United States Patent (19) 11 Patent Number: 4,508,732 Hausberg et al. (45) Date of Patent: Apr. 2, 1985

54 BASIC ETHERS USEFUL AS ANTIDEPRESSANTAGENTS OTHER PUBLICATIONS 75) Inventors: Hans-Heinrich Hausberg, Joullie et al., Chem. Abstr., 82,72789e (1975) (Abstract Weiterstadt; Helmut Pricher, of Ger. Offen. 2,413,605). Heppenheim; Jirgen Uhl, Seeheim; Klosa, Jour. fir Prartische Chemie, 311, 183 (1969). Christoph Seyfried, Primary Examiner-Nicky Chan Seehiem-Jugenheim; Klaus Minck, Attorney, Agent, or Firm-Millen & White Ober-Ramstadt, all of Fed. Rep. of Germany 57 ABSTRACT 73) Assignee: Merck Patent Gesellschaft mit Basic ethers of the formula beschrankter Haftung, Darmstadt, Fed. Rep. of Germany 21) Appl. No.: 459,928 22 Filed: Jan. 21, 1983 Related U.S. Application Data wherein Z is CH3-NR2-CH2CH2-CHR1-, (1-R2-3- 62 Division of Ser. No. 216,454, Dec. 15, 1980, Pat. No. piperidyl)-CHR3-, (1-R2-2-piperidyl)-CH2-CHR3- or 4,376,123. 1-R2-3-R- hexahydroazepinyl; R1 is cyclopropyl or Ar; R2 is H, alkyl of 1-4 C atoms, alkenyl of 2-4 C 30 Foreign Application Priority Data atoms, cycloalkylalkyl of 4-8 C atoms or benzyl; R3 is H Dec. 13, 1979 IDE Fed. Rep. of Germany ...... 295O135 or Ar; R4 is H or alkyl of 1-4 Catoms, Y is -O-CHQl 51 Int. Cl...... A61K 31/36; A61K 31/135; CHQ2-CH2-, -O-CHQ-CHQ2-CO-, -O- CO7C 93/14 CQl-CQ2-CO- or -CH2-CHQl-CHQ2-CO-; Q1 52 U.S. Cl...... 514/466; 549/437; and Q2 are independently each H, alkyl of 1-4 Catoms, 564/352; 564/338; 564/337; 514/657 cycloalkyl or alkylcycloalkyl each of 3-6 total C atoms 58) Field of Search ...... 564/352, 338, 337; or Ar; and Ar is phenyl or phenyl substituted by F, Cl, 424/330, 282; 549/437 alkoxy or alkylthio, each of 1-4 C atoms, methylenedi oxy or CF3; with the proviso that when Z is (CH3)2N 56) References Cited CH2CH2-CHR in 7-position and Y is -O- U.S. PATENT DOCUMENTS C(C6H5)=CH-CO- or -O-C(C6H5)=C(CH3)-CO-, R1 is cyclopropyl, or phenyl substituted by F, Cl, alk 3,476,767 11/1969 Bencze ...... 564/352 3,506,653 4/1970 Fried ...... 564/352 oxy or alkylthio, each of 1-4C atoms, methylenedioxy 3,637,718 1/1972 Krämer et al. ... 546/196 or CF3; or a physiologically acceptable acid addition 4,194,009 3/1980 Molloy et al...... 564/352 salt thereof, have valuable pharmacological properties, e.g., are antidepressants. FOREIGN PATENT DOCUMENTS 1357633 6/1974 United Kingdom . 7 Claims, No Drawings 4,508,732 1. 2 poxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy. BASIC ETHERS USEFUL AS ANTIDEPRESSANT Alkenyl (in the radical R2) is preferably allyl and is also AGENTS vinyl, propenyl, isopropenyl, 1-butene-1-yl, 1-butene 2-yl, 2-butene-1-yl, 2-butene-2-yl, 3-butene-1-yl, 3 This is a division of application Ser. No. 216,454 filed 5 butene-2-yl, 2-methyl-1-propene-1-yl, 2-methyl-1-pro Dec. 15, 1980, now U.S. Pat. No. 4,376,123. pene-2-yl or 2-methyl-2-propene-1-yl. Cycloalkylalkyl (in the radical R2) is preferably cyclopropylmethyl, but BACKGROUND OF THE INVENTION is also, for example, 1-cyclopropylethyl, 2-cyclo The present invention relates to new basic ethers propylethyl, 1-, 2- or 3-cyclopropylpropyl, 1-cyclopro having valuable pharmacological properties. O pyl-1-methylethyl, 1-, 2-, 3- or 4-cyclopropylbutyl, 1 Certain related compounds are known from the Jour cyclopropyl-1-methylpropyl, 1-, 2-, 3-, 4- or 5-cyclopro nal flir praktische Chemie, Volume 311, pages 183 to pylpentyl, cyclobutylmethyl, 1-cyclobutylethyl, 2 186 (1969), in particular 7-(1-phenyl-3-dimethylamino cyclobutylethyl, 1-, 2- or 3-cyclobutylpropyl, 1-, 2-, 3 propoxy)-flavone and 3-methyl-7-(1-phenyl-3-dime or 4-cyclobutylbutyl, cyclopentylmethyl, 1-cyclopen thylaminopropoxy)-flavone. However, it is stated in this 15 tylethyl, 2-cyclopentylethyl, 1-, 2- or 3-cyclopentylpro reference that the disclosed substances exhibit "no phar pyl, cyclohexylmethyl, 1-cyclohexylethyl, 2-cyclohex macodynamically usable properties'. In light of this ylethyl or cycloheptylmethyl. Alkylthio (in the radical statement, the valuable pharmacological properties of Ar) is preferably methylthio, but is also ethylthio, n the present new compounds are particularly surprising. propylthio, isopropylthio, n-butylthio, isobutylthio, SUMMARY OF THE INVENTION 20 sec-butylthio or tert-butylthio. It is an object of this invention to provide new com The radical Air is preferably phenyl and secondarily pounds which can be used for the preparation of medi p-fluorophenyl, p-chlorophenyl, p-methoxyphenyl, 3,4- cannents. methylenedioxyphenyl or m-trifluoromethylphenyl, Upon further study of the specification and appended 25 and also o-fluorophenyl, m-fluorophenyl, o-chlorophe claims, further objects and advantages of this invention nyl, m-chlorophenyl, o-methoxyphenyl, m-methox will become apparent to those skilled in the art. yphenyl, o-, m- or p-methylthiophenyl, 2,3- These objects have been attained by providing new methylenedioxyphenyl, o-trifluoromethylphenyl or p basic ethers of Formula I trifluoromethylphenyl. If several radicals Air are pres 30 ent in the same molecule, they can be identical or differ ent from one another. In detail, R is preferably phenyl, p-fluorophenyl, p-chlorophenyl or p-methoxyphenyl; R2 is preferably H or methyl and secondarily is preferably ethyl, allyl, 35 cyclopropylmethyl or benzyl; R3 is preferably H or wherein Z is CH3-NR2-CH2CH2-CHR1-, (1-R2 phenyl; and R4 is preferably H or methyl. 