US3655737A - 1-(3-hydroxy-4-methyl-phenyl)-propylamine (-2) and the salts thereof - Google Patents

Abstract

COMPOUNDS REPRESENTED BY THE FORMULA

1-(H2N-CH(-R1)-H2C-),3-HO,R2-BENZENE

WHEREIN R1 IS A MEMBER OF THE GROUP CONSISTING OF CH3, C2H5 AND C3H7, AND R2 IN POSITION 2, 4, 5 OR 6 ON THE BENZENE NUCLEUS IS A MEMBER OF THE GROUP CONSISTING OF F, CL, BR, CH3, C2H5 AND C3H7, PHARMACEUTICAL COMPOSITIONS CONTAINING THESE COMPOUNDS, AND THE USE THEREOF FOR THERAPEUTIC PURPOSES.

Description

United States Patent 1-(3-HYDROXY-4-METHYL-PHENYL)-PROPYL- AMINE (-2) AND THE SALTS THEREOF Per Arvid Emil Carlsson, Goteborg, Hans Rudolf Corrodi,

Askim, Sven Giiran Hallhagen, Molndal, and Ulf Krister Junggren, Goteborg, Sweden, assignors to Aktiebolaget Hassle, Goteborg, Sweden No Drawing. Filed Mar. 28, 1969, Ser. No. 811,662 Claims priority, application Sweden, Apr. 1, 1968,

Int. Cl. C07c 87/28 US. Cl. 260-50117 2 Claims ABSTRACT OF THE DISCLOSURE Compounds represented by the formula NHz CH2(|3H wherein R is a member of the group consisting of CH C H and C3H7, and R in position 2, 4, 5 or 6 on the benzene nucleus is a member of the group consisting of F, Cl, Br, CH C H and C H pharmaceutical compositions containing these compounds, and the use thereof for therapeutic purposes.

R wherein R is a member of the group consisting of CH;,, C H and C3H7, and R in position 2, 4, 5 or 6 on the benzene nucleus, is a member of the group consisting of F, Cl, BI, CH3, C2H5 and Cal I7- Prior art compounds are 3-hydroxy-4-methyl-norephedrine;

v HOCHCH OH; (H)

"Ice

and a-methyl-m-tyraminez NHz 0min: 2111.

(III) The compounds of this invention have been shown to possess antihypertensive and antidepressant properties without giving rise to undesired sympathomimetie side effects. Surprisingly it has been found that the compounds of the invention are able to penetrate into the brain, where they are taken up by the noradrenergic neutrons and act there as false transmitters. This valuable and unexpected property contributes to the antihypertensive and antidepressant activity of the compounds.

The prior art compound II has no antihypertensive and antidepressant elfects, since it does not penetrate into the brain and displace noradrenaline there.

The prior art compound III does penetrate the blood brain barrier, but shows a high sympathomimetic activity which leads to an increase in blood pressure. The increase in blood pressure caused by this side effect overshadows the antihypertensive etfect which might be expected from the ability of the compound to act as a false transmitter in the noradrenergic neurons of the brain. Furthermore, the compound III is more toxic than the compounds disclosed in this invention.

An additional advantage of the compounds of this invention over the mentioned prior art compounds is that the substances disclosed herein are able to liberate 5-hydroxytryptamine in the brain. This property contributes mainly to the antidepressant activity of the compounds. None of the mentioned prior art compounds shows this etfect.

The compounds of the invention may be prepared by known methods such as (A) Replacing Z with H in a compound of the formula NH: CH2|CH R (II) wherein R and R have the meanings specified above and wherein Z is a member of the group consisting of alkyl and acyl protecting groups, by means of a strong acid such as HBr to the formation of a compound of the Formula I;

(B) Replacing Z with H by catalytical hydrogenation of a compound of the formula 7 (iJHzCH R (III) wherein R has the meaning specified above; R is a member of the group consisting of ---CH,, C H and C H and wherein Z is a member of the group consisting of aralkyl protecting groups, such as benzyl; to the formation of a compound of the Formula I;

() Reducing a compound of the formula CHzC 0 R (IV) wherein R and K have the meanings specified above, in

the presence of HCOOH according to Leuckart to the formation of a compound of the Formula I; (D) Reducing a compound of the formula w HOCHCH wherein R has the meaning specified above and wherein R is a member of the group consisting of CH C H and C H to the formation of a compound of the Formula I;

(E) Reducing a compound of the formula wherein R and R have the meanings specified above, to the formation of a compound of the Formula I; whereafter the compound of the Formula I thus obtained if necessary is transformed into a therapeutically acceptable salt by reaction with the appropriate acid.

