6 carbon atoms; V is CH3; or CwOH? Het is selected from the group consisting of J ), 4-chlorophenylsulfonyl, 4-chlorophenylsulfonylmethyl, MHCOT dihydro or NF-i in Fusi is H-Sulfur C, a. L-. or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable acid addition salt thereof. wherein R 1 and X 2 are as the aforesaid secondary amino groups appropriately substituted with: (a) -NH- wherein R 2 and R 3 are as defined in claim 1, wherein R 1 is as defined in claim 1, wherein R 1 is as defined in formula (b). gs estructure (I.e. V Het in the presence of a suitable base, is acetone or acetonitrile. A process according to claim 1, characterized in that the compounds of the formula that K is NOR or methyl is 2-amido, Y is CH3 or CHOH, and He is hydrogenated. 0-5 of the group The. Wherein R 1 is H or methyl isophenamido and the pharmaceutically acceptable salts thereof. A process according to claim 2 wherein the N-C 4 -C 12 -hydroxy-3-methyl-2- quinolinylmethyl) amino] propyl] phenyl] methane-3-yl] amide and the pharmaceutically acceptable salts thereof: A process as claimed in claim 2; characterized in that N-E4-E3-methyl (2-quinolinylmethyl) benzofuranylphenanesulfonamide and pharmaceutically acceptable salts thereof. A process according to claim 2, The compound of Claim 2, which is characterized in that it is prepared by preparing a compound of the formula: ## STR1 ## in which the compound of the formula ## STR1 ## in which R 1 is hydrogen, halogen, trifluoromethyl, (4-nitrophenyl) -2-propanol and the pharmaceutically acceptable salts thereof. A process according to claim 2, wherein the compound of formula (I) (2-hydroxyethyl) aminoethylamino] -2-hydroxyphenylmethane sulfonamide and pharmaceutically acceptable salts thereof. A process according to claim 2, which is characterized in that it is prepared 1-methyl (2-quinolinylmethyl) amino] -3- (4-nitrophenoxy) -2-propanol and pharmaceutically acceptable salts thereof. The process according to claim 2, which is characterized in that it is prepared by preparing N- (2-benzofuranylmethyl) methylamino-3- (4-nitrophenyl) -2-propanol and its pharmaceutically acceptable salts. The process according to claim 2, wherein the M-R 4 -C 3 -L-C-benzofuranylmethyl) -methylamino-2-hydroxypropoxyphenylmethane sulfonate and its pharmaceutically acceptable salts thereof are prepared. (2-benzothiazolylmethyl) methylamino-3- (4-nitrophenoxy) -2-propanol and pharmaceutically acceptable salts thereof, A process for the preparation of a pharmaceutical composition having antiarrhythmic properties. characterized in that an effective amount of a compound of formula Cl) of claim 1 or of its physiologically tolerated acid addition salts and a carrier and / or diluent is included in said composition. The present invention relates to a process for the preparation of a pharmaceutical composition comprising a pharmaceutically acceptable carrier. Method of treatment of arrhythmia. ~ X. * By coaip ι · - 0 enoe r admi: π x s ir. A compound of formula (I) of claim 1 wherein the pharmaceutically acceptable acid addition salt of the compound of formula (I) of 2 mg per kilogram of body weight to J. PEREIRA DA CRUZ Official Agent! of Industrial Property RUA VtCTOR CORDON, 10-A 3.® 1200 US80A! ! θ · i d December of 1 V; J