3-piperidyl)-CHR3-, (1-R2-2-piperidyl)-CH2-CH Accordingly, the radical Z is preferably 1-phenyl-3- R3- or 1-R2-3-R-4-hexahydroazepinyl; R1 is cyclo dimethylaminopropyl and secondarily is preferably propyl or Ar; R2 is H, alkyl of 1-4 C atoms, alkenyl of 1-phenyl-3-methylaminopropyl, 1-phenyl-3N-benzyl 2-4 C atoms, cycloalkylalkyl of 4-8 C atoms or benzyl; 40 N-methylaminopropyl, (3-piperidyl)-methyl, a-(3- R3 is H or Ar; R' is H or alkyl of 1-4 C atoms; Y is piperidyl)-benzyl, (1-methyl-3-piperidyl)-methyl, al-(1- -O-CHQl-CHQ2-CH2-, --O-CHQl-CH methyl-3-piperidyl)-benzyl, 2-(2-piperidyl)-ethyl, 1 Q2-CO-, -O-CQl=CQ2-CO- or -CH2-CH phenyl-2-(2-piperidyl)-ethyl, 2-(1-methyl-2-piperidyl)- Ql-CHQ2-CO-; Q and Q2 are independently each ethyl, 1-phenyl-2-(1-methyl-2-piperidyl)-ethyl, 4-hex H, alkyl of 1-4 C atoms, cycloalkyl of 3-6 C atoms or 45 ahydroazepinyl, 1-methyl-4-hexahydroazepinyl, 3 Ar; and Ar is phenyl or phenyl substituted by F, Cl, methyl-4-hexahydroazepinyl and 1,3-dimethyl-4-hex alkoxy or alkylthio, each of 1-4 C atoms, methylenedi ahydroazepinyl, and also, for example, 1-phenyl-3- oxy or CF3; with the proviso that when Z is methylethylaminopropyl, 1-phenyl-3-(N-methyl-N- (CH3)2N-CH2CH2-CHR in 7-position and Y is allylamino)-propyl, 1-phenyl-3-(N-methyl-N-cyclo -O-C(C6H5)=CH-CO- Or 50 propylmethylamino)-propyl, (1-ethyl-3-piperidyl)- -O-C(C6H5)=C(CH3)-CO-, R is cyclopropyl or methyl, a-(1-ethyl-3-piperidyl)-benzyl, (1-allyl-3- phenyl which is substituted by F, Cl, alkoxy or alkylthio piperidyl)-methyl, a-(1-allyl-3-piperidyl)-benzyl, (1- each of 1-4C atoms, methylenedioxy or CF3; and the cyclopropylmethyl-3-piperidyl)-methyl, a-(1-cyclo physiologically acceptable acid addition salts thereof. propylmethyl-3-piperidyl)-benzyl, (1-benzyl-3- 55 piperidyl)-methyl, a-(1-benzyl-3-piperidyl)-benzyl, 2 DETALED DISCUSSION (1-ethyl-2-piperidyl)-ethyl, 1-phenyl-2-(1-ethyl-2- The invention relates to the basic ethers of Formula I piperidyl)-ethyl, 2-(1-allyl-2-piperidyl)-ethyl, 1-phenyl and to their physiologically acceptable acid addition 2-(1-allyl-2-piperidyl)-ethyl, 2-(1-cyclopropylmethyl-2- salts. piperidyl)-ethyl, 1-phenyl-2-(1-cyclopropylmethyl-2- In R2, Rt., Ql and Q2, alkyl is preferably methyl, and 60 piperidyl)-ethyl, 2-(1-benzyl-2-piperidyl)-ethyl, 1-phe also ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbu nyl-2-(1-benzyl-2-piperidyl)-ethyl, 3-ethyl-4-hexahy tyl or tert-butyl. Cycloalkyl (in the radicals Q and Q2) droazepinyl, 1-methyl-3-ethyl-4-hexahydroazepinyl, is preferably cyclopropyl, cyclobutyl, cyclopenty or 1-ethyl-4-hexahydroazepinyl, 1-allyl-4-hexahydroazepi cyclohexyl and also 1-methylcyclopropyl, 2-methylcy nyl, 1-cyclopropylmethyl-4-hexahydroazepinyl or 1 clopropyl, 1-, 2- or 3-methylcyclobutyl, 1-, 2- or 3 65 benzyl-4-hexahydroazepinyl, 1-cyclopropyl-3- methylcyclopentyl, 1-ethylcyclopropyl or 2-ethylcy methylaminopropyl, 1-p-fluorophenyl-3-methylamino clopropyl and the like. Alkoxy (in the radical Ar) is propyl, 1-p-chlorophenyl-3-methylaminopropyl, -m- preferably methoxy and also ethoxy, n-propoxy, isopro trifluoromethylphenyl-3-methylaminopropyl, 1-cyclo 4,508,732 3. propyl-3-dimethylaminopropyl, 1-p-fluorophenyl-3- dimethylaminopropyl, 1-p-chlorophenyl-3-dime thylaminopropyl or 1-m-trifluoromethylphenyl-3-dime thylaminopropyl. The radicals Q and Q2 can be identical or different. Preferably one of these radicals is H or alkyl of 1-3 C atoms and the other is Hor Ar, Arbeing, in particular, or one of its salts, with an amine of Formula III phenyl, p-fluorophenyl, p-chlorophenyl, p-methox yphenyl, 3,4-methylenedioxyphenyl or n-trifluorome Z-X III thylphenyl. O wherein X is Cl, Br, I or OH and Z is as defined above, The radical Y is, accordingly, preferably -O-CH or with one of its reactive derivatives; and, if appropri Q3-CHQ-CH2- (wherein the radicals Q3 and Q ate, in a resulting compound of Formula I, converting a are each H or alkyl of 1-3 C atoms, but one of these secondary amino group by treatment with an alkylating, radicals preferably is H; chromans), -O-CHAr-CH 15 alkenylating, cycloalkylating or benzylating agent into Q-CH2- (flavans), -O-CHQ3-CHAr-CH2 the corresponding tertiary amino group, or converting (iso-flavans), -O-CHQ-CHQ-CO- (chroma an N-benzyl group by treatment with a reducing agent nones), -O-CHAr-CHQ-CO- (flavanones), into an NH group, and/or converting a resulting base of -O-CHQ-CHAr-CO- (iso-flavanones), Formula I by treatment with an acid into one of its -O-CQ-CQ-CO- (chromones), -O-- physiologically acceptable acid addition salts. CArcCQ-CO- (flavones), -O-CQ-- The preparation of the compounds of Formula I is =CAr-CO- (isoflavones) or -CH2-CHQ3-CH effected in other respects in accordance with methods Q-CO- (tetralones). Among these, the isoflavones which are in themselves known such as are described in are particularly preferred and secondarily the tetralones 25 the literature (for example in