CA1049534A - B-or2-phenethylimino-pyrrolidines - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

.beta.-OR2-Phenethylimino-pyrrolidines are disclosed of the structural formula:

wherein:
Ar is phenyl with from one to three substituents chosen from lower alkoxy of from 1 to 8 carbon atoms, lower alkyl of from 1 to 8 carbon atoms and methylenedioxy;
R1 is hydroxy-ethyl or hydroxy propyl; and R2 is loweralkenyl, preferably allyl, cycloalkyl, preferably cyclopentyl or cyclohexyl or loweralkyl, preferably methyl or ethyl. The compound has been found useful in the treatment of cardiovascular disease states.

Description

10~9S34 BACKGROUND OF THE INVENTION:
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The invention pertains to the field of substituted phenethylimino-pyrrolidines which demonstrate such pharmacological properties as ganglionic blocking-hypotensive, cardiac slowing, and cardiac atrial and ventricular anti-arrhythmic activities, and are thus useful agents for the treatment of cardiovascular disease states. The subject pyrrolidines differ from those in the prior art by having, among other differences, an alkenoxy, cycloalkoxy or an alkoxy group (i.e., "OR2") in the ~-position of the phenethyl function and an hydroxy lower alkyl substituent on the l-position of the pyrrolidine group. Prior art compounds are as described in Canadian Patent 850,116.

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DESCRIPTION OF THE PRl~FERRED EMBODIMENTS:
The novel ~B-OR2-phenethylimino-pyrrolidines of this invention may be structurally represented by the formula:

J~N-CH2-CH-Ar R l (I) wher e in:
Ar is phenyl with from one to three substituents chosen from lower alkoxy (1-8 carbon atomsj, lower alkyl (1-8 carbon atoms) and 10 methylenedioxy;
Rl is hydroxy-ethyl or hydroxy propyl, preferably hydroxyethyl:
and R2 is loweralkenyl, (preferably allyl), cycloalkyl, preferably cyclopentyl or cyclohexyl), or loweralkyl, (preferably methyl or ethyl).
The therapeutically active non-toxic acid addition salts of the foregoing pyrrolidines (I) are also embraced within the scope of this ~, !: ... .
invention.
As used herein, "loweralkyl" and "loweralkoxy" may be straight or branch chained and have from 1 to 6 carbon atoms, such as, for example, 20 methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexylandthe like alkyls, and, respectively, the corresponding alkoxys, such as methoxy, ethoxy, propoxy, isopropoxy, etc.; and "loweralkenyl" is an unsaturated (one double ;' bond) hydrocarbon having from 3 to 6 carbon atoms, such as, for example, `
allyl, 3-butenyl, etc.

Due to the asymmetric ~-carbon atom of the phenethyl function, it is evident that the existence of the formula (I) compounds in the form of stereochemical isomers (enantiomorphs) is possible. Thus, by standard methods of resolution, the corresponding (-) or (+) forms may be obtained.
Such pharmacologically active isomers are naturally intended to be included 30 within the scope of this invention.
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The compounds of formula (I) are generally prepared by reacting a fluoborate of formula (II) with a primary amine having the formula:
NH2-CH2-CH(OR2)-Ar (III). Stoichiometric quantities of reactants are preferably employed. Suitable organic solvents for conducting the reaction include lower aliphatic alcohols, such as, for example, methanol, ethanol, 2-propanol, tert-butanol and the like; ethers, such as, for example, di-ethylether, tetrahydrofuran, dioxane and the like; lower halogenated hydro-carbons, such as, for example, chloroform, methylene chloride, 1,2-dichloroethane~ and the like; and aromatic hydrocarbons, such as, for 10 example, benzene, toluene, xylene and the likeO Ambient to 0C tempera- -tures may generally be employed. The resulting product (IV), in the form of the fluoborate salt, is converted to the corresponding base form (I) by conventional means, for example, by treatment with a suitable alkali such as alkali metal or alkaline earth metal hydroxides, carbonates and the like.
The reaction may be illustrated as follows:
_ _ ~

OEt ~3F4 + NH2-G~2-C~ ORz)-Ar Rl :, (II) (ILI) (IV) ~

Fluoborate salts of formula (II) have for the most part been described in the literature (see Canadian Pat. NoO 850,116) and may be 30 prepared according to BerO, 89, 2060 (1956) by treating an appropriate pyrrolidin-2-one with triethyloxonium fluoborate [also see Meerwein et al., Annalen der Chemie, 641: 1-39 (March) 1961]:

