US3345411A - 2-alkyl-3, 3-diphenyl-propen-(2)-yl-amines and salts thereof - Google Patents

Description

United States Patent 3,345,411 2-ALKYL-3,3-DIPHENYL-PROPEN-(2)-YL-AM1NES AND SALTS THEREOF I Werner Heinrich and Walter Heigel, Ludwigshafen (Rhine), Germany, assignors to Gehr. Giulini G.m.b.H., Ludwigshafen (Rhine), Germany, a corporation of Germany No Drawing. Filed Nov. 19, 1963, Ser. No. 324,824 Claims priority, application Germany, Nov. 23, 1962,

G 36,467 23 Claims. (Cl. 260-570) This invention relates to propylamine derivatives and provides novel compounds of this class, new methods for production of such compounds, and methods for use of such compounds.

This application is a continuation-in-part of application Ser. No. 231,018, filed Oct. 16, 1962, which in turn is a continuation-in-part of application Ser. No. 54,542, filed Sept. 7, 1960, both now abandoned.

The novel compounds of the invention are according to the following formula:

wherein they diminish or eliminate the undesirable depressive side elfects of morphine on respiration.

R is preferably ethyl, propyl or butyl. With respect to the salts of these preferred compounds, the disclosure here inafter with reference to salts of the vasopressor agents of the invention apply, and with respect to the amines,

these preferences apply to each the secondary and primary derivatives.

The invention further utilizes compounds of the following formula: I I I wherein R, R and R are as above. These alcohol-amines are useful in the production of compounds of Formula I.

The invention further provides the method of providing a vasopressor effect. This is accomplished by administering a therapeutic amount of a compound according to Formula I.

Of the compounds according to Formula I, preferred ice chlorides. Specific compounds within this group are: 2- ethyl 3,3-diphenyl-propen-(2)-yl-amine, and cyclohexyl- [2-ethyl-3,3-diphenyl-propen-(2)-yl]-amine. A compound to be accorded special mention in this group is cyclohexylwherein R is hydrogen, lower alkyl, or cyclohexyl. This group includes the medicinally acceptable salts of the compounds of Formula III.

In Formula In Where R is of the type conventionally present as a su-bstituent in organic amino compounds designed for therapeutic application, and preferably'contains not more than about 6 carbon atoms. R can be for example, methyl, butyl, ethyl, propyl, isopropyl, isobutyl, secondary butyl, isoamyl, heXyl, isohexyl, cyclohexyl and similar or related radicals.

Thecompounds of Formula III can be used in the form of the hydrochloride, but preferably are used as salts, e.g. acid addition salts. The salts are crystalline solids which are soluble in water and therefore constitute an advantageous embodiment of this invention.

The organic bases of the type shown in Formula III form salts with a variety of inorganic and organic acids conventionally used for therapeutic application of organic C5115 R (IV) wherein R is an alkyl group containing 2 to about 8 carbon atoms, especially 4 to about 8 car-bon atoms. These compounds can be in the form of their medicinally acceptable acid addition salts. Particularly preferred compounds within this group are those in which R is.n-butyl, n-pentyl, or n-octyl. What is said herein-with reference to salts ofFormula I, applies also to salts of Formula IV.

Included within this group of Formula IV is 2-propyl- 3,3-d-iphenyl-propen (2")-yl-amine. This compound has been found well suited to the purposes of the invention. j Another preferred group of compounds withinthe compounds of Formula I is the group represented by the following formula:

-Q O=CCHzNHz our,

in which R is lower alkyl, lower alkoxy or chloro. These compounds can bein the form of their medicinally acceptable salts. Particular compounds of this group which have been found well suited for the purposes of the invention are the compounds wherein R is chloro, methyl or methoxy. What has been said herein with reference to salts of compounds of Formula I, applies also to salts of compounds of Formula V.

Compounds according to Formula I can be produced by hydrogenating compounds of the formula:

wherein the substituents are as is described with reference to Formula I, to produce the corresponding alcohol-primary amine. If a secondary amine according to Formula I is to be produced, the said alcohol-primary amine can be reacted with an alkyl or cycloalkyl carbonyl compound under reducing conditions for the desired alkylation. The product propene amine can then be obtained by dehydrating the alcohol-primary, or -secondary amine, as the case may be.