Z is preferably a methyl group, and Z is preferably a benzyl group.

Z may be split oif by strong acids such as HBr, and Z may be split off by hydrogenolysis.

The reaction way D is applicable only in those cases when the substituent R in the compound of the Formula I is -CH -C H or C3H7. Catalytical removal of araliphatic protecting groups is not applicable when the substituent R is F, C1 or Br. When R is CH -C H or -C H all the outlined reaction ways can be used, and catalytical removal of an araliphatic protecting group is possible.

The reduction of the compound of the Formula V is preferably carried out by catalytical hydrogenation.

The reduction of the compound of the Formula VI is preferably carried out by means of a complex metal hydride such as lithium aluminium hydride.

Starting materials for the processes described above may be prepared in any desired way. Some of the possible ways for preparation of starting materials used in the methods A, B, C and E above are outlined in the following reaction schemes, which also serve as further illustrations of the various methods of preparation as described above. The substituents R R R used in the reaction formulas have the meanings given above, Z is hydrogen or the radical Z and Z is hydrogen or the radical Z Starting materials for the reaction Way D may be prepared by methods well known per se.

4 Method A:

CHO CH=CNO2 RCHaNOz LlAlH4 CHZCHNHQ CH1 E HBr OZ OH Method B:

CHO CH=CNO RCHzNOz Fe HCl Q-OZ -OZ Ra 33 NH: NH: (3112310 $112+H 1112 I H 1100011 (Leuckart;

reaction) 112/ P d LD-oz HCONHZ 0z -o1-r R R3 R3 Method C:

CHO CH=CNO2 l l Q R cHrNoz Fe HCl 0Z OZ NH2 $11260 (ilHfll o CH2 I H Q Q nooon (Leuckart HBr reaction) v -oz OH HCONHI -on Method E:

NH: CH=CNO CHZH I l R1 LlA1H4 -OH -OH The compounds of the invention exist in the form of optically active isomers, which may be isolated in any principally known way for resolution of an amine, and it is understood that such a manner will be included within the scope of this invention.

The racernate obtained at the above reactions can be resolved into the enantiomers 'by converting the free base into a salt or an amide of an optically active acid such as tartaric acid or any other optically active acid capable of forming crystalline salts with the amine, and regeneration of the amine after the usual separation of the diastereomeric mixture thus obtained.

It will also be understood that the compounds of the present invention may be used either as a purified isomer which is biologically active or in the form of the mixed isomeric product obtained as a natural consequence of the reaction sequences described above, or any other reaction sequence for the preparation of the compounds which results in a mixed isomeric product containing the biologically active isomer or isomers.

The new compounds according to the invention may be administered in the form of salts with physiologically acceptable acids. Suitable acids which may be used are, for example, hydrochloric, hydrobromic, sulphuric, fumaric, citric, tartaric, maleic or succinic acid.

The invention further provides pharmaceutical compositions comprising as active ingredient at least one of the compounds according to the invention in association with a pharmaceutical carrier. Such compositions may be designed for oral, rectal or parenteral administration.

To produce pharmaceutical preparations in the form of dosage unit for oral application containing a compound of the invention in the form of the free base, or a pharmaceutically acceptable salt thereof, the active ingredient may be mixed with a solid, pulverized carrier, for example lactose, saccharose, sorbitol, mannitol, a starch such as potato starch, corn starch, maize starch or amylopectin, a cellulose derivative of gelatin, and also may include lubricants such as magnesium or calcium stearate or a C-arbowax or other polyethylene glycol waxes and compressed to form tablets or centres for drages. If drages are required, the centres may be coated, for example with concentrated sugar solutions which may contain gum arabic, talc and/or titanium dioxide, or alternatively with a lacquer dissolved in easily volatile organic solvents or mixtures of organic solvents. Dyestuffs can be added to these coatings. For the preparation of soft gelatin capsules (pearl-shaped closed capsules) consisting of gelatin and, for example, glycerol, or similar closed capsules, the active substance may be admixed with a Carbowax. Hard gelatin capsules may contain granulates of the active substance with solid, pulverized carriers such as lactose, saccharose, sorbitol, mannitol, starches (for example potato starch, corn starch or amylopectin), cellulose derivatives or gelatin, and may also include magnesium stearate or stearic acid. Dosage units for rectal application may be in the form of suppositories comprising the active substance in admixture with a neutral fatty base, or gelatin rectal capsules comprising the active substance in admixture with a Carbowax or other polyethylene glycol waxes. Each dosage unit preferably contains 1 to 200 mg. of active ingredient.