the standard works such as and the flavones. Houben-Weyl, Methoden der Organischen Chemie Accordingly, the invention relates particularly to ("Methods of Organic Chemistry"), Georg-Thieme those compounds of the Formula I in which at least one Verlag, Stuttgart; or Organic Reactions, John Wiley of the mentioned radicals has one of the meanings indi and Sons, Inc., New York) and, in particular, under 30 reaction conditions such as are known and suitable for cated above, especially one of the preferred meanings these reactions. In these reactions it is also possible to indicated above. Some preferred groups of compounds make use of variants which are in themselves known, can be expressed by means of the partial Formulae Ia to but are not described in greater detail herein. Ic which follow, which correspond to the Formula I, The starting materials of Formulae II and III can, if and wherein the radicals not designated in greater detail 35 desired, also be formed in situ, in such a way that they have the meanings indicated for Formula I, but are not isolated from the reaction mixture, but are in wherein: in Ia: Z is CH3-NR2-CH2CH2-CHRl-; mediately reacted further to produce the compounds of R is phenyl; R2 is H, methyl or benzyl; Y is Formula I. -O-CH2CH2CH2-, -O-CHAr-CH2CH2-, The phenols of Formula II are in most cases known. -O-CH2-CH(C6H5)-CH2-, -O-CH2C When they are new, they can be prepared by methods H2-CO-, -O-CHAr-CHQ-CO-, -O-- which are in themselves known, for example by split CAT=CQ-CO-, -O-CH=CAr-CO- or ting corresponding benzyl or methyl ethers. -CH2CH2CH2-CO-, Ar is phenyl, p-fluorophenyl, In the bases of Formula III, the radical X is prefera p-chlorophenyl, p-methoxyphenyl, 3,4-methylenediox bly Cl or Br. Reactive derivatives of these bases in 45 clude, in particular, the reactive esters of the alcohols of yphenyl or m-trifluoromethylphenyl; and Q is H or Formula III (X= OH), preferably the corresponding alkyl of 1-3 C atoms; in Ib: Z is CH3-NR2-CH2C alkylsulfonates (wherein the alkyl group is of 1-6 C H2-CHR; R is phenyl; R2 is H, methyl or benzyl; and atoms) and the corresponding arylsulfonates (wherein Y is -O-C(C6H5)=CH-CO-, -O-CH=C(C6H the aryl group is of 6-10 C atoms), for example the 5)--CO- or -CH2CH2CH2-CO-; and in Ic: Z is 50 corresponding methanesulfonates, benzenesulfonates, CH3-NR2-CH2CH2-CHR1-; R is phenyl; R2 is H, p-toluenesulfonates, naphthalene-1-sulfonates or nap methyl or benzyl; and Y is -O-CH=C(C6H thalene-2-sulfonates. 5)-CO-. Some of the bases of Formula III are known. Those The compounds of Formula I can contain one or bases of Formula III which have not been disclosed more asymmetric carbon atoms. They can therefore 55 hitherto can be prepared by methods which are in then exist in the form of racemates and, if several asymmetric selves known in analogy to their use with known com pounds. Thus the compounds of Formula III (X = OH) carbon atoms are present, also in the form of mixtures of can be obtained, for example, by reducing correspond several racemates, as well as in various optically active ing esters or ketones of the type CH3-NR2-CH2C forms. H2-CO-Ri, (1-R2-3-piperidyl)-COO-alkyl, (1-R2 The present invention relates further to a process for 3-piperidyl)-CO-R3, (1-R2-2-piperidyl)-CH preparing the compound of Formula I and their physio 2-COO-alkyl, (1-R2-2-piperidyl)-CH2-CO-R3 or logically acceptable acid addition salts, comprising re 1-R2-3-R-hexahydroazepin-4-one, while the com acting a phenol of Formula II pounds of Formula III (X = Cl, Br or I) can be obtained 65 from the alcohols by means of inorganic halides, such as HO--G I SOCl2, PBr3 or HI, and the sulfonates can be obtained by esterifying the alcohols with the corresponding sul wherein G is the group fonyl chlorides. The tertiary amines among those of 4,508,732 5 6 Formula III (in which R2 is not H) are also accessible ing alkyl halides, for example methyl chloride, methyl from the secondary amines (III, R2 = H) by alkylation, bromide, methyl iodide, ethyl chloride, ethyl bromide, alkenylation, cycloalkylalkylation or benzylation. Con ethyl iodide and n-propyl chloride, bromide or iodide versely, the secondary amines (III, R2 = H) can be ob and the like, and also the corresponding dialkylsulfates, tained from the corresponding N-alkyl derivatives (III, 5 such as dimethylsulfate, and the corresponding sulfonic R2 = alkyl having 1-4 C atoms) by dealkylation by acid alkyl esters, such as p-toluenesulfonic acid methyl means of chloroformic acid ethyl ester. Furthermore, ester. A methyl group can also be introduced, for exam the amines of Formula III can be prepared by reducing ple by treatment with formic acid and aqueous formal corresponding pyridines or azepines. Thus, for example, dehyde solution, preferably by heating for several hours it is possible to metallize 2-methylpyridine with 10 at temperatures of 50 to 100° C. In general, the N-alky C6H5Li, subsequently to react the product with benzal lation is preferably effected in the presence or absence dehyde to give 1-phenyl-2-(2-pyridyl)-ethanol and to of an inert solvent at temperatures of about 0° to about reduce the latter to give 1-phenyl-2-(2-piperidyl)- 120° C., preferably of 40' to 100° C., and it is also possi ethanol. 