US3929871A - 1-(3-Hydroxy-4-alkyl-phenyl)-alkylamines(-2) and the salts thereof - Google Patents

Abstract

Compounds represented by the formula

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

States Carlsson et a1.

atent 1 1 Dec. 30, 1975 [54] l-(3-HYDROXY-4-ALKYL-PHENYL)- ALKYLAMlNES(-2) AND THE SALTS THEREOF [75] Inventors: Per Arvid Emil Carlsson, Goteborg;

Hans Rudolf Corrodi, Askim; Sven Goran Hallhagen, Molndal; Ulf Krister Junggren, Goteborg, all of Sweden [73] Assignee: Aktiebolaget Hassle, Gothenburg,

Sweden [22] Filed: June 21, 1973 [21] Appl. No.: 372,088

Related U.S. Application Data [60] Division of Ser. No. 811,662, March 28, 1969, Pat. No. 3,655,737, which is a continuation of Ser. No. 171,017, Aug. 11,1971, abandoned.

[30] Foreign Application Priority Data Apr. 1, 1968 Sweden 4332/68 [52] U.S. Cl 260/501.17; 260/570.8 R; 260/600;

260/612 D; 424/316; 424/330 [51] Int. Cl. C07C 87/29 [58] Field of Search.... 260/570.8 R, 501.17

[56] References Cited UNITED STATES PATENTS Green 260/570.8

10/1970 Keck et a1 260/50l.1 X 8/1971 Gold 260/570.8 X

OTHER PUBLICATIONS Wenner, Journal Organic Chemistry, Vol. 16, pp. 457-460, (1951).

Primary ExaminerR. V. Hines Attorney, Agent, or Firm-Brumbaugh, Graves, Donohue & Raymond wherein R is a member of the group consisting of CH C H and C H 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 11 and C H,, pharmaceutical compositions containing these compounds, and the use thereof for therapeutic purposes.

2 Claims, No Drawings 1-(3-HYDROXY-4-ALKYL-PHENYL)- ALKYLAMINES(-2) AND THE SALTS THEREOF This application is a division of Ser. No. 81 1,662 filed 03/28/69 and now U.S. Pat. No. 3,655,737; which is a continuation of application Ser. No. 171,017, filed Aug. 1], 1971 and now abandoned.

The present invention relates to substituted hydroxyphenyl-alkylamines having valuable pharmacological properties and pharmaceutically acceptable salts thereof. The compounds of the invention are of particular value as hypertensive agents and as agents for treatment of mental illness, especially as antidepressant agents. The invention also relates to methods for the preparation of such compounds, compositions containing them and the use of such compounds for therapeutic purposes. In particular the invention relates to compounds of the formula wherein R is a member of the group consisting ofCl-1 C H and C l-1 and R in position 2, 4, 5 or 6'0n the benzene nucleus, is a member of the group consisting of F, Cl, Br, CH C 11 and C l-1 Prior art compounds are 3-hydroxy-4-methylnorephedrine;

Nll

HOCHCH and a-methyl-m-tyramine:

N11 CH %H CH (III) without giving rise to undesired sympathomimetic 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 neurons 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 effects, since it does not penetrate into the brain and displace noradrenaline there.

The prior art compound 111 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 effect 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 effect.

The compounds of the invention may be prepared by I known methods such as A. replacing Z with H in a compound of the formula HCH 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 1;

B. replacing Z with H by catalytical hydrogenation of a compound of the formula 11 on on 1 III 3 4 wherein R has the meaning specified above; R is a member of the group consisting of CH;,, C H and Sill CNO C H and wherein Z is a member of the group conl sisting of aralkyl protecting groups, such as benzyl; to R the formation of a compound of the formula I; 5 VI C. reducing a compound of the formula OH i 1 wherein R and R have the meanings specified above,

to the formation of a compound of the formula I; IV [5 whereafter the compound of the formula I thus obtained if necessary is transformed into a therapeutically R OH 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 off by strong acids such as HBr, and

Z may be split off by hydrogenolysis.

The reaction way D is applicable only in those cases wherein R and R have the meanings specified above, when the substituent R in the compound of the forin the presence of HCOOH according to Leuckart to l I i CH C l-{ r C H catal ti l removal the formation of a COmPOLmd 0f the formula I; of araliphatic protecting groups is not applicable when D. reducing a compound f t fOrmula the substituent R is F, Cl 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 2 preferably carried out by catalytical hydrogenation. HOCHCH The reduction of the compound of the formula V] is 1 preferably carried out by means of a complex metal hydride such as lithium aluminium hydride.