The hydrogenation of the nitrile can be a catalytic hydrogenation. A desirable catalyst for the reaction is platinum, and the reaction is preferably carried out in a solvent for the nitrile, for example acetic acid or methanol.

The dehydration of the alcohol-amine can be carried out by the known and conventional dehydrating methods,

and preferably employing as dehydrating agent gaseous hydrogen chloride with the alcohol-amine in solution. Solvents such as acetic acid can be used, and the dehydration can be effected by heating the solution under reflux for a time sufficient to complete the dehydration.

Where, in accordance with Formula I, halogen is present, the hydrogenation is with lithium aluminum hydride rather than catalytically. In such cases the nitrile containing chloro substituent can first be dehydrated to form an acrylonitrile derivative and this derivative can be hydrogenated with lithium aluminum hydride to form the propene-primary amine.

A further feature of the invention is provision of a process for the production of primary amines. Thus, the invention provides for production of primary amines such as amines of Formula I wherein R is hydrogen, and the substituents on the phenyl groups are hydrogen, alkyl, or alkoxy, or hydrogen or alkyl. The procedure involves catalytically hydrogenating the corresponding Z-hydroxypropionitrile to form therefrom the corresponding alcoholprimary amine, and dehydrating the alcohol-primary amine to form the product primary amine.

Where the primary amine to be produced includes halogen substituents on either or both of the phenyl groups, the corresponding 2-hydroxypropionitrile can be dehydrated to produce the corresponding acrylonitrile, and the acrylonitrile can be hydrogenated to form the primary amine.

Another feature of the invention is the provision of a process for production of secondary amines. Thus, there can be produced compounds according to Formula I wherein R is lower alkyl or cyclohexyl, and the substituent on the phenyl group is of the group hydrogen,

lower alkyl, lower alkoxy, and chloro, or of the group hydrogen, lower alkyl, or lower alkoxy, or of the group hydrogen or lower alkyl. In this procedure, the corresponding alcohol-primary amine, wherein the hydroxy group of the alcohol is in the 3-position, is contacted with an alkyl or cycloalkyl carbonyl compound under reducing conditions to produce the corresponding alcoholsecondary amine, and the alcohol-secondary amine is dehydrated to produce the secondary amine product.

Further details of preparation of compounds of the invention are set out below.

COMPOUNDS OF FORMULA III Compounds of this invention can be prepared utilizing the step of catalytically hydrogenating l-ethyl-Z-hyd-roxyreaction is preferably carried out in a solvent for the nitrile, for example acetic acid or methanol.

The 1-ethyl-2-hydroxy-2,2-diphenyl-propionitrile, which is necessary as basic product, is obtained by condensation of benzophenone and butyronitrile, which was proposed by Lettre.

The 2-ethyl-3,3-diphenylpropen-(2)-yl-amine is prepared by dehydration of the 2-ethyl-3-hydroxy-3,3-diphenylpropylamine. The dehydration is carried out by the known and conventional dehydrating methods, and preferably there may be employed as dehydrating agent gaseous hydrogen chloride with the 2-ethyl-3-hydroxy-3,3- diphenylpropylamine in solution. As solvent for the 2- ethyl-3-hydroxy-3,3-diphenylpropylamine, acetic acid can be used. The dehydration is preferably carried out by heating the solution under reflux for a time sufficient to complete the dehydration.

The mono-alkylated derivatives of the hydroxylated compound are prepared by reacting the compound containing a primary amino group with an alkyl or cycloalkyl carbonyl compound under reducing conditions, and preferably the alkylation is achieved by catalytic hydrogenation of the free base in the presence of carbonyl compounds. Thus, in accordance with the invention, alkylation of the 2 ethyl 3 hydroxy-3,3-diphenyl-propylamine is carried out and thereafter the mono-alkylated 2-ethyl-3- hydroxy-3,3-diphenyl-propylamine is subjected to dehydration to thereby obtain the mono-alkylated 2-ethyl-3,3- diphenyl-propene-amine.