1.-Methyl-4-hydroxy-hexahydroazepine is ac ble for a catalyst to be present, preferably a base such as cessible by ring enlargement of 1-methyl-4-piperidone 15 potassium tert-butylate. by means of CH2N2 to give 1-methyl-hexahydroazepin It is also possible to carry out alkylation by treating a 4-one and reduction of the latter using NaBH4. secondary base I (R2 = H) with an aldehyde or ketone in Before the reaction with III, the phenol II is prefera the presence of hydrogen and a hydrogenation catalyst bly first converted into a salt, particularly into a metal (for example Raney nickel) at temperatures of about 50 salt, for example an alkali metal salt (Li, Na or K salt) or 20 to 100 C. and pressures of about 1 to 200 atmospheres; a thallium salt. The phenol can be reacted with a rea thus, using acetone, the corresponding isopropyl com gent which forms metal salts, for example an alkali pound I (R2=isopropyl) is obtained. metal (for example Na), an alkali metal hydride or It is also possible to carry out alkylation in several amide (for example LiH, NaH, NaNH2 or KNH2), a stages. For example, a compound of Formula I (R2 = H) metal alcoholate (wherein the alcohol part preferably 25 can first be acylated in a manner which is in itself has 1-4C atoms, for example lithium methylate, ethyl known (for example acylated by treatment with acetic ate or tert-butylate, sodium methylate, ethylate or tert anhydride/pyridine) and the resulting N-acylation butylate, potassium methylate, ethylate or tert-butylate product (for example N-acetylation product) can then or thallium methylate, ethylate or tert-butylate), an be reduced to give the desired tertiary amine, for exam organometallic compound (for example butyllithium, 30 ple by means of a complex metal hyride, such as phenyllithium or phenylsodium) or a metal hydroxide, LiAlH4, in an inert solvent, such as diethyl ether or carbonate or bicarbonate (for example of Li, Na, Kor THF, preferably at temperatures of 20° to 60° C. Ca). The preparation of the phenolate is advantageously A secondary amine of Formula I (R2 = H) can be effected in the presence of a solvent or mixture of sol treated in a completely analogous manner with al vents. Examples of suitable solvents are hydrocarbons 35 kenylating, cycloalkylalkylating or benzylating agents (such as hexane, benzene, toluene or xylene), haloge (for example alkenyl halides, such as allyl chloride or nated hydrocarbons (such as CH2Cl2, CHCl3 or CC4), bromide, cyclopropylmethyl halides, such as cyclopro ethers (such as diethyl ether, diisopropyl ether, tetrahy pylmethyl chloride or bromide, or benzyl halides, such drofuran (THF), dioxane or diethylene glycol dimethyl as benzyl chloride or bromide), in which case com ether), amides, such as dimethylformamide (DMF), pounds of Formula I (R2 = alkenyl of 2-4 C atoms, alcohols (such as methanol or ethanol) or ketones (such cycloalkylalkyl of 4-8 C atoms or benzyl) are formed. as acetone or butanone). Furthermore, in a compound of Formula I (R2 =ben The phenol II, or its salt, is preferably reacted with zyl), the benzyl group can be removed by reduction by the amine III in the presence of a diluent, for example a method indicated in the literature, preferably by hy the solvent which has been used for the preparation of 45 drogenolysis in the presence of a noble metal catalyst or the salt, but this can be replaced by another solvent or with the aid of a dealkylating agent, for example diluted with another solvent. A particular variant con CICOOC2H5/NaOH. sists in carrying out the reaction in two phases (for A resulting base of Formula I can be converted by example in CH2Cl2/aqueous sodium hydroxide solu means of an acid into the appropriate acid addition salt. tion), in which case it is also possible to add a catalyst Acids suitable for this reaction are those which provide (for example a crown ether, an ammonium salt, such as physiologically acceptable salts. Thus it is possible to a trialkylbenzylammonium halide or a phosphonium use inorganic acids, for example sulfuric acid, hydrogen salt). The reaction is generally carried out at tempera halide acids, such as hydrochloric acid or hydrobromic tures of about -20° to 180° C., preferably 20' to 160° C. acid, phosphoric acids, such as orthophosphoric acid, The phenolate can also be formed in situ. IN this case 55 nitric acid or sulfamic acid, and also organic acids, in the phenol II and the amine III are allowed to react particular aliphatic, alicyclic, araliphatic, aromatic or with one another in the presence of a base. heterocyclic monobasic or polybasic carboxylic, sul A variant of the reaction consists in reacting a phenol fonic or sulfuric acids, such as formic acid, acetic acid, of Formula II with a hydroxyamine of Formula III propionic acid, pivalic acid, diethylacetic acid, malonic (X = OH) in the presence of a dehydrating agent, for 60 acid, succinic acid, pimelic acid, fumaric acid, maleic example an azodicarboxylic acid dialkyl ester, in the acid, lactic acid, tartaric acid, malic acid, benzoic