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Publication numberUS3758691 A
Publication typeGrant
Publication dateSep 11, 1973
Filing dateAug 11, 1971
Priority dateApr 1, 1968
Also published asDE1915230A1, DE1915230B2, DE1915230C3, US3655737
Publication numberUS 3758691 A, US 3758691A, US-A-3758691, US3758691 A, US3758691A
InventorsP Carlsson, H Corrodi, S Hallihagen, U Junggren
Original AssigneeHaessle Ab
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Illness new substituted hydroxyphenyl-alkylamines in the treatment of mental
US 3758691 A
Abstract  available in
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Claims  available in
Description  (OCR text may contain errors)

United States Patent m1 Carlsson et al.

1451 Sept. 11, 1973 NEW SUBSTITUTED llYDROXYPHENYL-ALKYLAMINES IN THE TREATMENT OF MENTAL ILLNESS Inventors: Per Arvid Emil Carlsson, Goteborg;

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

Sweden Filed: Aug. 11, 1971 Appl. No.: 171,018

Related US. Application Data Division of Ser. 1655811562, M56158, 196??55 No. 3,655,737.

Foreign Application Priority Data Apr. 1, 1968 Sweden 4332/68 US. Cl. 424/330 Int. Cl A6lk 27/00 Field of Search 424/330 References Cited UNITED STATES PATENTS 2/1939 l-lildebrandt et a1 260/5708 Compounds represented by the formula wherein R is a member of the group consisting of C11 C 11,, and C l-l 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 11,, pharmaceutical compositions containing these compounds, and the use thereof for therapeutic purposes.

4 Claims, No Drawings NEW SUBSTITUTED IIYDROXYPIIENYL-ALKYLAMINES IN THE TREATMENT OF MENTAL ILLNESS; This is a divisional application of Sher. i a- 1,662 filed Mar. 28, 1969, now issued as US .Pat. 7 No. 3,655,737.

The present invention relates to substituted hydroxyphenyl-alkylamines having valuable pharmacological properties and pharmaceutically acceptable salts thereof. The compounds of the invention are of partic-- ular 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 where R is a member of the group consisting of CH C l-I 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,I'I and C,,H,.

Prior art compounds are 3-hydroxy-4-methyl norephedrine;

V NH HOCHJJH and a-methyl-m-tyramine:

(III) 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 III does penetrate the bloodbrain 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 known methods such as A. replacing Z with H in a compound of the formula CH3 H 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 I-IBr to the formation of a compound of the formula I;

B. replacing Z with H by catalytical hydrogenation of acompound of the formula 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 ar'alkyl protecting groups, such as benzyl; to the formation of a compound of the formula I;

C. reducing a compound of the formula wherein R and R have the meanings specified above, in the presence of HCOOl-l according to Leuckart to the formation of a compound of the formula I;

D. reducing a compound of the formula 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 ofa compound of the formula I E. reducing a compound of the fomrula Starting materials for the reaction way D may be prepared by methods well known per se.

03 M65651? bum" my WMW" W 0H0 cH=cNo, R v1 l n cmNo, Luuni --e wherein R and R have the meanings specified above, 30 to the formation of a compound of the formula I; v R, R, whereafter the compound of the formula I thus obtained if necessary is transformed into a therapeutically acceptable salt by reaction with the appropriate acid. 35 CHCHNH, CH H Z is preferably a methyl group, and Z IS preferably l I a benzyl group. Hm 1 Z may be split off by strong acids such as H81, and I V 2 may be split off by hydrogenolysis. 0Z OH The reaction way D is applicable only in those cases 'iistimd B:

CHO CH=ENO1 fir oz Fe HG] NH! X NH, CHQCO CH; H CH3 H HCOOH (Leuckart reaction) HJPd O IICONII! oz. o1,r RI R m Method C:

CHO (DH-END,

mcmNo, Fe H01 -"-I 0Z -QZI R! RI 011,00 CHzCO HCOOH (Leuckart HBr reaction) oz; H HCONH:

when the substituentR in the compound of the formula I is CH;,', C2H5 or C l-l,. Catalytical removal of araliphatic protecting groups is notapplicable when 'the substituent R is F, C1 or Br. When R is CH,,, -C,l-l,, or -C li all the outlined reaction ways can be used, and catalytical removal of an araliphatic protecting group is possible. 7

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

The reduction of the compound of the formula V1 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 meaningsgiven above, 2 is hydrogen or the radical Z ,and. Z is hydrogen or the radical Z.