Alternatively, the mono-alkylated derivatives may be obtained by reacting the 2-ethyl-3-hydr-oxy-3,3-diphenylp-ropylamine with carbonyl compounds to form the corresponding 1,3-oxazine and, through catalytic hydrogenation, to split the 1,3-oxazine to form the amino alcohol.

EXAMPLE 1 Preparation of 1-ethyl-2-hydroxy-2,Z-diphenylpropio'nitrile 54.6 g. of benzophenone and 20.7 g. of butyronitrile are dissolved in 400 ml. of absolute ether. 16 g. of sodium amine powder are added and the mixture is boiled for 7 hours at a temperature of 40 C. under reflux. Thereafter, the solution is given into 500 ml. of ice/water and stirred for 5 min. The reaction product separates at once in a crystalline form (the raw yield amounts to 66 g.=88%) which is recrystallized by means of benzene with a loss of 20%. The melting point thereby obtained is 162 C.

. EXAMPLE 2 Preparation of Z-ethyZ-S-hydroxy-3,3-diphenylpropylamine 10 g. of 1-ethyl-2-hydroxy-2,2-diphenyl-propionitrile are dissolved in 200 ml. of methanol. 10 ml. of acetic acid are added to the mixture, and the mixture is hydrogenated in the presence of platinum as catalyst. After the hydrogen uptake or consumption has ceased, the reaction is interrupted, the catalyst is filtered off and the filtrate is evaporated in vacuo to dryness. The residue is dissolved in water, and, after the addition of one ml. of hydrochloric acid, the solution is extracted with ether. The acidified ether-phase is discarded. The aqueous phase is made alkaline with ammonia, whereby the base crystallizes out. The crystals are recovered and crystallized from methanol. The melting point of the 2-ethyl-3-hydroxy-3,3-

dip-henylpropyl-amine thereby obtained is 132 C.

EXAMPLE 3 Preparation of Z-ethyl-3,3-diphenyl-pr0pen-(2)-ylamine-hydrochloride 5 g. of 2-ethyl-3-hydroxy-3,3-diphenylpropylamine are dissolved in 50 ml. of acetic acid. Gaseous hydrogen chloride is passed through the solution for 10 minutes, and thereafter the solution is boiled for one hour under reflux. The solution is then distilled to dryness. The residue is dissolved in water and the acidified solution EXAMPLE 4 Cyclohexyl-[Z-ethyl-3-hydr0xy-3,3-diphenyl-pr0pyl] amine 6 g. of 2-ethyl-3-hydroxy-3,3-diphenyl-propylamine are dissolved in 200 ml. of methanol. 10 ml. of freshly distilled cyclohexanone are added to the solution and the solution is hydrogenated'in the presence of a platinum catalyst. The hydrogen consumption takes place very quickly. The catalyst is filtered oif and the filtrate concentrated to dryness. The residue is taken up in dilute hydrochloric acid and extracted with ether. The hydrochloride salt Which is partially recovered from the ether phase, is crystallized out from methanol ether. The crystals thereby obtained have a melting point 'of 180-182" C. The Water phase is made alkaline with ammonia and thereafter extracted with ether. After drying over sodium sulfate, the ether extract is subjected to distillation. The residue thereby obtained recrystallized from a mixture of acetone and water in the ratio of 2:1. The base thus recovered has a melting point of 7880 C.

EXAMPLE 5 3.37 g. of cyclohexy-[ 2-ethyl-3-hydroxy-3,3-diphenylpropylJ-amine are dissolved in 50 ml. of acetic acid and gaseous hydrogen chloride is passed through the solution until the reaction mixture is strongly acidic. The mixture is heated for tWo hours in a boiling water bath. The acetic acid solution is thereafter distilled under vacuo to dryness. The residue is dissolved twice in 50 ml. portions of methanoL and each time the solution is evaporated to dryness. The final residue is dissolved in a small amount of methanol and the hydrochloride salt crystallized out by addition of absolute ether. The crystalline substance thereby obtained has a melting point of 212215 C.