acid, presence of triphenylphosphine in an inert solvent, such salicyclic acid, 2-phenylpropionic acid, citric acid, glu as THF, at about -10° to +30 C. conic acid, ascorbic acid, nicotinic acid, isonicotinic Furthermore, it is possible, if desired, to alkylate a acid, methanesulfonic acid, ethanesulfonic acid, resulting secondary amine of Formula I (R2 = H) on the 65 ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, nitrogen atom, in which case tertiary amines of Formula benzenesulfonic acid, p-toluenesulfonic acid, naph I (R2 = alkyl having 1-4C atoms) are obtained. Exam thalenemonosulfonic acid, naphthalenedisulfonic acid ples of suitable N-alkylating agents are the correspond and laurylsulfuric acid. 4,508,732 8 The free bases of Formula I can, if desired, be liber substances which are suitable for enteral (for example ated from their salts by treatment with strong bases, oral) or parenteral administration or for local applica such as sodium hydroxide or carbonate or potassium tion, and which do not react with the new compounds, hydroxide or carbonate. for example water, vegetable oils, benzyl alcohols, It has been found that the compounds of Formula I polyethylene glycols, gelatines, carbohydrates, such as and their physiologically acceptable acid addition salts lactose or starch, magnesium stearate, talc or petroleum possess valuable pharmacological properties. Thus they jelly. Tablets, dragees, capsules, syrups, elixirs, drops or exhibit, in particular, effects on the central nervous suppositories are especially used for enteral administra system, above all anti-depressant activity. In detail, it is tion; solutions, preferably oily or aqueous solutions, and possible to demonstrate a reserpine-antagonistic action O also suspensions, emulsions or implants are especially (which can be detected, for example on mice, in respect used for parenteral administration; and ointments, of reserpine, by a technique modeled on the method of creams or powders are especially used for topical appli Askew, Life Science, Volume 10 (1963), pages cation. The new compounds can also be lyophilized and 725-730), an anticataleptic action (which can be de the resulting lyophilizates can be used, for example, for tected, for example on rats, in respect of tetrabenazine, 15 the preparation of injection preparations. The formula by a technique modeled on the method of Giurgea et al., tions indicated can be sterilized and/or can contain Medicina Experimentalis, Volume 9, (1963), pages adjuvants, such as lubricants, preservatives, stabilizing 249-262) and an antiptotic action (which can be de agents and/or wetting agents, emulsifiers, salts for regu tected, for example in respect to reserpine, by a tech lating the osmotic pressure, buffer substances, color nique modeled on the methodology of Domenjoz and 20 ants, flavoring substances and/or aroma generating Theobald, Arch. int. pharmacodyn., Volume 120 substances. If desired, they can also contain one or more (1959), pages 450 et seq., using the evaluation according additional active compounds, for example one or more to Rubinet al., J. Pharmacol. Exp. Therap., Volume 120 vitamins. (1957), pages 125-136). Furthermore, the action of 5 The invention further relates to the use of the com hydroxy-tryptophan in mice (method similar to that of 25 Ross et al., Acta pharmacol. et toxicol., Volume 39 pounds of Formula I and their physiologically accept (1976), pages 152-166) can be potentiated, and the ef able acid addition salts in combating diseases, particu fects on the central nervous system of excitation and larly depressions of various etiologies and symp increase in temperature, which can be initiated by D tomatologies, and to their use in the therapeutic treat amphetamine sulfate (for example 1.5 mg/kg adminis 30 ment of the human or animal body. tered subcutaneously 1 hour after the test substance, In this connection, the substances of this invention which is also administered subcutaneously) and aggre are generally administered in a manner analogous to gation (putting 5 rats together in a glass container) that of known psychopharmacological agents which are (methodology according to Miller-Calgan et al., in commercially available (for example Imipramine), pref. Zippel, H. P. (Ed.): Memory and Transfer of Informa 35 erably in dosages of about 2-500 mg, particularly of tion, Plenum Press, New York-London, 1973, pages 10-50 mg, per dosage unit. The daily dosage is prefera 87-125), can be increased and/or prolonged. The sub bly about 0.05 to 10 mg/kg of body weight. The partic stances have an effect on the biogenous amines of CNS. ular dose for each specific patient depends, however, on Thus, for example, in vitro they lead to inhibition of the a very wide variety of factors, for example on the activ absorption of nor-adrenalin, 5-hydroxytryptamine and ity of the particular compound employed, on the age, dopamine (methodology: Kannegieger et al., Biochem. body weight, general state of health, sex, and diet of the Pharmacol., Volume 22 (1973), pages 73-84) in synapto patient, on the time and route of administration, on the somes, and in vivo they inhibit