Method E:

CH=G NO, OH, H

in is LiAlHi --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 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 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 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 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 percent to 20 percent 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 percent to 2 percent 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. arachisoil, 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 l-(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-l00 mg/day, preferably about 10-50 mg/day may be used.

The invention is further illustrated by the following Examples.

EXAMPLE 1 Preparation of Starting Material a. Preparation of l-(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 nbutylamine 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 l 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.

TABLE 1 R R Z M.p.C CH; 4-CH CH; 5 l CHhd 3 5 -CH; CH; C H; 6-CH, CH, 48 C H, 4-C H COCH, 47 CgH 4-CH; CH; 76 C 4-CH CH; 65 CH, 4-Cl CH; 80 C 4-Cl CH; 88

b. Preparation of m-methoxy-p-methyl-phenylacetone To a solution of 0.8 mole of l-(m-methoxy-pmethylphenyl)-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 80C. 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 1-(rn-methoxy-p-methyl-phenyl)-v propylamine (-2) 0.044 mole of the substituted Z-phenylpropanone, 13.5 g of freshly distilled formamide and 2.5 g of 100 percent 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 percent 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-1- propene in 200 ml of dry ether was added to a stirred mixture of 32 g of LiAlH in 1,000 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. 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 R2 2 Yield Chg 4-CH; CH;, 68 CH, S-Cl-l CH, 40 CH, 6CH, CH;I 75 C,H 4-CH, CH g7 C,H-, 4-Cl-l, CH3 80 CH, 4-Cl CH, 55

EXAMPLE 2 Preparation of 1-(m-hydroxy-p-methylphenyl propylamine-2 a. 39.3 g of 1-(m-methoxy-p-methylphenyl)- propylamine-(Z) in 300 ml of concentrated hydrobromic acid (d=l.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 cu, 4-cl-i, 1:44 cu, 54:11, 100 CH, s-cn, m cm. 4-1:, 107 cm, 401, 1 17 CH, 4-Cl m b. 1.81 g of m-hydroxy-p-methyl-norephedrine was dissolved in 20 ml of l-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 134C. The substance was identical with the one obtained in example2a.

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

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

Example 4. Tablets Each tablet contains:

Active substance 50.0 mg Maize starch 25.0 mg Lactose 160.0 mg Gelatin 1.5 mg Talc 12.0 mg Magnesium stearate 1.5 mg

Example 5. Suppositories Each suppository contains:

Active substance 50.0 mg Ascorbyl palmitate 1.0 mg Suppository base (lmhausen H) ad 2000.0 mg

Example 6. Syrup Active substance 0.500 g Liquid glucose 30.0 g Sucrose 50.0 g y Ascorbic acid 0.1 g Sodium pyrosulfite 0.01 g Disodium edetate 0.01 r g 1 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 1.00 mg Example 8. Solution for rectal administration (Rectal vials) Active substance 2 Sodium pyrosulfite Disodium edetate Sterile water Example 9. Drops Active substance 2 Ascorbic acid 1 Sodium pyrosulfite 0 Disodium edetate 0. Liquid glucose 50 Absolute alcohol 0 Purified water EXAMPLE 10 (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 i 9 ng/g).