Compounds havingalkyl substituents on the amino group other than the instances disclosed in the examples may be obtained by carrying out the foregoing experiments using in the alkylation reaction other alkyl compounds, as for example methyl, pentyl, hexyl, butyl, diethyl, etc. It is furthermore possible to prepare, in lieu of hydrochlorides, corresponding salts of other acids by contacting the base-in the form of its solution with an acid as forexample hydrobromic, hydroiodic, phosphoric,

citric, oxalic, in place of the hydrochloric acid, until the reaction mixture-is strongly acidic. The said solution may .have [to be concentrated somewhat for crystallization, upon chilling, to occur.

COMPOUNDS OF FORMULA IV These compounds can be made by reactions as are are dissolved in 350ml. glacial acetic acid, 0.5 g. platinum catalyst are added and then. hydrogenated. After -co'mpleted hydrogenation, the catalyst is filtered Off, and

the filtrate is evaporated in vacuum to dryness. The residue is treated with water, treated with hydrochloric acid until the acid reaction, filtered off from the undissolved materiaL and extracted with ether. The aqueous phase is 6 made alkaline with ammonia solution, extracted with ether and the ether part dried via sodium sulfate. After distilling off of the ether the 2-n-butyl-3-hydroxy-3,3-diphenyl-propyl-amine is obtained. Melting point: 84 C.

EXAMPLE 6b 2-n-butyl-3,3-diphenyl-propen-(2 -yl-amine-hydr0- chloride EXAMPLE 7a Z-n-pentyl-3-hydr0xy-3,3-diphenyl-propyl-amine Through hydrogenation of l-n-pentyl-2-hydroxy-2,2- diphenyl-propionitrile one obtains the 2-n-pentyl-3-hydroxy-3,3-diphenyl-propyl-amine in analogous manner according to Example 6a. Melting point: 57 C.

EXAMPLE 7b 2-n-pentyl-3,3-diphenyl-prop en- (2 -yl-amine-hydro. chloride The solution of 9.5 g. 2-n-pentyl-3-hydroxy-3,3-diphenyl-propyl-amine in ml. glacial acetic acid is saturated with hydrogen chloride and subsequently heated for three hours to 100 C. The acetic acid is distilled olf in vacuum, and the 2-n-pentyl-3,3-diphenyl-propen-(2)- yl-amine-hydrochloride remaining is recrystallized from benzene. Melting point: 138140 C.

EXAMPLE 8a 2-n-0clyl-3-hydroxy-3,3-diphenyl-propyl-amine Through hydrogenation of 1-n-octyl-2-hydroxy-2,2- diphenyl-propionitrile one obtains the 2 n-octyl-3-hydroxy-3,3diphenyl-propylamine in analogous manner according to Example 6a. Melting point: 88 C.

EXAMPLE 8b 2-n-0ctyl-3,3-diphenyl-pr0pen-(2 -yl-amine-hydrochloride The solution of 38.5 g. 2-n-octyl-3-hydroxy-3,3-diphenyl-propyl-amine in 200 ml. glacial acetic acid is saturated with hydrogen chloride gas and subsequently heated for three hours to 100 C. The crystals of 2-noctyl-3,3-diphenyl-propen-(2) yl amine-hydrochloride remaining behind after distilling off of the acetic acid in vacuum, are washed-out with absolute ether. Melting point: 157 C.

The comments made above with respect to the examples under Formula III as to substitutions in the examples, applyto the foregoing examples of compounds of Formula IV.

COMPOUNDS OF FORMULA V These compounds can be'produced in a manner analogous to production of compounds of Formula III, that is, through hydrogenation of 1-ethyl-2-hydr0Xy-2,2-di

aryl-propionic-nitrile and separation of water. In the cases in which a halogen substitution exists, hydrogenation can be by means of lithium aluminum hydride. In all other cases, the reduction can be effected catalytically. In these 'reactions, there is formed a mixture of two cis-transforms.

- EXAMPLE 9 .2 ethyl-3-phenyl-3-(p-methyl-phenyl)-propen- (2)- l yl-amine-hydrochloride 13.3 g. 1-ethyl-2-hydroxy-2-phenyl 2 (p-methylphenyl)-propionic nitrile are dissolved in 400 ml. glacial acetic acid, 200 mg. platinum catalyst are added and subsequently hydrogen is introduced. After completion of hydrogen absorption, one filters off from catalyst, and the filtrate is evaporated in vacuum until dry. The residue is dissolved in water, treated with hydrochloric acid until the acid reaction, filtered off from the residue, and the filtrate added drop by drop into 20% soda lye. Therein the 2-ethyl-3-hydroxy-3-phenyl-3 (p-methyl phenyl)- propyl-amine precipitates. Melting point: 88-90 C.