, V 3 5 Starting materials for the processes described above H may be prepared in any desired way. Some of the possi- R ble 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 wherein R has the meaning specified above and reaction formulas have the meanings given above, Z is wherein R is a member of the group consisting of hydrogen or the radical Z, and Z is hydrogen or the CH C H and C H to the formation of a comradical Z pound of the formula I; Starting materials for the reaction way D may be E. reducing a compound of the formula prepared by methods well known per se.

Method A. CH0 CH=FNO Hzcmmfl 1 2 k 4 1 R R CH NO L1All-l 023 I 0Z3 2 0Z3 R R R r l-LCl-l Method B:

CHO

l 1 2 R CH2NO2 4 s Z R3 02 3 T NH l CH CH 2 HzCllH l l (Leuckort reaction) H /Pd 4 OZ OH R R Method C:

CHO cl-tzfimo CH fo l l l R CH NO Fe HCl HBr 3 3 a R oz R R 02 'T 2 l:o CH2C\H \R l v HCOOH (Leuckcrt l reaction) 2 OH R2 H R HCQNH2 Method E: NH

CHZCNO 1 2 CH CH R L LiAlH 4 OH 2 R OH The compounds of the invention exist in the form of 60 regeneration of the amine after the usual separation of optically active isomers, which may be isolated in any principially 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 racemate obtained at the above reactions can be resolved into the enantiomeres 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

the diastereomeric mixture thus obtained.

It will also be understood that the compounds of the present invention may be used either as a purified isome'r 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 or gelatin, and also may include lubricants such as magnesium or calcium stearate or a Carbowax or other polyethylene glycol waxes and compressed to form tablets or centres for dragees. If dragees 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 aslactose, 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 l 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 adjuvants 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. pyrogen-free 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-pmetylphenyl)-butylamine (-2) and 1-(m-hydroxy)-pmethylphenyl-propylamine (-2), may be given in widely varying dosages from, for example, 20 mg/day to l g/day, but dosages of 50-500 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 5O mg/day may be used.

The invention is further illustrated by the following 7 Examples.

EXAMPLE 1 Preparation of Starting Material a. Preparation of 1-(m-methoxy-p-methyl-phenyl)-2- nitrol -propene 28.9 g of m-methoxy-p-methylbenzaldehyde was dissolved in ml of toluene and refluxed with 46.8 g of nitroethane, 1.5 ml of acetic acid, 1.5 ml of n-butylamine and 0.15 g of p-toluenesulfonic acid until the theoretical amount of water was split off. The solution was evaporated and the residue was purified by recrystallisation from ethanol-water.

The compounds specified in the following Table 1 were obtained in an analogous manner. R and R have the significance given above, and Z is used to designate the protecting group used in the synthesis.

b. Preparation of m-methoxy-p-methyl-phenvlacetone To a solution of 0.8 mole of l-(m-methoxy-p-methylphenyl)-2-nitro-l-propene in 300 ml of toluene and 875 ml of water was added 326 g of iron powder and 3.3 g of ferric chloride hexahydrate. The mixture was stirred and heated to C. 292 ml 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 one half hour, and thereafter steam-distilled. The distillate was extracted with ether, and the organic layer washed twice with a 3 per cent sodium bisulphite solution, then water, dried over anhydrous magnesium sulphate and evaporated. The remainder was pure enough for the next step. c. Preparation of l-(m-methoxy-p-methyl-phenyl)- propylamine (-2) 0.044 mole of the substituted Z-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 ether. The organic layer was dried and evaporated.

d. Preparation of l-(m-methoxy-p-methylphenyl)- propylamine-Z 67.1 g of l-(m-methoxy-p-methylphenyl)-2-nitro-lpropene 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 2 hours. 20 ml of ethyl-acetate was then added carefully with 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.

Table 2 R R 2 Yield c11 4-c11 c11 68 CH. 5-c11 c11 40 CH 6-011 C11. 75 c 11 4CH3 ca. 87 C 11. 4-c1-1 C11 30 c11 4 c1 CH;, 55

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-isopropylether.