Liquid preparations for oral application may be in the form of syrups, suspensions or emulsions, for example containing from about 0.1% to 20% by weight of active substance and also, if desired, such adj'uvants as stabilizing agents, suspending agents, dispersing agents, flavouring agents and/ or sweetening agents.

Liquid preparations for rectal administration may be in the form of aqueous solutions containing from about 0.1 to 2% by weight of active substance and also, if desired, stabilizing agents and/ or buffer substances.

For parenteral application by injection the carrier may be a sterile, parenterally acceptable liquid e.g. pyrogenfree water or an aqueous solution of polyvinylpyrrolidone, or a parenterally acceptable oil, e.g. arachis oil, and optionally stabilizing agents and/or buffer substances. Dosage units of the solution may advantageously be enclosed in ampoules.

When given by oral or rectal administration, the compounds of the invention such as l-(m-hydroxy-p-methylphenyl)-butylamine (-2) and 1-(In-hydroxy)-p-methylphenyl-propylamine (-2), may be given in widely varying dosages from, for example, 20 mg./day to 1 g./ day, but dosage-s of 50500 mg./day will ordinarily be given, amounts between 100 and 300 mg./day being usually preferred. When given by i.v. administration, dosages of about 5-100 mg./day, preferably about -50 mg./day may be used.

The invention is further illustrated by the following examples.

Example I.Preparation of starting material (a) Preparation ofl- (m-methoxy-p-methyl-phenyl)-2- nitro-l-propene TABLE 1 M.P., Z C.

CH3 51 CH3 CH 48 CO CH3 47 CH3 76 CH3 65 CH3 80 CH; 88

(b) Preparation of m-methoxy-p-methyl-phenylacetone To a solution of 0.8 mole of 1-(m-methoxy-p-methyl phenyl)-2-nitro-1-propene in 300 m1. of toluene and 875 m1. of water was added 326 g. of iron powder and 3.3 g. of ferric chloride hexahydrate. The mixture was stirred and heated to 80 C. 292 m1. of cone. hydrochloric acid was added at such a rate that reflux was maintained. After addition of the hydrochloric acid, the mixture was stirred and refluxed for /2 hour, and thereafter steam-distilled. The distillate was extracted with ether, and the organic layer washed twice With a 3 percent sodium bisulphite solution, then water, dried over anhydrous magnesium sulphate and evaporated. The remainder was pure enough for the next step.

(c) Preparation of 1-(m-methoxy-p-methyl-phenyl)- propylamine (-2) 0.044 mole of the substituted 2-phenylpropanone, 13.5 g. of freshly distilled formamide and 2.5 g. of formic acid was refluxed with stirring during 5 hours. After cooling 50 ml. of water and 50 ml. of hydrochloric acid was added and the mixture refluxed for 5 hours. After alkalisation with 30% NaOH the product was taken up in either. The organic layer was dried and evaporated.

(d) Preparation of l-(m-methoxy-p-methylphenyl)- propylamine-2 67.1 g. of 1-(m-methoxy-p-methylphenyl)-2-nitro-1- propene in 200 ml. of dry ether was added to a stirred mixture of 32 g. of LiAlH in 1000 ml. of dry ether at such a rate that the solvent refluxed gently without external heating. The mixture was stirred and heated for two hours. 20 ml. of ethyl-acetate was then added carefully w th vigorous stirring, followed by 40 ml. of water. The mixture was filtered and the ethereal solution was shaken with 2-N hydrochloric acid. The amine was obtained upon alkalisation of the acidic solution and ether extraction. The product could be used without further purification in the subsequent step. The compounds specified in Table 2 were prepared by the same method. R and R have the significance given above, and Z is used to designate the protecting group used.