4.8 g. 2-ethyl-3-hydroxy-3-phenyl3-(p-methyl-phenyl)- propyl-amine are dissolved in 50 ml. glacial acetic acid. This solution is saturated with hydrogen chloride gas and subsequently heated for 3 hours to 100 C. The acetic acid is distilled off in vacuum. The residual crystals are dissolved in methanol and the 2 ethyl 3 phenyl-3-(pmethyl phenyl)-propen-(2)-yl-amine hydrochloride precipitated through addition of absolute ether. Melting point: 223-225" C.

EXAMPLE l 2-ethyl-3-phenyl-3- (p-methoxyphenyl) -pr0pen-(2 yl-amine-sulfate Through hydrogenation of 1-ethyl-2-hydroxy-2-phenyl- 2-(p-methoxy-phenyl)-propionic nitrile one. obtains the 2- ethyl-3-hydroxy-3-phenyl-3-(p-methoxyphenyl) propylamine in the manner described in Example 9. Melting point: 148 C.

Into a solution of 4.2 g. 2-ethyl-3-hydroxy-3-phenyl-3- (p-methoxyphenyl)-propyl-amine one introduces for 25 minutes dry hydrogen chloride gas and subsequently heats for 2 /2 hours to 100 C.; thereafter, the material distilled until dry. The residue is dissolved in water, made alkaline with diluted soda lye, and then extracted with ether. The ether part is dried with sodium sulfate, the ether distilled off, and the thus obtained 2-ethyl-3-phenyl- 3-(p-methoxyphenyl)-propen-(2)-yl-amine converted into its sulfate. The substance melts at l45165 C.

EXAMPLE 1 1 2-eth'yl-3-ph enyl-3- p-chlorophenyl -pr0pen- (2 -ylamin e-hydr0chl0ride To a hot solution of 16.3 g. l-ethyl-2-hydroxy-2-phenyl- 2-(p-chlorophenyl)-propionic-nitrile in 300 ml. absolute benzene, there is very quickly added 20 g. phosphoruspentoxide. The reaction mixture is boiled for 45 minutes under reflux, the benzene solution decanted, and the residue is twice boiled-out with each 100 ml. absolute benzene. After distilling off of the benzene, there remains the l-ethyl-2-phenyl-2-(p-chlorophenyl)-acrylo-nitrile in almost quantitative yield as yellowish oil.

A solution of 5.4 g. 1 ethyl-2-phenyl-2-(p-chlorophenyl)-acrylo-nitrile in 20 ml. absolute ether is added drop by drop within half an hour to a suspension of 0.76 g. lithium aluminum hydride in 100 ml. absolute ether under ice-cooling and stirring, so that the temperature does not rise above 5 C. The reaction mixture is still further stirred for half an hour and then treated, successively, with 0.8 ml. water, 0.6 ml. soda lye, and 2.8 ml. water. The yellow-colored ether solution is then decanted from the granular precipitate, and this is then washed three times with 30 ml. absolute ether. The 2- ethyl-3-phenyl-3-(p-chlorophenyl) propen-(2)-yl-amine present in the ether solution is isolated as hydrochloride. Melting point: 208-211 C.

As noted above, with reference to compounds of Formula III, in the case of the compounds of Formula V various acid addition salts of the compounds can be provided.

3-PROPYL DERIVATIVE OF COMPOUNDS 0]? FORMULA III Through hydrogenation of 1-propyl-2-hyd-roxy-2,2-diphenyl-propionic-nitrile and subsequent separation of water from the 2-propyl-3,3-diphenyl-3-hydroxy-propyl- .arnine formed, the 2-propyl-3,3-diphenyl-propen-(2)-yl- '8 amine can be obtained. The starting material for production of the 2-propyl derivatives can be obtained in a manner analogous to the manner in which the starting material for the compounds of Formula III is obtained.

