United States Patent (19) 11 3,962,238 Mauvernay et al. (45) June 8, 1976

54 ETHERS OF N-PROPANOLAMINE 51) Int. C.’...... C07D 295/00 75 Inventors: Roland Yves Mauvernay, ; 58 Field of Search...... 260/326.5 L, 247.2 B, Norbert Busch, ; Jacques 260/247.5 R, 293.76, 296 AE, 570.9, 570.6, Moleyre, , André Monteil, 573 ; Jacques Simond, Chamalieres, all of 56 References Cited 73) Assignee: Centre Europeen de Recherches UNITED STATES PATENTS Mauvernay "CERM', Riom, France 2,600,301 6/1952 Kerwin...... 260/570.9 2,832,795 4/1958 Hempel et al...... 260/570.9 22 Filed: Feb. 27, 1973 3,666,811 5/1972 Van der Steldt...... 260/570.9 (21) Appl. No.: 336,357 Primary Examiner-Paul J. Killos Attorney, Agent, or Firm-Haseltine, Lake & Waters 30 Foreign Application Priority Data Mar. 6, 1972 France ...... 72.O7647 57 ABSTRACT 52 U.S. Cl...... 260/247.2 B: 260/247.5 R; Ethers of n-propanolamine, preparation thereof and 260/293.79; 260/296 AE; 260/326.5 L their use in treatment of cardiovascular conditions. 260/326.5 R; 260/570.6; 260/570.9; 260/573; 424/248; 424/267; 424/274; 6 Claims, No Drawings 424/325 3,962,238 1. 2 in which A has the same meaning as in the general ETHERS OF N-PROPANOLAMINE formulae I and II above, whilst Ar and Arare aromatic groups. (Ehrhart/Ruschig Arzneimittel I, pages This invention relates to ethers of n-propanolamine, 208-210). to the preparation thereof and to the use thereof. 5 The compounds according to the present invention The present invention provides an ether of an n having the general formula l, are manifestly different propanolamine having the general formula: from any of these groups of compounds. The compounds of the present invention may be Ar-CH. CH-O-R 10 prepared from amino alcohols having the general for N mula: - 1 N-CH () Ar Ych - A -o-clich-H (V) 15 in which A is a tertiary aliphatic, cycloaliphatic or heterocyclic amino group, R is a straight or branched in which A and R are as defined above in connection chain lower alkyl group or an aralkyl group, Ar is an with formula I. aromatic group and Ar is an aromatic or heterocyclic In the first step of such preparation, the amino alco group, and addition salts thereof with pharmacologi 20 hols (IV), which are known materials, and are de cally acceptable acids. scribed inter alia in Belgium Pat. No. 718 425, are When Ar and Arare both aromatic groups they may treated with thionyl chloride dissolved in a suitable be like or unlike. Ar and Ar may both be monocyclic solvent such as chloroform in order to obtain the corre aromatic groups and Ar may be a heteromonocyclic sponding chloro compounds having the general for group which may contain a nuclear nitrogen atom with 25 mula: or without an additional nuclear hetero atom. The compounds of the present invention are useful as R-O-Ch-CH-CH-A (V) medicaments especially in the treatment of cardiovas cular conditions. In earlier patent applications we have described com 30 The latter compounds are then condenscd with amines pounds having the general formula: having the general formula -

Ar-CH-N-Ar 35 H CH-CH-A () CH-O-R which have previously been converted to their sodium derivatives by reaction with sodium amide, to obtain the compounds of the present invention. in which A and R have substantially the same meanings 40 The invention also includes the addition salts of the as in formula I above, and X respectively represents the compounds having the general formula I with pharma following groupings in the various cases: ceutically acceptable organic and inorganic acids such as hydrochloric acid and fumaric acid. -O-CO-Ar French Special Medicine Patent As an example of the process of the invention there No. 6571 M - 352 CAM 45 will now be described the synthesis of 1-(3-isobutoxy -N-CO-Air French Special Medicine Patent 2-(phenylbenzyl)-amino)-propyl-pyrrolidino-hydro No. 7700 M chloride (Compound No. 1). H OH Ar 50 -C French Patent No. 70/00018 CH, Ar Hi-O-CH-CH H CH Ar 55 -C French Patent No. 69124645 ()’."NO Ar First step Moreover, compounds having the following general Preparation of 1-(3-isobutoxy-2-chloro)propyl pyr formula are already known for their properties as anti rolidine histamines:

Ar-CH CH N-CH-CH-A (II) Yih-ch-o-ch-ch-ch-n Ar / CH, d 3,962,238 3 4. 345 ml of thionyl chloride dissolved in 345 ml of chlo ml of diethyl ether. After the ether has been evapo roform are added, drop by drop, to 275 g of 1 (3- rated, the residue is distilled under reduced pressure isobutoxy-2-hydroxy)-propyl-pyrrolidine dissolved in and has Bpt = 184°C/0.1 mm, n = 1.5538. 350 ml of chloroform, while maintaining the tempera 77 g of the pure base in the form of a viscous liquid ture at approximately 45°C. The reaction mixture is is thus obtained. heated to reflux until gas is no longer evolved. The The hydrochloride, which is prepared in conven chloroform and the excess of thionyl chloride are re tional manner, has a melting point of 128°C. moved under reduced pressure. The residue is poured on to 400 g of crushed ice. The reaction mixture is rendered alkaline with soda and the resulting mixture is Analysis C7 H% N6% extracted twice with 250 ml of diethyl ether. The com Calculated: 752 8.75 6.95 bined ethereal extracts are dried over anhydrous so Found: 7.20 9.01 6.93 dium sulphate. After evaporation of the solvent the residue is distilled under reduced pressure: 220 g of 15 Table which follows sets out a series of products product are obtained having the following properties: according to the present invention which were ob Boiling point = 96°C/3 mm, n = 1,4575, tained using the foregoing method but substituting the Second step appropriate intermediates containing the desired Main product o groups R and A and Ar and Arrespectively.

TABLE I COM- Ar Ar" R A Meiting ANALYSS POUND Points of C9. H% N% No. Salts C Theory Found Theory Found Theory Found

l CH Hydro DCH-CH,- N- chloride 7.52 71.20 8.75 9.01 6.95 6.93 CH 128

CH-CH- N- Fumarate 67.08 66.90 7.66 7.20 869 8.75 2 & 2.CH/ D 50° 3 & )- K)- Cha DCH-CH,- Chs YN- Fumarate 69.39 69.46 8.31 8.34 5.77 5.72 CH CH-1 98

4 & X- & X-ch- . N- Fumarate55 68.6 68.42 7.32 7.30 6.35 6.3

5 CH / y ycH-CH, N - Fumarate CH-1 95° 6744 67.90 7.68 7.76 5.6 5.64

6 ch N - Hydro chloride 33 74.55 7405 7.82 7.40) 6.2 6.4

23.4 g of sodium amide is added little by little to a The pharmacological activity of the compounds of solution of 92 g of N-benzylaniline in 500 ml of anhy 55 the invention in the cardiovascular field was deter drous xylene. The reaction mixture is then heated at mined on the dog in the manner described below: 130° to 135°C for 6 hours. An incision is made in the right-hand chest wall of an Whilst maintaining the temperature at 110°C, 10 g animal, which has been anaesthetised with chloralose of the product of the first step dissolved in 150 ml of and given artificial respiration, to enable the blood xylene is added and the product heated for 6 hours at 60 from the venus sinus to be drawn off and the apparatus 120°C. required to record the following parameters to be in The product having been allowed to cool to ambient serted in position: temperature, 200 ml of cold water are added. The a. Output of the coronary sinus; organic phase is separated and extracted with an aque b. PO, of the blood from the coronary sinus; and ous solution of hydrochloric acid. 65 c. Amplitude of the contractions of the right ven After twice washing with 100 ml of diethyl ether, the tricule. acqueous phase is made alkaline with 50% caustic soda At the same there were also measured: solution. The liberated base is twice extracted with 50 d. Arterial pressure in a main carotid artery: and 3,962,238 5 6 e. The rate of heart-beat determined cardiota The following Table III gives the average percentage chometrically...... inhibition of the cardiovascular effects of isoprenaline Table II which follows records the determinations and of the cardiac effects of the stimulation of the right made of the various parameters, the results being ex Stellar ganglion. TABLE III . Number of PERCENTAGE INHIBITION OF animals Hypotension Rate of Positive Heart-beat inotropic effect ISOPRFNALNE (5 uglkg Intravenous) 4. -54% -32.7% -46.5% STMULATION OF THE RIGHT STELLAR GANGLON 3 -30% -21.3% pressed as a maximum percentage variation relative to These results show that a partial inhibiting effect is the pre-treatment values. achieved as regards the g-adrenergic receptors at the TABLE II COMPOUND DOSE NUMBER OF CORONARY RATE OF SNUSAL ARTERAL AMPUDE OF No. mg/kg. ANMAS OUTPUT 9% HEART-BEAT PO, PRESSURE WENTRICULAR (intra- % c. CONTRACTION venous) % 2.5 7 --51.2 -28.6 -- 19.2 -39.8 -0.7 5 7 --36.9 -31.8 -- 20.8 -40.2 -223 2 5 3 --55 -28 --71 -43 -25.5 3 5 4 --117.8 -92 --158 -30.5 -3 4. 5 4 -- 10.5 -14.5 -56 -26 -- 75 5 5 3 --24 -35 -- 1.6 -15 --.5