7 EXAMPLE 2 Preparation of 1-(m-hydroxy-p-methylphenyl)- propylamine-2 (a) 39.3 g. of 1-(m-methoxy-p-methylphenyl)-propylamine-(2) in 300 ml. of concentrated hydrobromic acid (d.=1.49) was refluxed for 3 hours. The solution was then evaporated to dryness and dissolved in water. The Water solution was made slightly alkaline with ammonia and the precipitate recrystallized from di-isopropyl-ether.

In an analogous way the following substances were prepared. R and R have the significance given above.

TABLE 3 (b) 1.81 g. of m-hydroxy-p-methyl-norephedrine was dissolved in 20 ml. of 1 N hydrochloric acid and hydrogenated with Pd/C as catalyst at 50. After 5 hours 250 ml. of H had been taken up and the desoxybase was isolated by alkalisation of the filtered solution. After recrystallization from di-isopropylether the melting point was found to be 134 C. The substance was identical with the one obtained in Example 2a.

EXAMPLE 3 Preparation of 1-(rn-hydroxy-p-ethyl-phenyl)- propylamine (-2) 1-(rn-hydroxy-p-ethyl-phenyl)-propylamine (-2) was prepared by reduction of 1-(m-hydroxy-p-ethyl-phenyl)- 2-nitro-l-propene by means of LiAlH by the same method as in Example 1d. M.P.: 109 C.

The following examples illustrate how the compounds of the instant invention can be incorporated in pharmaceutical compositions.

EXAMPLE 4.--TABLETS Each tablet contains:

Mg. Active substance 50.0 Maize starch 25.0 Lactose 160.0 Gelatin 1.5 Talc 12.0

Magnesium stearate 1.5

250.0 EXAMPLE 5.-SUPPOSITORIES Each suppository contains:

8 EXAMPLE 7.-INJECTION SOLUTION Mg. Active substance 0.100 Sodium pyrosulfite 0.500 Disodium edetate 0.100 Sodium chloride 8.500 Sterile water for injection ad 1.00

EXAMPLE 8.SOLUTION FOR RECTAL ADMINISTRATION (RECTAL VIALS) Active substance20.0 mg. Sodium pyrosulfite-LS mg. Disodium edetate0.3 mg. Sterile water-ad 3.0 ml.

EXAMPLE 9.DROPS Active substance2.00 g. Ascorbic acid-1.00 g. Sodium pyrosulfite0.l0 g. Disodium edetate-0.l0 g. Liquid glucose50.00 g. Absolute alcohol10.00 g. Purified water-ad 100.0 ml.

EXAMPLE 10.TABLETS Active substance g.), lactose g.), calcium citrate (50 g.), and starch (50 g.) are mixed together and granulated using a 10% aqueous gelatin solution. The granules are passed through a ZO-mesh sieve, mixed with magnesium stearate (1.5 g.) and tale (5 g.), and then tabletted using a 9 mm. punch.

PHARMACOLOGICAL TESTS (I) Effect as releasers and displacers of noradrenaline in the mouse brain The substances were given intraperitoneally to mice (male, NMRI, b.w. of 18-22 g.) in a dosage of 30 mg./kg. 6 animals per group were used. The noradrenaline in the brains was determined fluorometrically according to Bertler, Carlsson and Rosengren, Acta. physiol. scand. 44, 273 (1958) 1, 2, 4 and 8 hours after the administration. The values are given in percents of normal values (450 :9 ng./g.).

TABLE 4 Sympath- Amount of noradrenaline in omimetie the brain. Percent of normal effect;

values after- (piloerection.

salivation, R R 1 hr. 2 hrs. 4 hrs. 8 hrs. exophthalmos) This test shows:

(a) That the prior art compound II, 3-hydroxy-4- methyl-norephedrine, does not penetrate into the brain and displace noradrenaline, which would result in a decrease of noradrenaline in the brain,

(b) That the prior art compound III, u-methyl-m-tyramine, has an unwanted high sympathomimetic effect leading to excessive signs of piloerection, salivation, exophthalmos.

(c) That the substances disclosed in this invention penetrate into the brain and cause release of noradrenaline through displacement (expressed as a decrease in noradrenaline) without causing disturbing sympathomimetic effects.