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1~91L~S3 ~) s (~ Q ~ OEt BF4 O 3 ) Rl ~ Rl .~ , (II) The amino-ethers of formula (III), iOe., wherein R2 is alkoxy, cycloalkoxy or alkenoxy may be obtained from the nitrostyrenes of formula -(VI) which are generailly known in the literature and may be prepared 10 according to the directions described by Ao Dornow et al., ArchO Pharm., 284, 153-60 (1951). The formula (VI) nitrostyrene is converted to the nitro-ether (VII), wherein "alk" represents the loweralkyl, cycloalkyl and ,;, .:, - . . ..
loweralkenyl functions of R2, according to the directions described by MoG~
Tsatsas , Bull, SocO ChimO France, 884 (1949), iOeO, by treatment with , ~
excess alkali "alk"-oxide in a suitable organic solvent such as a lower ~- -alkanol, for example, sodium methoxide in methanol, sodium ethoxide in ethanol, and the like, or in an ether, for example sodium cyclohexyloxide in tetrahydrofuran, sodium allyloxide in dioxane, and the likeO The reaction -is conducted under an inert atmosphere, such as nitrogen, helium, argon !
20 and the like, and at temperatures below 0C, preferably between -10 to 0C.
After reaction is complete, the excess-alkoxide is neutrali~edby quenching the reaction mixture with a siight excess of acetic acid. The nitro function `-;
of (VII) is then reduced, for example, by means of lithium aluminum hydride or by catalytic hydrogenation, e.g., hydrogen over Raney nickel, to yield the desired aminoether of formula (III-a)O The foregoing reactions may be -illustrated by the following diagram: ' O - "alk"
NO2-CH=CH-Ar Na lklk 1Xide ~ HOAc > No2-cH2-cH-Ar (VI) (VII) O-"alk"

redn.NH2-CH2-CH-Ar ` ~
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The formula (I) bas0s are con~rertible to therapeutically active non-toxic acid addition salts by treatment with an appropriate acid, such as, for example, an inorganic acid, such as, a hydrohalic acid, e.g., hydro-chloric, hydrobromic or hydroiodic acid, and sulfuric acid, nitric acid, phosphoric acid and the like; or an organic acid, such as, acetic, propionic, glycolic, lactic, pyru~ric, malonic, succinic, maleic, fumaric, malic, ;
tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic, ethane-sulfonic, hydroxyethanesulfonic, benzenesulfonic, E~-toluenesulfonic, cyclo-hexanesulfamic, salicylic, l~-aminosalicylic, 2-phenoxybenzoic, 2-acetoxy-10 benzoic and the like acids. Conversely, the salt form can be converted by treatment with alkali into the free base form.
At doses ranging from 0.25 - 17.5 mg/kg i~vo J the s~lbject com- :
pounds antagonize automaticity of atrial tissue (S.A. node and other atrial tissue) by decreasing phase IV depolarization which effectively lowers heart rate and suppresses atrial arrhythmias. (See the following tests B. and D. ) lin addition, these compounds also demonstrate either ventricular antiarrhythmic or antifibrillatory activity hy one or more of the following tests C-l; C-2; C-3 and C-4 within the dose range pre~iously described. -Specifically the compound of Example IV, (namely 2[(3,4-diethoxy-20 ~-methoxyphenethyl)imino]-l-pyrrolidine ethanol) is active in the following tests B; D; C-3 and C-40 Test A. Ganglionic Blockin~ Activity (Antihypertensive):
The methodology followed is that reported by G.H. Acheson and SoA~ Pereira, J. Pharmacol & Exper. Therap. ~7, 273 (1946) on anesthetized cats.
According to this test, blockage of pre-ganglionic stimulation o the nicti-tating membrane of the anesthetized cat without affecting the post-ganglionic stimulation constitutes ganglionic-blocking activityO
Test B. Reflexogenic Sinus Tachycardia (Cardiac-slowin~
A bilateral vagotomy is performed on the anesthetized dog [anesthesia consists 30 of i~vo administration of thiopental sodium t20 mg/kg) maintained by sub-sequent i~vo injections of c~-chloralose (60 mg/kg)]0 Two doses of amino-. .
.