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

Table 3 R R M.p. c

CH 4CH3 134 CH 5CH,, 10o CH 6C1-l;, 131 c 11 4Cl-l 107 C 11 4-CH3 1 17 CH3 4-Cl 137 b. 1.81 g of m-hydroxy-p-methyl-norephedrine was dissolved in 20 ml of 1N 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 134C. The substance was identical with the one obtained in example 2a.

EXAMPLE 3 EXAMPLE 4 Tablets Each tablet contains: Active substance 50.0 mg Maize starch -continued Lactose 160.0 mg Gelatin 1.5 mg Talc 12.0 mg Magnesium stearate 1.5 mg 250.0 mg

EXAMPLE 5 Suppositories Each suppository contains: Active substance 50.0 mg Ascorbyl palmitate 1.0 mg Suppository base (Imhausen H) ad 2000.0 mg

EXAMPLE 6 Syrup Active substance 0.500 g Liquid glucose 30.0 g Sucrose 50.0 g Ascorbic acid 0.1 g Sodium pyrosulfite 0.01 g Disodium edetate 0.01 g Orange essence 0.025 g Certified colour 0.015 g Purified water ad 100.0 g

EXAMPLE 7 Injection Solution Active substance 0.100 mg Sodium pyrosulfite 0.500 mg Disodium edetate 0.100 mg Sodium chloride 8.500 mg Sterile water for injection ad mg EXAMPLE 8 Solution for Rectal Administration (Rectal Vials) Active substance 20.0 mg Sodium pyrosulfite 1.5 mg Disodium edetate 0.3 mg Sterile water ad 3.0 ml

EXAMPLE 9 Drops Active substance 2.00 g Ascorbic acid 1.00 g Sodium pyrosulfite 0.10 g Disodium edetate 0.10 g Liquid glucose 50.00 g Absolute alcohol 10.00 g Purified water ad 100.0 ml

EXAMPLE 10 Tablets Active substance (50 g), lactose (100 g), Calcium citrate (50 g), and starch (50 g) are mixed together and granulated using a 10% agueous gelatin solution. The granules are passed through a 20-mesh sieve, mixed with magnesium stearate (1.5 g) and talc (5 g), and then tabletted using a 9 mm punch.

PHARMACOLOGICAL TESTS I. Effect as Releasers and Displacers of Noradrenaline in the Mouse Brain 111. Antihypertensive Effect When 1(m-hydroxy-p-methylphenyl)-propylamine- 2 was given as a solution in the drinking water to re- The substances were given intraperitoneally to mice hypertensive rats in doses of 5 l0 mg/kg/day their (male, NMRI, b.w. of 1822 g) in a dosage of 30 blood Pressure (170400 mmHg) .decreased mg/kg. 6 animals per group were used. The noradrena- 1004 g m a few days and remamed there 9 line in the brains was determined fluorometrically acthe admlmstranon of the l was 9: The pnor cording to Bertler Carlsson and Rosengren Acta art compounds II and 111 did not react similarly when phySiOL Scand' 44 273 (1958) 1 2 4 and 8 hours after 10 administered in the same dosage; compound 11 does not the administration. The valves are given in percents of 1 blQOd Pressure and Compound In Causes an 1mnormal values (450 i 9 ng/g) tial increase in blood pressure to 190-210 mm Hg due Table 4 R R2 Amount of noradrenaline in the brain. sympathomimetic Percent of normal values after effect (piloerection salivation, exoftall 2 4 8 hrs mos) CH 4CH3 60.6 48.6 37.5 4811 CH3 4C2H5 75.8 68.3 60.5 6815 C l-l 4CH3 91.0 85.4 80.0 92.5 C2115 4-CH3 90.1 87.4 88.1 96.3 CH3 5CH3 70.8 51.4 68.3 87.2 CH3 6CH;, 74.5 59.8 67.8 99.0 Com- 11 97.2 99.0 102.5 103.7 llpound Com- 111 72.5 54.2 53.1 61.3 -lll1- pound This test Shows to its sympathomimetic effect, whereafter the blood a. that the prior art compound II, 3-hydroxy-4-methpress ure decreaseshmoderately h yl-norephedrine, does not penetrate into the brain and Thls test shows t at Compounds l penetrate displace noradrenaline which would result in a into the brain and cause liberation and displacement of Crease of noradrenaline in the brain noradrenaline there have antihypertensive activity. The

b. that the prior art compound Ill, a-methyl-m-tyracompound has an l f l acuon mine, has an unwanted high sympathomimetic effect Whlch 1S masks? by the y lP l q of leading to excessive Signs of piloerection salivation, substance leading to an initial undesirable increase in exoftalmos blood pressure.