9 (II) Toxicity The intraperitoneal and the peroral toxicity was determined as LD in mice.

This test shows that the compounds disclosed in this invention have a low intraperitoneal and oral toxicity compared with the prior art compounds 11 and III.

(III) Antihypertensive effect When 1 (m-hydroxy-p-methylphenyl)-propylamine-2 was given as a solution in the drinking water to renally hypertensive rats in doses of 5-10 mg./kg./day their blood pressure (170-200 mm. Hg) decreased to 100-120 mm. Hg in a few days and remained there until the administration of the drug was stopped. The prior art compounds II and III did not react similarly when administered in the same dosage; compound II does not lower blood pressure and compound III causes an initial increase in blood pressure to 190-210 mm. Hg due to its sympathomimetic efi'ect, whereafter the blood pressure decreases moderately.

This test shows that only compounds which penetrate into the brain and cause liberation and displacement of noradrenaline there have antihypertensive activity. The prior art compound III has an antihypertensive action which is masked by the sympathomimetic action of the substance leading to an initial undesirable increase in blood pressure.

(IV) Efiect as releasers and displacers of 5- hydroxytryptamine in the mouse brain Substances according to the invention were given intraperitoneally to mice (male, NMRI, b.w. 18-22 g., 6 animals/ group). The amount of S-hydroxytryptamine in the brain was determined fluorimetrically according to Bertler and Rosengren, Experientia 15 382 (1959), 4 hours after the administration.

The values are given in percents of normal values (460:14 ng/g).

TABLE 6 Amount of fi-hydroxytryptamine after 4 hours, percent of nor- Dose, mgJkg. mal values This test shows that the compounds disclosed in the invention are able to liberate and displace S-hydroxytryptamine in the mouse brain, in contrast to the related prior art compound III, u-methyl-m-tyramine. Higher doses than 50 mg./kg. could not be used for the prior art compounds II and III due to the toxicity of these compounds.

What is claimed is:

1. 1 (3 hydroxy 4-methyl-phenyl)-propylamine (-2) and therapeutically acceptable salts thereof.

2. A compound according claim 1 in form of their optical antipodes, or a therapeutically acceptable salt thereof.

References Cited UNITED STATES PATENTS 2,146,476 2/1939 Hildebrandt et al. 260-5708 3,187,046 6/ 1965 Curtis 260570.8 3,188,349 6/1965 Krohs et al. 260570.=8 3,198,833 8/1965 Beregi et al. 2-60570.8

OTHER REFERENCES Wenner, Chemical Abtracts, Vol. 46, pages 1487-88 ROBERT V. HINES, Primary Examiner U.S. Cl. X.R.

@2 3 UNITED STATES PATENT OFFICE @ERTIFCTE F QRREC@N Patent No. ,737 Dated April 1972 Inventor-( Per CarlSSOn et 3.1.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Col. 2, line 14, "neutrons should be -neuron's;

Col. 5, 7

line 53, "0.1" should be 0.l%;

Col. 6, line 2, "ofl" should be of l-;

line 22 of Table l, "4C H should be 4-C H Col. 7, line 7, "(d.=1.49)" should be -(d=l.49);

Col. 10, line 9, after "hours" should be line 17, "191.1" should bev --1l9.l--;. line 19, "the" second occurrence" should be --this-.

Signed and sealed this 26th day of September 1972.

(SEAL) Attest:

EDWARD M.FLETCHER,JR, ROBERT GOTTSCHALK Attesting Officer Commissioner of Patents AUliU H050 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Petent No. 3r655r737 Dated April 1972 lnventoifls) Per Arvid Emil Carlsson et al It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Col. 2, line 14, "neutrons should be neurons--;

line 53, "0.1" should be -O.l%--;

Col. 6, line 2, 'ofl" should be .of l;

line 22 of Table l, "4C=H should be -4C H Col. 7, line 7, (d.=l.49) should be (d=l.49)-;

Col. 10, line 9, after "hours" should be line 17, "191.1" should be --ll9 .l-; line 19, "the" second occurrence" should be -this-.

Signed and sealed this 26th day of September 1972 (SEAL) Attest:

EDWARD M.FI.ETCHER, JR. ROBERT GOTTSCHALK Attesting Officer Commissioner of Patents