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phyl~line (5 rng/kg i~vo ) are administered at 15-minute intervalsO The hypotensive effect of aminophylline activates the baro-receptors of the carotid sinus which, in turn, stimulates the sympathetic nervous system causing a reflex rise in the heart rate. Fifteen minutes after the second dose of aminophylline, the compound to be tested is administered iovo and the effect on the heart rate is noted over a 30-minute periodO Compounds showing heart-rate lowering activity of at least 18 sinus beats per minute for at least 5 minutes are considered to be active. Such compounds are useful in the treatment of angina pectoris since heart rate is considered to 10 be a major determinant of myocardial oxygen consumption.
Test CO ~entricular Anti-arrhythmic ACtivitv is eyaluated by .
e ither of the following te sts O
Test C-l. Mongrel dogs are anesthetized with pentobarbital sodium (30 mg/kg)' iov~ A left-sided thoracotomy is performed and the left anterior descending coronary artery is ligated according to the procedure of S.A. Harris, Circ. 1, 1318 (1950)o Eighteen to twenty-four hours later, the animal recovers from the anesthesia and a full blown multifocal ventricular tachycardia develops. The test compound is then administered iovo and the effect on the arrhythmia is notedO The degree of protection is determined 20 by expressing the ratio of normal sinus beats to heart rate as a percentage.
At least a 25% reversion to normal sinus rhythm lasting at least 15 minutes indicates positive ventricular anti-arrhythmic activity. ~ -Test C-20 A cuabain-induced ventricular antiarrhythic test:
Limb lead II of the electrocardiogram and arterial blood pressure recordings ;
on the anesthetized dog (anesthesia same as in Test B) are first obtained~ ` -Ouabain (70 mcg/kg i.v.) is given and readministered at 15-minute intervals `
in 10 mcg/kg increments until a ventricular tachycardia is sustained for 10 minutesO The test compound is then administered i.v. Effectiveness is assessed by the ability of the drug to revert the tachycardia to normal sinus 30 rhythm.

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Test C-30 Describecl in "Ethyl-3-ethoxycarbonyl-4-hydroxy-2H-1, 2-benzothia~7ine -2-acetate -1, 1 -dioxide, a compound producing ventricular arrhythmias", T.P. Pruss, ToxicolO andApplO Pharmacol. 14: 1-5 (1969)o Test C-4. Hernodvnamic Evaluation Anestesia was induced in mongrel dogs with thiopental sodium, 20 mg/kg i.v. and maintained with ot-chloralose, 60 mg/kg i~vo A cuffed endotracheal was inserted to main-tain a patent airway, but animals are allowed to breathe spontaneously. A
femoral artery and vein were isolated and catheterized for recording arterial pressure and for intravenous injection respectively. Both common carotid arteries were isolated for performance of bilateral carotid occlusion. The right vagus nerve was isolated and cut centrallyO The peripheral end of the vagus nerve was stimulated electrically for 10 seconds at 5 volts, 20 pulses per second of 2~ 5 msec duration to obtain cardiac arrestO The electro-cardiogram was monitored through Limb Lead IIo Two control responses were obtained to the following pharmacological procedures.
epinephrine - 4 mcg/kg i.v.
bilateral carotid occlusion ~
DMPP*- 16 mcg/kg i.v. (~1,1-dimethyl-4-phenylpiperazinium `
iodide) peripheral vagal stimulation acethylcholine - 10 mcg/kg iov~
angiotensin - 1 mcg/kg i~vo In this procedure, both epinephrine and DMPP* produce a pressor response as well as ventricular arrhythmias consistently. (*l, l-dimethyl-4-phenylpiperazinium iodide) Any compound possessing activity in preventing such arrhythmias has potential as a ventricular anti-arrhythmic or anti-fibrillatory agent.
Test D~ Atrial Anti-arrhvthmic Test: The right atrium of an anesthetized dog (anesthesia same as in Test B) is exposed by right thoracotomy and retraction of the pericardium. Atrial fibrillation, as determined by standard ECG limb lead (II), is induced by placing two drops `
of a 10% solution of acetylcholine on the atrium and then stroking the atrium 7 _ !9S34 with a blunt spatulaO The period of fibrillation is recordedO Two control periods of fibrillation are produced at 15-minute intervals. The compound to be tested is administered i.v. ten seconds after the next inductionO A
compound is classified as active if it decreases the period of fibrillation by at least 50%0 The minimum dose which causes such 50% decrease is called the minimum effective dose (MED).
The subject compounds (I), in base or acid addition salt form, may be formulated into conventional pharmaceutical dosage forms and prepara-tions, for example, for oral and parenteral administration, according to -10 standard pharmaceutical techniques in the art.
The following examples are intended to illustrate, but not to limit, ; , the scope of the present inventionO
EXAM PL E
This example demonstrates a procedural method of making the nitro-ethers of formula (VII). -~
A. ,~-(3,4-Diethoxyphenyl)-~-methoxy-nitroethane: A suspension of pulverized 3~4-di-ethoxy-w-nitrostyrene (7108 g.; 003 mole) in 3 pints of absolute methanol is cooled under nitrogen with vigorous stirring to -10C
in an ice-salt bathO A solu~ion of 27. 6 g. (1. 2 g. atom) of sodium dissolved 20 in 2 pints of absolute methanol is added such that the temperature does not exceed 0C. Stirring is continued at -10 to 0C~ for 3.5 hours. Then ;~
75 g~ (1. 25 moles) oI glacial acetic acid is added with stirring. The solution is filtered from some unreacted nitrostyrene starting material. Most of the methanol is removed from the filtrate in vacuo. The syrupy residue is poured into ice-waterO The resulting gummy solid is dissolved in 1.5 liters of benzene. The ben~ene solution is dried over anhydrous magnesium sulfate, filtered and the solvent removed in vacuo to give an oilO Addition of ether and scratching gives crystals of ~B-(3,4-diethoxyphenyl~ 3-methoxy-nitroethane which are recovered by filtration and dried, m~pO 86_87Co B. The procedure of Example I -A is repeated except that an equivalent quantity each of 3,4-di-methoxy-W-nitrostyrene, 3-ethoxy-4- ~

