United States Patent to 11) 4,017,542 Wilhelm et al. 45 Apr. 12, 1977 54) 9-(2-HYDROXY-3-AMINO-PROPYL)-9,10 56) References Cited DIHYDRO-9,10-ETHANO-ANTHRACENES UNITED STATES PATENTS AND SALTS THEREOF 2,403,483 7/1946 Cusic .............................. 260/570.8 75 Inventors: Max Wilhelm, Watchung, N.J.; 2,541,342 2/1951 Cusic .......................... 260/570.8 X Raymond Bernasconi, Oberwil, 3,399,201 8/1968 Schmidt et al. ............ 260/570.8 X Switzerland; Angelo Storni, 3,674,841 7/1972 Boissier et al. ............... 260/501. 12 Rheinfelden, Switzerland; Dieter Beck, Basel, Switzerland; Karl Primary Examiner-Robert V. Hines Schenker, Binningen, Switzerland Attorney, Agent, or Firm-Joseph G. Kolodny; (73) Assignee: Ciba-Geigy Corporation, Ardsley, Theodore O. Groeger; John J. Maitner N.Y. 22 Filed: Apr. 2, 1975 57 ABSTRACT (21 Appl. No.: 564,580 9-(2-A-3-R-propyl)-9,10-dihydro-9,10-ethanoanthra cenes containing the nucleus of the formula Related U.S. Application Data 63 Continuation-in-part of Ser. No. 226,329, Feb. 14, 8 () 1972, abandoned. (30) Foreign Application Priority Data 2 Feb. 23, 1971 Switzerland ....................... 2578/71 3 Feb. 17, 1972 Switzerland ......................... 669/72 52) U.S. Cl. ........................ 260/570.6; 260/243 B; 5 10 260/247; 260/268 TR; 260/293.56; 260/307 C; 260/326.14 T; 260/340.5; 260/343.7; wherein R denotes a secondary or tertiary amino group 260/348 R; 260/465 F; 260/501.11; and A denotes a free, etherified or acylated hydroxyl 260/501.12; 260/501. 18; 260/501.19; group, their pharmaceutically acceptable salts are use 260/544 N; 260/566 B; 260/567.5; 260/599 ful as psychotropics, especially as anti-depressants. (51) Int. Cl'......................................... C07C 91122 58) Field of Search ................. 260/501.18, 501.1 1, 260/501. 19,501. 12,570.6 5 Claims, No Drawings 4,017,542 2 Divalent radicals are above all lower alkylene and 9-(2-HYDROXY-3-AMINO-PROPYL)-9,10-DIHY alkenylene radicals which are optionally substituted by DRO-9,10-ETHANO-ANTHRACENES AND SALTS hydroxyl, oxo and/or amino groups, especially those THEREOF radicals which contain 3-7, preferably 4, 5 or 6, chain 5 members and accordingly form rings with 4-8, and This application is a continuation-in-part of part of preferably 5, 6 or 7, members with the nitrogen atom of the amino groups. Such radicals are, for example, 1,4- applicants' Ser. No. 226,329, filed Feb. 14, 1972, and butylene, 1,4-pentylene, 1-4-hexylene, 1,5-pentylene, now abandoned. such as 1,5-dimethyl-1,5-pentylene, 3-methyl-1,5-pen SUMMARY OF THE INVENTION 10 tylene, 1,5-pentenylene, 1,6-hexylene and 1,5-hexylene The subject of the invention are 9-(2-A-3-R-propyl)- radicals. Radicals of this nature which are interrupted 9,10-dihydro-9,10-ethano-anthracenes containing the by hetero-atoms are above radicals in which the hetero nucleus of the formula atom is separated from both ends of the chain by at least two carbon atoms, that is to say the chain contains R 9 () 15 more than 4, and preferably 5, members and accord ingly forms a more than 5-membered, and preferably 6-membered, ring with the nitrogen atom. As examples there may be mentioned: Lower oxaalkylene, azaalkylene and thiaalkylene 20 radicals which are optionally substituted by hydroxyl, s ? 4. oxo and/or amino groups, such as 3-aza-, 3-oxa- and 3-thia-1,5-pentylene radicals, such as, for example, wherein R denotes a secondary or tertiary amino group 2,4-dimethyl-3-thia-1,5-pentylene, 1,5-dimethyl-3-aza and A denotes a free, etherified or acylated hydroxyl 1,5-pentylene, 3-lower alkyl-3-aza-1,5-pentylene, such group, and acid addition salts, particularly pharmaceu 25 as 3-methyl-3-aza-1,5-pentylene, 3-hydroxy-lower al tically acceptable acid addition salts thereof, as well as kyl-3-aza-1,5-pentylene, such as 3-hydroxyethyl-3-aza process for their manufacture, pharmaceutical prepa 1,5-pentylene, 3-oxa-1,6-hexylene and 3-aza-1,6-hexy rations containing them and their use as antidepres lene radicals. Sants. The amino group is above all a mono- or di-lower A N-monosubstituted amino group is described as a 30 alkylamino group, such as the monopropylamino or Secondary amino group and a N-disubstituted amino dipropylamino group, or preferably the monoe group is described as a tertiary amino group. Possible thylamino or diethylamino group, but above all the Substituents are, above all, hydrocarbon radicals of diemthylamino group and very particularly the aliphatic character which can also be interrupted by monomethylaminoamino group, or the N-methyl-N- hetero-atoms, such as oxygen, sulphur or nitrogen, 35 ethylamino group, a cycloalkylamino group, such as and/or be substituted by oxo, hydroxyl and/or amino the