TABLE 4 Amount, of noradrenaline In Sympathomlmetic lo the brain. Percent 01' normal efiect values nlter- (plloerection sullvation It R2 1 hr. 2 hrs. 4hrs. Shrs. exottnlmos) onn 1-0113 00.0 40.0 37.5 38.1 on. 4-onh 75.8 68.3 00.5 68.5 (Julh 4-011, 01.0 85.4 80.0 02.5 (1211. 1-0113 00.1 87.4 88.1 00.3 (1113 5-0113 70.8 51.4 0&3 87.2 on 0-0113 74.5 59.8 07. s 00.0

Compound II 07.2 00.0 102.5 103.1 Compound III 72.5 54.2 53.1 61.3

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,

TABLE 5 LD LD Sympatho- R R in mice in mice mimetic mg/kg i.p. mg/kg p.o. efi'ect observed CH, 4-C1l 200 400 CH, 4-C,H 300 S00 C 11 4-CH, 400 700 C,H, 4-CH, 400 800 CH, S-CH, 400 750 CH, 6-CH, 400 750 Compound III 100 200 -HH- Coumpound 11 150 300 +H+ This test shows that the compounds disclosed in this invention have a low intraperitoneal and oral toxicity compared with the prior art compounds [I and III. III. Antihypertensive Effect When l-(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 mmHg) 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 11 and III did not react similarly when administered in the same dosage; compound II does not lower blood pressure and compound 111 causes an initial increase in blood pressure to 190-210 mm Hg due to its sympathomimetic effect, 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 sympafzhomimetic action of the substance leading to an initial undesirable increase in blood pressure.

IV Effect as Releasers and Displacers of S-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 flourimetrically according to Bertler and Rosengren, Experientia 15 382 (1959), 4 hours after the administration.

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

TABLE 6 R R Dose mg/kg Amount of S-hydroxytryptamine after 4 hours; percent of normal values CH, 401, 50 82.2 CH, 4-c,H, 50 62.2 C,H, 4-CH, 51.0 CH, S-CH, 100 89.1 CH, 6-CH, 100 87.3 (3,11 4-CH, 100 85.4 Compound 11 50 103.3 Compound Ill 50 119.1

This testshows thatthe compounds disclosed in this invention are able to liberate and displace S-hydroxytryptamine in the mouse brain, in contrast to the related prior.art compound III, a-methyl-m-tyramine. Higher doses than 50 mg/kg could not be used for the prior art compounds 11 and III due to the toxicity of these compounds.

We claim:

1. A method for the treatment of mental illness which comprises administering to animals a therapeutically effective amount of 1-(3-hydroxy-4-methyl-phenyl)- propylamine (-2) or a therapeutically acceptable salt thereof.

2. The method according to claim 1 in which the compound is in the form of an optical antipode or a therapeutically acceptable salt thereof.

3. A composition for oral, rectal or parenteral administration to animals containing as an active ingredient a therapeutically effective amount of l-(3-hydroxy-4- methyl-phenyl)-propylamine (-2) or a therapeutically acceptable salt thereof and a carrier therefor.

4. The composition according to claim 3 in which the compound is in the form of an optical antipode or a therapeutically acceptable salt thereof.

l II I I UNITED. STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,758, 691 Dated September 11, 1973 Inventor(s) Per Arvid Emil Carlsson et a1.

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

Column '6', "line 57 change ""CHhdB" to "CH Column 7',"'l'i'n'e' 62 change, C' H- to -C H v Column '9',' line '48 change "compound" to "Compound".

Signed and sealed this-191th day'of Mar-ch 19m.

( A Attest:

EDWARD FLETCHERQTR, Attesting Officer 0. MARSHALL DANN Comis'sior'ier f Patents USCOMM-DC 60376-PO9

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US20050130243 *Dec 15, 2003Jun 16, 2005Zheng Yi F.Assay for entactogens
US20050130244 *Dec 15, 2003Jun 16, 2005Zheng Yi F.Assay for entactogens
US20050208603 *Mar 22, 2004Sep 22, 2005Zheng Yi FAssays for amphetamine and methamphetamine using stereospecific reagents
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Classifications
U.S. Classification514/654
International ClassificationC07C45/00, A61K31/135, C07C215/52, A47L23/05
Cooperative ClassificationC07C45/00, A61K31/135, A47L23/05
European ClassificationA47L23/05, C07C45/00, A61K31/135