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methoxy-~-nitrostyrene, 4-ethoxy-3-methoxy~lJ-nitrostyrene and 4-n-butoYy-3-ethoxy-W-nitrostyrene is substituted for the nitrostyrene starting material ~sed tllerein to yiel~l, as respective products, 13-(3,4-c~irnethoxy phenyl)-6-methoxy-nitroethane, ~B-(3-ethoxy-4-methoxyphenyl)-~-methoxy-nitroethane, ,~-(4-ethoxy-3-methoxyphenyl)-~B-methoxy-nitroethane and ~-(4-_-butoxy-3-ethoxyphenyl)-R-methoxy-nitroethane.
EXAMPLE II
A . 3 ~ 4 - Die thoxy - B- m ethoxyphenethylam in e Hydr o chl or ide To a slurry of 36. 8 g. (0. 97 mole) of lithium aluminum hydride in 1 liter 10 of ether is added 65.1 g. (0.242 mole) of ~B-(3,4-diethoxyphenyl)-~B-methoxy-nitroethane as a solution in 1 liter of anhydrous ether. The addition is carried out with stirring and such that gentle reflux is maintained without external heat. The addition requires about 50 min. After the addition is complete, the reaction mixture is heated under reflux for 3 hours, then cooled in ice water, and, with stirring, 36.8 ml. of water is added drop-wise with caution, followed by 36. 8 ml. of 10% sodium hydroxide `
(dropwise) and, finally 111 ml. of water which can be added more rapidly. Stirring gives a white precipitate of inorganics which is filtered off and washed with ether. The filtrate is dried over anhydrous magnesium 20 sulfate and the solvent removed in vacuo. The residual oil is taken up in fresh ether (200 ml. ), and the solution is filtered, concentrated to about 100 ml., and then seeded and scratched to yield a precipitate which is filtered off, to give about 32.1 g. (55%~ of crystalline free base, 3,4-di-ethoxy-,6-methoxyphenethylamine. The mother liquors are treated with anhydrous hydrogen chloride, affording about 16.2 g. of the crude hydro-chloride salt. Several recrystallizations from ethanol (95%) and ethanol ~95%) acetone gives about 5. 0 g. (7%) of pure salt; m.p. 178-179C.
B. Alternatively, the reduction of the nitro-ether of Example II-A, namely, ~ -(3 ,4-diethoxyphenyl)-,~-methoxynitroethane, can be performed , 30 by hydrogenation over Raney nickel in glacial acetic acid. Following filtra- -tion from catalyst and solvent removal in vacuo, the residue is triturated ~ ;~
and washed with ether to give the acetate salt of 3,4-diethoxy-,~-methoxy- ~

phenethylamine, m. p. 90-94C . ~ ;