0. that the substances disclosed in this invention pen- Eff t as Reieasers and Dispiacers f etrate into the brain and cause release of noradrenaline 5 Hydroxytryptamine in the Mouse Brain through displacement (expressed as a decrease in nor- 4O Substances according to the invention were given adrenaline) without causing disturbing sympathomimetic effects.

11. Toxicity The intraperitoneal and the peroral toxicity was determined as LD in mice.

4 hours after the administration.

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 111.

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

Table 6 R R Dose mg/kg Amount of S-hydroxytryptamine after 4 hours; percent of normal values CH 4CH 82.2 CH 4C H 50 62.2 C 11 4CH 51.0 CH, 5-CH 100 89.1 CH; 6--Cl-l 100 87.3 C H 4CH 100 85.4

Table 6-continued R R Dose mg/kg Amount of S-hydrox tryptamine after 4 hours; percent normal values Compound 11 50 103.3

Compound lll 50 119.1

l. l-(3-hydroxy-4-ethyl-phenyl)-propylamine(-2 or their optical antipodes) or therapeutically acceptable salts thereof.

2. l-(3-hydroxy-4-methyl-phenyl)-butylamine(-2) or their optical antipodes or therapeutically acceptable salts thereof.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. I 3, 929,871

DATED I December 30, 1975 rNyg o rs) 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:

First Page, Item [60], "Division of Ser. No. 811,662, March 28, 1969, Pat. No. 3,655,737,- which is a continuation of Ser. No. 171,017, Aug. 11, 1971, abandoned." should read -Continuation of Ser. No. 171,017, Aug. 11, 1971, abandoned, which is a division of Ser. No. 811,662, March 28, 1969, Pat. No. 3,655,737.-; Col. 1, lines 3-6, "This application is a division of Ser. No. 811,662 filed 03/28/69 and now U.S. Pat. No.

3,655,737; which is a continuation of application Ser. No.

171,017, filed Aug. 11, 1971 and now abandoned." should read --This application is a continuation of application Ser. No. 171,017, filed Aug. 11, 1971, abandoned, which is a division of U.S. application Ser. No. 811,662, filed March 28, 1969, and now U.S. Pat. No. 3,655,737.-; Col. 14, line 10, after "(2 insert and Col. 14, line 11, after "antipodes" delete Signed and Scaled this v Sixth Day of July 1976 sue A rtesl:

RUTH C. MASON C. MARSHALL DANN Arresting Officer Commissioner of Parents and Trademarks UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3, 929,871

DATED December 30, 1975 0 (5) Per Arvid Emil Carlsson et a1.

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

First Page, Item 0 "Division of Ser. No. 811,662, March 28, 1969, Pat. No. 3,655,737, which is a continuation of Ser. No. 171,017, Aug. 11, 1971, abandoned." should read --Continuation of Ser. No. 171,017, Aug. 11, 1971, abandoned, which is a division of Ser. No. 811,662, March 28, 1969, Pat. No. 3,655,737.-; Col. 1, lines 3-6, "This application is a division of Ser. No. 811,662 filed 03/28/69 and now U.S. Pat. No. 3,655,737; which is a continuation of application Ser. No. 171,017, filed Aug. 11, 1971 and now abandoned." should read -This application is a continuation of application Ser. No. 171,017, filed Aug. 11, 1971, abandoned, which is a division of U.S. application Ser. No. 811,662, filed March 28, 1969,

and now U.S. Pat. No. 3,655,737.--; Col. 14, line 10, after (-2" insert and Col. 14, line 11, after "antipodes" delete Signed and Scaled this Sixth Day of July 1976 sen Arrest:

RUTH C. MASON C. MARSHALL DANN Commissioner of Parents and Trademarks Arresting Officer

Claims (1)

1. 1-3-HYDROXY-4-ETHYL-PHENYL)-PROPYLAMINE(-2 OR THEIR OPTICAL ANTIPODES) OR THERPEUTICALLY ACCEPTABLE SALTS THEREOF. 2. 1=(3-HYDROXY-4-METHYL-PHENYL)-BUTYLAMINE(-2) OR THEIR OPTICAL ANTIPODES OR THERAPEUTICALLY ACCEPTABLE SALTS THEREOF.