EXAMPLE l2 2-pr0-pyl-3,3-diphenyl-propen (2) yl-amine-hydrochloride 13.1 g. l-propyl-2-hydroxy 2,2 diphenyl-propionicnitrile are dissolved in 400 ml. glacial acetic acid, 200 mg. platinum catalyst are added, and subsequently hydrogen is introduced. After hydrogen absorption ceases, the catalyst is filtered off, and the filtrate evaporated in vacuum until dry. The residue is dissolved in water, treated with hydrochloric acid until acid reaction, the residue is filtered off, and the filtrate added drop by drop into 20% soda lye. The precipitated 2-propyl-3,3-diphenyl-3-hydroxypropyl-amine is recovered. Melting point: l08-l10 C.

4.8 g. 2-propyl-3,3-diphenyl 3 hydroxy-propyl-amine are dissolved in 50 ml. glacial acetic acid. This solution is saturated with hydrogen chloride gas and subsequently heated for 3 hours at C. The acetic acid is distilled off in vacuum. The crystals remaining behind are dissolved in methanol and the 2-propyl-3,3-diphenyl-propen- (2)-yl-amine hydrochloride is precipitated through addition of absolute ether. Melting point: 213-215 C.

What is said above with reference to salts of the compounds of Formula III, applies as well to the salts of the 2-propyl derivatives.

Utility data The compounds of the invention are substantially more effective than the corresponding 2-methyl derivatives. This can be' demonstrated by tests on anesthetized animals to which the Z-methyl derivative and a 2-ethyl derivative have been administered. Further information on utility follows.

COMPOUNDS OF FORMULA III The following details were found by experimenting with 2-ethyl-3,3-diphenyl-propen (2)-yl-amine hydrochloride on animals:

(1) Acute toxicity DL 50, white mouse, i.v. 35.5 mg./kg.

DL 50, white mouse, p.o. 87.5 mg./kg.

DL 50, white mouse, s.c. approx. 100 mg./kg. DL 50, white rat, p.o. 183 mg./kg.

(2) Chronic toxicity White rat, per os 18.3 mg./kg. pro die, 20 animals: During a 30 days feeding body Weight and general behavior normal. No toxic signs. Action of erythrocytes and leucocytes within physiological limits. Macroscopic and microscopic no organic conditions.

(3) Picture of actions For the most part chronic convulsions with point .of action on motor brain centers; besides tonic components of convulsion (stimulative effect) vasomotor center, breath center, mainly centrally conduced increase of blood pressure, central excitation.

(4) The efiect on the blood pressure in cats under chl0- ralose-urethane-anaesthesia 0.5 rug/kg. i.v.: increase of blood pressure of 40-60 mm. Hg, effective for 6-8 minutes;

0.1 mg./kg. i.v.: increase of blood pressure of 30-50 mm. Hg, effective for about 5 minutes;

1 mg./kg. i.v.: increase of blood pressure of 45-60 mm. Hg, with longer efficiency;

2 mg./kg. i.v.: increase of blood pressure of 50-60 mm.

Hg, with long efiiciency.

With normal or reduced initial blood pressure the hypertensive effect is stronger than with an increased initial blood pressure.

() Efiect on the experimentally condu cec l circulatory collapse in cats (a) Circulatory collapse by Evipan-Sodium' continuous infusion:

0.1-2.0 mg./kg. i.v.: strong hypertensive efiect for a prolonged time. (b) Circulatory collapse by acetylcholine continuous infusion:

0.1-2.0 mg./kg. i.v.: with long efiiciency.

(6) Effect on the breathing in narcotized cats 0.1-2.0 mg./kg. i.v.: strong stimulation of breathing.

(7) Efiect on the heart (a) Frog, in situ perfused according to Biil'bring.