the liberation, within the excretion rate and combination of medicaments and on brain, of catecholamine and serotonin which is induced the severity of the particular disease to which the ther by tyramine derivatives (methodology: Carlsson et al., 45 apy applies. Oral administration is preferred. Europ. J. Pharmacol., Volume 5 (1969), pages 357-366; Without further elaboration, it is believed that one 367-373). A hypotensive action and a spasmolytic ac skilled in the art can, using the preceding description, tion are also produced, and these can be determined by utilize the present invention to its fullest extent. The methods in current use for this purpose. following preferred specific embodiments are, there Compounds of Formula I and their physiologically 50 fore, to be construed as merely illustrative, and not acceptable acid addition salts can, therefore, be used as limitative of the remainder of the disclosure in any way medicinally active compounds and also as intermediate whatsoever. In the following examples, all temperatures products for the preparation of other medicinally active are set forth uncorrected in degrees Celsius; unless oth compounds. erwise indicated, all parts and percentages are by Thus, the invention further relates to the use of the 55 weight. compounds of Formula I and their physiologically ac Each of the compounds of Formula I mentioned in ceptable salts for the preparation of pharmaceutical the examples which follow is particularly suitable for formulations, particularly by a non-chemical route. In the preparation of pharmaceutical formulations. this connection they can be brought into a suitable dos In the following examples, "customary working-up" age form together with at least one excipient or adju denotes: vant and, if appropriate, in combination with one or Water is added if necessary, the mixture is extracted more other active compound(s). with an organic solvent, such as benzene, chloroform or The present invention further relates to agents, espe methylene chloride, the phases are separated and the cially pharmaceutical formulations, containing a com organic phase is dried over sodium sulfate, the mixture pound of Formula I and/or one of its physiologically 65 is filtered, the filtrate is evaporated and the product is acceptable acid addition salts. These formulations can purified by chromatography and/or crystallization. be employed as medicaments in human or veterinary The Rf values were obtained on silica gel using 8:2 medicine. Suitable excipients are organic or inorganic toluene/triethylamine, unless otherwise indicated. 4,508,732 9 10 25 . 7-(1,3-Dimethyl-4-hexahydroazepinyloxy)-flavan. EXAMPLE 1. 26. 6-(1-Phenyl-3-methylaminopropoxy)-isoflavan. A solution of 23.8g of 7-hydroxyisoflavone in 250 ml 27 . 7-(1-Phenyl-3-methylaminopropoxy)-isoflavan. of 0.5N ethanolic KOH is evaporated, the residue is 28 . 6-(1-Phenyl-3-dimethylaminopropoxy)-isoflavan. dissolved in 200 ml of DMF and the solution is heated 5 29 . 7-(1-Phenyl-3-dimethylaminopropoxy)-isoflavan, to 150; a solution of 20 g of 1-chloro-1-phenyl-3-dime m.p. 98-100'. thylaminopropane in 50 ml of DMF is added, while 30 . 6-(1-Phenyl-3-N-benzyl-N-methylaminopropox stirring. The mixture is stirred for 1.5 hours at 150 and y)-isoflavan. 7-(1-phenyl-3-dimethylaminopropoxy)-isoflavone is 31. 7-(1-Phenyl-3-N-benzyl-N-methylaminopropox precipitated by adding water. M. p. 128-130' (from 10 y)-isoflavan. acetone). Hydrochloride, m.p. 259-260. 32 . 6-a-(1-Methyl-3-piperidyl)-benzyloxy)-isoflavan. EXAMPLES 2 TO 220 33 . 7-a-(1-Methyl-3-piperidyl)-benzyloxy)-isoflavan. 34 . 6-2-(1-Methyl-2-piperidyl)-ethoxy)-isoflavan. The following are obtained analogously to Example 1 35 . 7-2-(1-Methyl-2-piperidyl)-ethoxy)-isoflavan. by etherifying the Na salts of 6-hydroxychroman, 7 15 36 . 6-(1,3-Dimethyl-4-hexahydroazepinyloxy)-iso hydroxychroman, 6-hydroxyflavan, 7-hydroxyflavan, flavan. 6-hydroxyisoflavan, 7-hydroxyisoflavan, 6-hydroxy 37. 7-(1,3-Dimethyl-4-hexahydroazepinyloxy)-iso chromanone, 7-hydroxychromanone, 6-hydroxyflava flavan. none, 7-hydroxyflavanone, 6-hydroxyisoflavanone, 7 38. 6-(1-Phenyl-3-methylaminopropoxy)-chroma hydroxyisoflavanone, 6-hydroxychromone, 7-hydroxy 20 chromone, 5-, 6-, 7- or 8-hydroxyflavone, 5-, 6-, 7- or Ole. 8-hydroxyisoflavone or 5-, 6- or 7-hydroxytetralone 39. 7-(1-Phenyl-3-methylaminopropoxy)-chroma with 1-chloro-1-phenyl-3-methylaminopropane, 1 One. chloro-1-phenyl-3-dimethylaminopropane, 1-chloro-1- 40 6-(1-Phenyl-3-dimethylaminopropoxy)-chroma phenyl-3-N-benzyl-N-methylaminopropane, 3 25 none, hydrochloride, m.p. 188-191'. chloromethylpiperidine, 3-(a-chlorobenzyl)-piperidine, 41. 7-(1-Phenyl-3-dimethylaminopropoxy)-chroma 1-methyl-3-chloromethylpiperidine, 1-methyl-3-(o- OC. chlorobenzyl)-piperidine, 2-(2-chloroethyl)-piperidine, 42 6-(1-Phenyl-3-N-benzyl-N-methylaminopropox 2-(2-chloro-2-phenylethyl)-piperidine, 1-methyl-2-(2- y)-chromanone. chloroethyl)-piperidine, 1-methyl-2-(2-chloro-2- 30 43. 7-(1-Phenyl-3-N-benzyl-N-methylaminopropox phenylethyl)-piperidine, 1-benzyl-2-(2-chloroethyl)- y)-chromanone. piperidine, 4-chlorohexahydroazepine, 1-methyl-4- 44. 