cyclopropylamino, cyclobutylamino, cyclopen groups. Hydrocarbon radicals of aliphatic character are tylamino or cyclohexylamino group, or a pyrrolidino or radicals of which the first member, bonded to the nitro piperidino group which is optically C-lower alkylated gen atom, is not a member of an aromatic system. Radi and/or g-singly unsaturated in the ring, or an optically cals of this nature are, for example, aliphatic and cyclo 40 C-lower alkylated piperazino, N'-lower alkyl aliphatic hydrocarbon radicals and especially lower piperazino, such as N'-methylpiperazino, or N'-(hy radicals of this nature. The description lower aliphatic hydrocarbon radicals droxy-lower alkyl)-piperazino, such as N'-(6-hydrox is used for radicals which contain up to 7, and above all yethyl)piperazino, thiomorpholino or morpholino 1-4, carbon atoms. The description lower cycloali 45 group. The expression "C-lower alkylated" denotes phatic hydrocarbon radicals is used for radicals which here, as above and in the following text, that the partic possess 3-7, and especially 5 or 6, ring carbon atoms. ular radical is substituted at C atoms by lower alkyl The word "lower" used in conjunction with other radicals, such as those mentioned, and especially by groups containing carbon is to be understood, in the C-a-alkyl radicals. Subsequent text, to have the general sense which has 50 An etherified hydroxyl group is, for example, a phe just been indicated for hydrocarbon radicals. The hy nyl-lower alkoxy group, such as a benzyloxy group, an drocarbon radicals can be saturated or unsaturated. alkenyloxy group, above all a lower alkenyloxy group, As radicals of the type indicated, the following such as an allyloxy or methallyloxy group, or especially should above all be mentioned: lower alkyl and alkenyl an alkoxy group. Alkoxy groups are, above all, lower radicals, especially radicals with not more than 7 car 55 alkoxy groups, such as methoxy, ethoxy, propoxy, iso bon atoms, such as methyl, ethyl, propyl or isopropyl propoxy, butoxy or pentoxy groups. radicals, and butyl, penty, hexyl and heptyl radicals An acylated hydroxyl group, that is to say an acyloxy which are straight or branched and are bonded at any group, is preferably derived from a carboxylic acid, for desired position, lower hydroxyalkyl radicals, such as example an aromatic carboxylic acid, such as benzoic 2-hyroxyethyl and 3-hydroxypropyl radicals, allyl and 60 acid, or above all from an aliphatic carboxylic acid, methallyl radicals, lower cycloalkyl and cycloalkenyl such as an alkanoic acid, for example butryic acid, radicals, such as cyclopentyl, cyclohexyl, cyclopropyl, propionic acid and especially acetic acid. cyclopentenyl and cycohexenyl radicals, which are A preferably represents a free hydroxyl group. unsubstituted or have one, two or more lower alkyl The propyl radical which substitutes the 9-position of Substituents, lower cycloalkyl-alkyl and cycloalkenyl 65 the anthracene nucleus is preferably only substituted alkyl radicals, such as cyclopentyl- and cyclohexenyl by the radicals A and R, but can be further substituted methyl, -ethyl and -propyl radicals which are unsubsti by lower alkyl radicals, for example those mentioned, tuted or have one, two or more lower alkylsubstituents. above all by methyl or ethyl radicals. The propyl radi 4,017,542 3 4. cal mentioned preferably possesses not more than one The new compounds possess valuable pharmacologi such alkyl radical as a substituent. cal properties, especially a psychotropic, for example In the new compounds, the position 11 and/or 12 can anti-depressant action, as can be demonstrated, for be substituted by lower alkyl radicals, for example example, in test animals. Thus, they show, for example, those mentioned, but the positions l l and 12 are pref an inhibition of the norardrenaline uptake into the erably unsubstituted. heart and brain of rats, when administered in doses of The new compounds are preferably unsubstituted in about 0.5 to about 10 mg/kg s.c., of about 0.2 to about positions 1-8 of the anthracene ring, but can possess 5 mg/kg i.v. or of about 2to about 100 mg/kg p.o. (Mai substituents in these positions, for example lower alkyl, tre et al., Biochem. Pharmacol., vol. 20, p. 2,169 alkoxy, alkenyloxy and/or alkylmercapto groups, lower 10 (1971)). Furthermore, they act as antagonists of reser alkylsulphonyl and/or alkanoyl groups, but above all pine-induced effects. For example, at doses of about 1 trifluoromethyl or halogen, such as fluorine, bromine to about 5 mg/kg i.p. or p.o. they antagonize reserpine and iodine, but very particularly chlorine, alkyl radicals induced hypothermia in mice (Askew, Life Sci., vol 10, to be mentioned particularly being methyl, ethyl, pro p.