0.1 mg. percent (1:1,000,000): no change of frequency and minute volume 0.4 mg. percent (1:250,000): no influence on frequency and minute volume 1 mg. percent (1:100,000): decrease of ume with constant frequency. 7 (b) ECG in guinea-pigs: Doses of 0.63-2.0 mg./kg. cause no significant change in ECG apart from a temporary decrease of frequency. 7

stronger hypertensive effect minute vol- (8) Stimulative effect in rabbits under urethane anaesthesia r 4 0.1-2.5 mg./kg. i.v.: strong stimulative efl ect. (9) Eflect on the breathing of rabbits under morphine amine has a duration of 30-40 minutes on the blood 7 pressure of the cat in urethane chloralose narcosis, while 0.5 mg./kg. of 2-butyl-3,3-diphenyl-propen-(2)-yl-amine has a duration of upto 4 hours. COMPOUNDS OF FORMULA V These compounds are especially preferred since they have an especially pronounced eifect on blood pressure and this effect is particularly long-lasting." i

Effects on the blood pressure of the cat under urethane chloralose narcosis for compounds of Formula V, as

follows, were noted.

2-ethyl-3-phenyl 3 (p-chlorophenyl)-propen-(2)-ylamine as hydrochloride, gluconate and methanesulfonate:

1 mg./kg. i.v.: blood pressure increase of 40-50 mm.

Hg, lasting about 30-40 minutes;

2 mg./kg. i.v.: blood pressure increase of 60 mm.

Hg, lasting about 2-4 hours;

3 rug/kg. i.v.: blood pressure increase of 60-80 mm.

Hg, lasting about 4 hours and longer.

For lower starting blood pressure the blood pressure increase effect is stronger and lasts longer than in normal or high starting blood pressure.

1-(3-hydroxyphenyl)-1-hydroxy 2 N ethylaminoethane-hydrochloride of the structural formula Q-ouon-oumnmm-uor 1 ling/kg. i.v.: blood pressure increase of about 20 mm.

. 2 mg./kg. i.v.: blood pressure increase 10 'Hg, lasting about 4-8 minutes;

of 20-30 mm. Hg, lasting about 4-8 minutes; 3 mgJkg. i.v.: blood pressure increase Hg, lasting about 4-8 minutes; 4 rug/kg. i.v.: blood pressure increase Hg, lasting about 4-8 minutes.

ephedrine:

1 mg./kg. i.v.: blood pressure increase Hg, lasting about 30-40 minutes;

mg/kg. i.v.: 'blood pressure increase Hg, lasting about 30-40 minutes;

3 mg./kg. i.v.: blood pressure increase Hg asting about 30-40 minutes.

In all cases, the starting blood pressure was about the same and was'be tween and Hg.

PRoPYL DERIVATIVES OF COMPOUNDS 0F" FORMULA III Compounds of Formula III having a propyl group in the 2-position instead of an ethyl group, are of particular interest because of their long-lasting blood pressure elfect.

Effects as folows were noted for the blood pressure of the cat in urethane chloralose narcosis. v

2-propyl-3,3-diphenyl-propen (2) yl amine as hydrochloride, gluconate and rnethane-sulfonate:

of 40-60 mm.

of 40-60 mm.

of 20-40 mm.

2 of 40-50 mm.

of 40-50 mm.

@CHOH-CEIaNHCzHsHCI I OH 1 :mg./kg. i.v.: blood pressure increase of about 20 mm.

Hg, lasting about 4-8-minutes; I r V 2 rug/kg. i.v.: blood pressure increase of 20-30 mm.

Hg, lasting about 4-8 minutes;

3' nig'Jkg. i.y.: blood pressure increase of 40-60 rnm Hg. lasting-about4-8 minutes; i 1

. 4 mg./kg. i.v.z blood'pressure increase of 40-60 mm.

Hg, lasting about 4-'-8 minutes.-

The, effect of ephedrine is as reported above for compounds of Formula V. In allicases, the starting blood pressure was about the same and was between 80 and 100 mm. Hg.

Compositions The compounds in accordance with the invention may be given in dosage form hypodermically or intramuscularly in the form of HCl salt, or in the form of their salts in isotonic physiologically acceptable solutions, as for example water saline or peanut oil. Locally, they may be used in solution as a spray and in ointment.

The exact dosage in each instance is entirely dependent on the eifect sought to be achieved, the mode of administration employed and the degree of caution which must 'be observed. Dosage can be, for example, 15 mg. for parenteral administration. In any instance, there is employed at least that amount of the compound, i.e. active agent, necessary to produce the desired physiological elfect, but less than that amount producing an undesired toxic etfect.