6-a-(1-Methyl-3-piperidyl)-benzyloxy)-chroma chlorohexahydroazepine, 3-methyl-4-chlorohexahy Ole. droazepine and 1,3-dimethyl-4-chlorohexahydroaze 45 . 7-a-(1-Methyl-3-piperidyl)-benzyloxy-chroma pine or the corresponding bromine compounds: 35 OC. 2. 6-(1-Phenyl-3-methylaminopropoxy)-chroman, 46 . 6-2-(1-Methyl-2-piperidyl)-ethoxy)-chromanone. hydrochloride, m.p. 164. 47 . 7-2-(1-Methyl-2-piperidyl)-ethoxy-chromanone, 3. 7-(1-Phenyl-3-methylaminopropoxy)-chroman. hydrochloride, m.p. 182-184. 4. 6-(1-Phenyl-3-dimethylaminopropoxy)-chroman, 48. 6-(1,3-Dimethyl-4-hexahydroazepinyloxy)- hydrochloride, m.p. 137-139. 40 chromanone. 5. 7-(1-Phenyl-3-dimethylaminopropoxy)-chroman, 49. 7-(1,3-Dimethyl-4-hexahydroazepinyloxy)- hydrochloride, m.p. 182-183°. chromanone. 6. 6-(1-Phenyl-3-N-benzyl-N-methylaminopropoxy)- 50 . 6-(1-Phenyl-3-methylaminopropoxy)-flavanone. chroman, hydrochloride, m.p. 139-140°. 51 . 7-(1-Phenyl-3-methylaminopropoxy)-flavanone. 7. 7-(1-Phenyl-3-N-benzyl-N-methylaminopropoxy)- 45 52 . 6-(1-Phenyl-3-dimethylaminopropoxy)-flavanone. chroman. 53 . 7-(1-Phenyl-3-dimethylaminopropoxy)-flavanone. 8. 6-a-(1-Methyl-3-piperidyl)-benzyloxy)-chroman. 54. 6-(1-Phenyl-3-N-benzyl-N-methylaminopropox 9. 7-a-(1-Methyl-3-piperidyl)-benzyloxy)-chroman. y)-flavanone. 10. 6-2-(1-Methyl-2-piperidyl)-ethoxy-chroman, hy 55. 7-(1-Phenyl-3-N-benzyl-N-methylaminopropox drochloride, m.p. 100-103'. 50 y)-flavanone. 11. 7-2-(1-Methyl-2-piperidyl)-ethoxy-chroman. 56. 6-a-(1-Methyl-3-piperidyl)-benzyloxy)-flava 12. 6-(1,3-Dimethyl-4-hexahydroazepinyloxy)-chro OC. an. 57. 7-a-(1-Methyl-3-piperidyl)-benzyloxy)-flava 13. 7-(1,3-Dimethyl-4-hexahydroazepinyloxy)-chro Ole. al. 55 58 . 6-2-(1-Methyl-2-piperidyl)-ethoxy-flavanone. 14. 6-(1-Phenyl-3-methylaminopropoxy)-flavan. 59 . 7-2-(1-Methyl-2-piperidyl)-ethoxy-flavanone. 15. 7-(1-Phenyl-3-methylaminopropoxy)-flavan. 60 . 6-(1,3-Dimethyl-4-hexahydroazepinyloxy)-flava 16. 6-(1-Phenyl-3-dimethylaminopropoxy)-flavan. One. 17.7-(1-Phenyl-3-dimethylaminopropoxy)-flavan. 61. 7-(1,3-Dimethyl-4-hexahydroazepinyloxy)-flava 18. 6-(1-Phenyl-3-N-benzyl-N-methylaminopropox 60 One. y)-flavan. 62. 6-(1-Phenyl-3-methylaminopropoxy)-isoflava 19. 7-(1-Phenyl-3-N-benzyl-N-methylaminopropox Oe. y)-flavan. 63. 7-(1-Phenyl-3-methylaminopropoxy)-isoflava 20. 6-a-(1-Methyl-3-piperidyl)-benzyloxy-flavan. One. 21, 7-a-(1-Methyl-3-piperidyl)-benzyloxy-flavan. 65 64 . 6-(1-Phenyl-3-dimethylaminopropoxy)-isoflava 22. 6-2-(1-Methyl-2-piperidyl)-ethoxy-flavan. O6. 23. 7-2-(1-Methyl-2-piperidyl)-ethoxy-flavan. 65. 7-(1-Phenyl-3-dimethylaminopropoxy)-isoflava 24.6-(1,3-Dimethyl-4-hexahydroazepinyloxy)-flavan. One.

4,508,732 17 18 306. 6-(1-Phenyl-3-dimethylaminopropoxy)-3'-tri heated on a waterbath until evolution of gas ceases and fluoromethyl-isoflavone. is cooled, poured onto ice and worked up in the custom 307. 7-(1-Phenyl-3-dimethylaminopropoxy)-3'-tri ary manner to give 7-(1-phenyl-3-dimethylamino fluoromethyl-isoflavone, hydrochloride, m.p. propoxy)-isoflavone. M. p. 128-130'. 174-176. 5 308. 6-(1-p-Fluorophenyl-3-dimethylaminopropoxy)- EXAMPLE 319 4'-fluoro-isoflavone. 12g of allyl bromide and 26 g of anhydrous potassium 309. 7-(1-p-Fluorophenyl-3-dimethylaminopropoxy)- carbonate are added to a solution of 38.5g of 7-(1-phe 4'-fluoro-isoflavone, m.p. 121-123; hydrochlo nyl-3-methylaminopropoxy)-isoflavone in 1 of abso ride, m.p. 229-230. O 310. 6-(1-p-Fluorophenyl-3-dimethylaminopropoxy)- lute toluene and the mixture is boiled for 20 hours, 4'-chloro-isoflavone. cooled, poured into water and worked up in the cus 311. 7-(1-p-Fluorophenyl-3-dimethylaminopropoxy)- tomary manner to give 7-(1-phenyl-3-N-allyl-N- 4'-chloro-isoflavone, hydrochloride, m.p. methylaminopropoxy)-isoflavone. Hydrochloride, m.p. 213-215. 5 192-194. 312. 6-(1-p-Fluorophenyl-3-dimethylaminopropoxy)- 3'-trifluoromethyl-isoflavone. EXAMPLES 32O TO 326 313. 7-(1-p-Fluorophenyl-3-dimethylaminopropoxy)- The following are obtained analogously to Example 3'-trifluoromethyl-isoflavone, hydrochloride, m.p. 319 using allyl bromide, n-butyl iodide, cyclopropyl 174-176. methyl chloride or benzyl bromide: 20 320. 6-(1-Phenyl-3-N-allyl-N-methylaminopropoxy)- EXAMPLE 314 isoflavone. 23.8g of 7-hydroxyisoflavone is dissolved in 500 ml 321. 6-(1-Phenyl-3-N-n-butyl-N-methylaminopropox of absolute toluene, 7.1 ml of thallium-(I) ethylate are y)-isoflavone. added and the mixture is stirred for 1 hour at 20. After 25 322. 7-(1-Phenyl-3-N-n-butyl-N-methylaminopropox evaporation, the residue is dissolved in 100 ml of abso y)-isoflavone. lute acetonitrile, 20 g of 1-chloro-1-phenyl-3-dime 323. 6-(1-Phenyl-3N-cyclopropylmethyl-N- thylaminopropane is added and the mixture is boiled for methylaminopropoxy)-isoflavone. 3 hours while stirring and is evaporated. Working up in 324. 7-(1-Phenyl-3-N-cyclopropylmethyl-N- the customary manner gives 7-(1-phenyl-3-dime- 30 methylaminopropoxy)-isoflavone, hydrochloride, thylaminopropoxy)-isoflavone. M. p. 128-130'. m.p. 225-227. 325. 6-(1-Phenyl-3-N-benzyl-N-methylaminopropox EXAMPLE 315 y)-isoflavone. 2.7 g of azodicarboxylic acid ethyl ester is dissolved 326. 7-(1-Phenyl-3-N-benzyl-N-methylaminopropox in 25 ml of THF, 4 g of triphenylphosphine is added, 35 y)-isoflavone. while cooling and stirring; a solution of 2 g of 1-chloro 1-phenyl-3-dimethylaminopropane in 15 ml of THF is EXAMPLES 327 TO 331 then added dropwise, followed by a solution of 2.38g of The following are obtained analogously to Example 1 7-hydroxyisoflavone in 10 ml of THF and the mixture is from the corresponding Na phenolates and the corre stirred for 2 hours at 0'. After being allowed to stand 40 sponding basic chlorides: overnight at 20, the mixture is worked up in the cus 327. 6-(1-Cyclopropyl-3-methylaminopropoxy)-fla tomary manner. This gives 7-(1-phenyl-3-dime vone, Rf 0.45 (8:2 chloroform/triethylamine). thylaminopropoxy)-isoflavone. M. p. 128-130'. 328. 6-(1-Phenyl-3-dimethylaminopropoxy)-4'- methoxyflavone, m.p. 125-127, EXAMPLE 316 45 200 ml of 50% aqueous sodium hydroxide solution 329. 6-(1-Phenyl-3-dimethylaminopropoxy)-3',4'- and 1 g of triethylbenzylammonium chloride are added methylenedioxy-flavone, m.p. 159-160. to a solution of 23.8g of 7-hydroxyisoflavone in 100 ml 330. 7-(1-Cyclopropyl-3-methylaminopropoxy)-chro of CH2Cl2, 20g of 1-chloro-1-phenyl-3-dimethylamino man, Rf 0.24 (methanol). propane is added dropwise while stirring and stirring is 331. 7-(1-Cyclopropyl-3-dimethylaminopropoxy)- continued for a further hour. Working up in the custom chroman, Rf 0.74 (8:2 chloroform/triethylamine). ary manner gives 7-(1-phenyl-3-dimethylaminopropox The following examples relate to pharmaceutical y)-isoflavone. M. p. 128-130'. formulations containing amines of Formula I or their acid addition salts. EXAMPLE 317 55 A solution of 20 g of 7-(1-phenyl-3-N-benzyl-N- EXAMPLE A: Tablets methylaminopropoxy)-isoflavone in 400 ml of methanol A mixture of 1 kg of 7-(1-phenyl-3-dimethylamino is hydrogenated over 3 g of 5% Pd-on-C at 20 and 1 propoxy)-isoflavone hydrochloride, 4 kg of lactose, 1.2 atmosphere until absorption of hydrogen ceases. The kg of potato starch, 0.2 kg of talc and 0.1 kg of magne mixture is filtered and evaporated to give 7-(1-phenyl-3- 60 sium stearate is compressed in a customary manner to methylaminopropoxy)-isoflavone, hydrochloride, m.p. give tablets, in such a way that each tablet contains 10 210"-211. mg of active compound. EXAMPLE 318 EXAMPLE B: Dragees 30 g of formic acid, is added dropwise to 38.5 g of 65 Tablets are compressed analogously to Example A 7-(1-phenyl-3-methylaminopropoxy)-isoflavone, while and are then coated in a customary manner with a coat stirring and cooling, and 7 g of 25% formaldehyde ing consisting of sucrose, potato starch, talc, tragacanth solution is then added dropwise at 20. The mixture is and colorant. 4,508,732 19 20 EXAMPLE C: Capsules 2 kg of 7-(1-phenyl-3-dimethylaminopropoxy)-isofla vone hydrochloride is filled into hard gelatine capsules in a customary manner in such a way that each capsule contains 20 mg of the active compound. wherein Z is CH3-NR2-CH2CH2-CHR1-; R1 is EXAMPLE D: AMPOULES cyclopropyl or Ar; R2 is H, alkyl of 1-4C atoms, alke A solution of 1 kg of 7-(1-phenyl-3-dimethylamino nyl of 2-4 C atoms, cycloalkylalkyl of 4-8 C atoms or propoxy)-isoflavone hydrochloride in 30 l of twice-dis 10 benzyl; Y is -CH2-CHQ-CHQ2-CO-; Q and Q2 tilled water is filtered under sterile conditions and filled are independently each H, alkyl of 1-4C atoms, cyclo into ampoules, which are lyophilized under sterile con alkyl or alkylcycloalkyl each of 3-6 total C atoms or Ar; and Ar is phenyl or phenyl substituted by F, Cl, ditions and sealed under sterile conditions. Each an alkoxy or alkylthio, each of 1-4C atoms, methylenedi poule contains 10 mg of active compound. 15 oxy or CF3; Tablets, dragees, capsules and ampoules containing or a physiologically acceptable acid addition salt one or more of the remaining active compounds of thereof. Formula I and/or their physiologically acceptable acid 2. An ether of claim 1 wherein, Z is CH3-NR addition salts can be obtained analogously. 2-CH2CH2-CHR1; R1 is phenyl; R2 is H, methyl or The preceding examples can be repeated with similar 20 benzyl; and Y is -CH2CH2CH2-CO-. success by substituting the generically or specifically 3. A compound of claim 1, wherein R is cyclopropyl. described reactants and/or operating conditions of this 4. A compound of claim 1, wherein R is Ar. invention for those used in the preceding examples. 5. A pharmaceutical composition comprising an an From the foregoing description, one skilled in the art tidepressantly effective amount of a compound of claim 25 1 and a pharmaceutically acceptable carrier. can easily ascertain the essential characteristics of this 6. A composition of claim 5 containing 2-500 mg of invention, and without departing from the spirit and the antidepressantly active compound. scope thereof, can make various changes and modifica 7. A method of treating depression in a patient in need tions of the invention to adapt it to various usages and of such treatment comprising administering to the pa conditions. 30 tient an antidepressantly effective amount of a com What is claimed is: pound of claim 1. 1. A basic ether of the formula s : *k sk k

35

45

55

60

65