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EXAMPLE III
The reduction procedures of Example II may be followed to pre-pare the amino-ethers of formula (III). Accordingly, by utilizing an equivalent quantity of each of an appropriate nitro-ether as the starting material to be reduced, the following respective products are obtained, both in the form of the free base and the corresponding HCl and/or acetate salts:
3, 4-dimethoxy-~-methoxy-,~-phenethylamine;
3-ethoxy-4-methoxy-~-methoxy-~-phenethylamine;
4-ethoxy-3-methoxy-~-methoxy-,B-phenethylamine; and 4-n -butoxy - 3 - ethoxy-~- methoxy -~-phenethylamine .
EXAMPLE IV
This example demonstrates a procedural method of making the ; ~ ~ -N-hydroxyalkyl derivatives of formula (I).
2-[(3, 4-Diethox~ ~methoxyphenethyl)imino] -1 -Pvrrolidin-ethanol saccharinate:
Triethyloxonium fluoroborate, prepared in the usual manner from 9. 25 g (û. 10 mole) of epichlorohydrin and 18. 90 g (0O 133 mole) of boron trifluoride etherate, is dissolved in 70 ml of methylene chloride, treated with 12. 92 g (0. 10 mole) of 2-keto-l-pyrrolidinethanol in 30 ml of methylene chloride, and the solution stirred under nitrogen at room temperature for 3 hrsO
The mixture is cooled (ice-bath) and a solution of 3,4-diethoxy-~-methoxy-phenethylamine (21.51 g, 0O09 mole) in methylene chloride is added, and the mixture stirred at room temperature overnight (about 15 hours). The solvent is then removed in vacuo to give about 43O 7 g of the crude fluoro-borate salt as an oily residue~ The fluoroborate salt is converted to the free base using cold 3N sodium hydroxide and extracting with ether-methylene chloride (2:1). The extracts are combined, washedwith saturatedbrine, dried over potassium carbonate, and the solvent removed in vacuo. The -residual oily 2-[(3,4-diethoxy-~-methoxyphenethyl)imino]-l-pyrrolidin-ethanol is dissolved in acetone and added to an equimolar amount of saccharin ,, - 1 0 - ,:

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in the same solvent. Several recrystalli~7ations from ethyl acetate-ether (1:1) affords about 16.46 g of 2-[(3,4-diethoxy-~-methoxyphenethyl)imino]-l-pyrrolidin-ethanol saccharinate as a white solid, m.pO (100) 109-113C.
EXAMPLE V
The procedure of Example IV is repeated except that an equivalent quantity of an appropriate amino ether (such as that which may be obtained according to the procedure of Example II) is substituted for the amino alcohol used therein, to yield the following respective products:
Z - (4 -_- Butoxy- 3 - ethoxy-~ -methoxyphenethyl )imino - I -pyr r olidine ethanol O
2 - (~, 3, 4- Triethoxyphenethyl)imino -1 -pyrrolidineethanolO ~ -2-(,~,2,4-Trimethoxyphenethyl)imino-l-pyrrolidineethanolO
2-3, 4-Methylenedioxy-~-methoxyphenethyl)imino- l-pyrrolidineethanol.
2 - ( ~ , 4 - Dimethoxy - 3 -methylphenethyl )imino -1 -pyrr olidine ethanol .
2-(~, 4-Dimethoxy-2, 5 -dimethylphenethyl)imino -1 -pyrrolidineethanol.
2~ -~llyloxy-3, 4-diethoxyphenethyl)imino- 1 -pyrrolidineethanolO
2- (,~- Cyclopentyloxy - 3, 4 - diethoxyphenethyl) imino - 1 -pyr r olidine ethanol O ,, r ' ' ' : :' , ;

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Claims (4)

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

1. A process for the preparation of a 2-imino-pyrrolidine having the formula:

wherein:
Ar is phenyl with from one to three substituents chosen from lower alkoxy of 1 to 8 carbon atoms, lower alkyl of 1 to 8 carbon atoms and methylenedioxy;
R1 is hydroxy-ethyl or hydroxy propyl;
R2 is loweralkyl, loweralkenyl, cyclopentyl or cyclohexyl;
and the therapeutically active non-toxic acid addition salts thereof; which comprises reacting a compound of the formula with a compound of the formula NH2-CH2-CH(OR2)-Ar in a solvent, and, if desired, preparing a therapeutically active acid addition salt of the product thereof, and further, if desired, resolving the (+) or (-) isomeric form therefrom by standard methods.

2. A process for preparing 2[(3,4-diethoxy-.beta.-methoxyphenethyl)imino]-1-pyrrolidineethanol, which comprises reacting a compound of the formula with 3,4-diethoxy- .beta. -methoxyphenethylamine.

3. 2-Imino-pyrrolidine having the formula:

or the therapeutically active non-toxic acid addition salt thereof wherein Ar is phenyl with from one to three substituents chosen from lower alkoxy of 1 to 8 carbon atoms, lower alkyl of 1 to 8 carbon atoms and methylenedioxy;
R1 is hydroxy-ethyl or hydroxy propyl;
R2 is loweralkyl, loweralkenyl, cyclopentyl or cyclohexyl;
or the (+) or (-) isomeric form thereof, whenever prepared according to the process claimed in claim 1, or by the obvious chemical equivalent thereof.

4. The compound 2[(3,4-diethoxy- .beta. -methoxyphenethyl) imino]-1-pyrrolidineethanol, whenever prepared according to the process claimed in claim 2, or by the obvious chemical equivalent thereof.