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.