These results show that, taken as a whole, the prod ucts under examination have the ability to increase the cardiovascular level of treatment. output of coronary blood, to reduce the rate of heart In conclusion, it is apparent that the members of the beat and especially, with the exception of compound 35 series of compounds possess a distinct cardio-vascular No. 4, to increase the oxygen content of the venous activity which is manifested by an improvement in cardiac blood. The latter action is demonstrated by an circulation by the enhanced oxygenation of the myo excess in the supply of oxygen relative to the require cardium in consequence of a slow rate of heart-beat. ments of the myocardium. The arterial pressure is also In addition to the general properties of the com lowered for a short time. In most cases there is little 40 pounds of the present invention, compound No. 1 is alteration in the ventricular inotropism. also of interest in that it also possesses inhibiting effects Particular note should be taken, in the case of com with respect to the stimulation of the 6-adrenergic pound No. 1, of the very considerable increase in the receptors. oxygen content of the venous cardiac blood in relation The pharmacological activities of the compounds to the increase in coronary output, which may be sim 45 having the general formula I thus enable their applica ply attributed to the improved circulation of the blood. tion in human therapy to be anticipated, as mcdica The extremely slow rate of heart-beat brought about by ments intended for treating particularly: the products certainly plays an important role in this Myocardiac anoxaemia, respect. Coronary deficiencies, angina pectoris, It then seemed interesting, using compound No. 1, to 50 Infarction of the myocardium, and seek the existence of an action on the B-adrenergic Cardiac deficiencies associated with coronary cir receptors in the manner outlined below: culatary trouble. A stimulating electrode was placed in position on the When admixed with the usual excipients, they may be right stellar ganglion of dogs anaesthetised as described administered orally or rectally, in daily doses of be above and for which there were recorded: 55 tween 100 and 800 mg. a. The arterial pressure, What we claim is: b. Ventricular inotropism (the amplitude of contrac 1. An ether of n-propanolamine having the formula tion of the right ventricle), and c. The rate of heart-beat. Ar-CH CH-O-R The chest of the animals were not open and they 60 were breathing freely. The 6-adrenergic receptors, both cardiac and vascu AY> ( HA lar, were stimulated by electrical stimulation of the right stellar ganglion or by intravenous injection with wherein A is morpholino, pyrrolidino, piperidyl, and isoprenaline (5 pug/kg). The measurements were taken 65 di-lower-alkyl amino, R is a straight or branched chain both before and after administration of compound No. lower alkyl, or benzyl, Ar is aryl and Ar is aryl or 1 by the intravenous route in a dose of 5 mg/kg body pyridyl, and pharmacologically acceptable salts weight. thereof. 3,962,238 7 8 2. The ether of claim 1 in which A is pyrrolidino, R is acid fumarate thereof. isobutyl and Ar and Air are both phenyl, and the hy 5. The ether of claim 1 in which A is morpholino, R drochloridc thereof. is isobutyl and Ar and Ar' are both phenyl and the acid 3. The ether of claim 1 in which A is pyrrolidino, R is fumarate thereof. isobutyl, Ar is phenyl and Ar is 2-pyridyl, and the acid 6. The ether of claim 1 in which A is piperidyl, R is fumarate thereof. benzyl and Ar and Arare both phenyl and the hydro 4. The ether of claim 1 in which A is diethylamino, R chloride thereof. is an isobutyl and Ar and Ar' are both phenyl, and the ck ck ck ck ck O

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