The compounds of the invention, as can be readily appreciated, also constitute valuable tools for use in medical research, as for instance in connection with animal experiments and in particular in the study of their elfect on the blood pressure by stimulating the contraction of the muscular tissue of the capillaries and arterioles.

What is claimed is: 1. Compounds of the formula:

(a) R is alkyl having 2 to 8 carbon atoms; (b) R is selected from the group consisting of hydrogen, lower alkyl and cyclohexyl; (c) R is selected from the group consiting ofhydrogen,

lower alkyl, lower alkoxy and chlorine; and medicinally acceptable salts thereof. 2. Compound according to claim 1, ethyl.

3. Compound propyl.

.4. Compound according to n-butyl.

5. Compound n-pentyl.

6. Compound n octyl.

7. Compound according to claim 1, wherein R and R is each hydrogen.

8. Compounds of the formula:

Q (III) wherein R is selected from the group consisting of hydrogen, lower alkyl, and cyclohexyl, and medicinally acceptable salts thereof.

9. Compounds according to claim 8, wherein R is cyclohexyl.

10. The hydrochloride of a compound according to wherein R according to claim 1, wherein R is claim wherein R is according to claim wherein R is according to claim wherein R is claim 8.

11.- 2-ethyl-3,3-diphenyl-propen-(2)-y1-amine.

12. Cyclohexyl-[2-ethy1-3,3-diphenyl-propen-(2) -yl] amine.

13. Cyclohexyl-[2-ethyl-3,3-diphenyl-propen-(2) yl] amine in the form of a medicinally acceptable salt with a member selected from the group consisting of hydrochloric, hydrobromic, and hydroiodic acid.

14. Compounds of the formula:

CaHs (IV) wherein R is an alykyl radical containing 2 to about 8 carbon atoms, and medicinally acceptable salts thereof.

15. Compounds according to claim 14, wherein R is n-pcntyl.

16. Compound according to claim 14, wherein R is !'1butyl.

17. Compound according to claim 14, wherein R is n-octyl.

18. The hydrochloride of a compound according to claim 14.

19. 2-propyl-3,B-diphenyLprOpen-(Z)-yl-amine and medicinally acceptable salts thereof. 20. Compounds of the formula:

O=CCHNI-I,

in which R is selected from the group consisting of lower alkyl, lower alkoxy, and chlorine, and medicinally acceptable salts thereof.

21. 2-ethyl-3-phenyl-3-(p-chlorophenyl)-propen (2) yl-amine and medicinally acceptable salts thereof.

22. 2-ethyl-3-phenyl-3-(p-methylphenyl)-propen- (2) yl-amine, and medicinally acceptable salts thereof.

23. 2-ethyl-3-phenyl-3-(p-methoxypenyl)-propen-(2) O yl-amine and medicinally acceptable salts thereof.

References Cited UNITED STATES PATENTS 2,681,934 6/1954 Hodge 260-570 2,705,245 3/1955 Norton 260570 3,056,726 10/ 1962 Marsh 167-65 3,057,780 10/ 1962 Shapiro 16765 FOREIGN PATENTS 525,752 6/1956 Canada.

627,139 7/1949 Great Britain. 811,659 4/1959 Great Britain.

OTHER REFERENCES Kjaer et al., A-cta Chimica Scan, vol. 5, pp. 1145-50 1951 Lettre et al., Ann., vol. 603, pp. 189-99 (1957). White et al., Brit. Jour. PharmacoL, vol. 6, pp. 560-71 (1951).

CHARLES B. PARKER, Primary Examiner.

R. V. HINES, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,345,411 October 3, 1967 Werner Heinrich et a1.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

In the heading to the printed specification, lines 9 and 10, for "Claims-priority, application Germany, Nov. 23, 1962, (3 36,467" read" Claims priority, applications Germany, G 27,898, September 8, 1959; Germany, G 34,027, January 16, 1962; Germany, G 34,038, January 17, 1962 and Germany, G 36,467, November 23, 1962 column 11, the formula in claim 14 should appear as shown below instead of as in the patent:

Signed and sealed this 10th day of September 1968.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. EDWARD J. BRENNER Attesting Officer Commissioner of Patents

Claims (1)

1. COMPOUNDS OF THE FORMULA: