Europäisches Patentamt (19) European Patent Office Office européen des brevets (11) EP 0 478 954 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int. Cl.7: C07D 209/08, C07D 319/20, of the grant of the patent: A61K 31/40 18.10.2000 Bulletin 2000/42 (21) Application number: 91114456.6 (22) Date of filing: 28.08.1991 (54) Serotonin 5HT1A and 5HT1D agonists Serotonin 5HT1A und 5HT1D Agonisten Agonistes 5HT1A et 5HT1D de la sérotonine (84) Designated Contracting States: • Bernotas, Ronald C. AT BE CH DE DK ES FR GB GR IT LI LU NL SE Cincinnati, Ohio 45249 (US) • Sprouse, Jeffrey S. (30) Priority: 29.08.1990 US 574710 Cincinnati, Ohio 45215 (US) 30.07.1991 US 735700 (74) Representative: (43) Date of publication of application: VOSSIUS & PARTNER 08.04.1992 Bulletin 1992/15 Postfach 86 07 67 81634 München (DE) (73) Proprietor: MERRELL PHARMACEUTICALS INC. (56) References cited: Cincinnati, Ohio 45215-6300 (US) EP-A- 0 054 304 EP-A- 0 252 005 EP-A- 0 271 099 US-A- 2 725 386 (72) Inventors: • McDonald, Ian A. Remarks: Loveland, Ohio 45140 (US) The file contains technical information submitted • Dudley, Mark W. after the application was filed and not included in Somerville, Ohio 45064 (US) this specification Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 0 478 954 B1 Printed by Xerox (UK) Business Services 2.16.7 (HRS)/3.6 EP 0 478 954 B1 Description [0001] The present invention is directed to a new class of serotonin 5HT1A and 5HT1D agonists as well as pharma- ceutical and diagnostic compositions containing them for use in the treatment of anxiety, depression, migraine, stroke 5 and hypertension. [0002] In EP-A-0 271 099 aminopropionamide derivatives are disclosed which are described as having nootropic properties. [0003] EP-A-0 054 304 relates to compounds wherein benzodioxan is linked to alkylenedioxybenzene having hypo- tensive activity. 10 [0004] EP-A-0 252 005 discloses hydrogenated 1-benzooxacycloalkylpyridine carboxylic acid derivatives which are nootropic. [0005] US-A-2725386 discloses sympatholytics which are derivatives of amino lower fatty acid amides bearing a 2- (1,4-benzodioxan)methyl substituent. [0006] In accordance with the present invention, a new class of serotonin 5HT1A and 5HT1D agonists has been dis- 15 covered which can be described by the following formula: 20 25 in which B is represented by a -CH2- or -C2H4-alkylene bridging group; Alk is represented by a linear alkylene bridging 30 group containing from 2-5 carbon atoms, X and Y are each independently represented by hydrogen or C1-4 alkyl, R1 is represented by a substituent selected from the group consisting of hydrogen, halogen, C1-5 alkoxy, CF3, -NR2R3, R2 and R3 are each independently represented by H or a C1-4 alkyl; Het is represented by one of the following substituents: 35 40 in which R is represented by a substituent selected from the group consisting of hydrogen, OH, C1-5 alkoxy, or car- 45 bamoyl; or a pharmaceutically acceptable salt thereof. [0007] The compounds endompassed by Formula I above may also be represented by the following subgeneric for- mulae: in which R, B, Alk, X, Y and R1 are as defined above. 50 55 2 EP 0 478 954 B1 5 10 15 20 25 [0008] These compounds mimic the effects of serotonin at the 5HT1A and 5HT1D receptor. Pharmaceutical compo- 30 sitions containing them are useful in the treatment of anxiety, depression, migraine, stroke and hypertension. [0009] As used in this application: a) the term "halogen" refers to a fluorine, chlorine, or bromine atom; 35 b) the term "C1-4 alkyl" refers to a branched or straight chained alkyl group containing from 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc.; c) the term "C1-5 alkoxy" refers to a straight or branched alkoxy group containing from 1-5 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, n-pentoxy, etc.; 40 d) the term "pharmaceutically acceptable salt" refers to either a basic addition salt or an acid addition salt. e) Representative examples of linear alkylene groups having 2-5 carbon atoms include ethylene, propylene, and butylene, 45 f) the term "indolyl derivative" refers to a compound in which Het is represented by: 50 55 k) the term "benzodioxan derivative" refers to a compound in which Het is represented by: 3 EP 0 478 954 B1 5 10 [0010] The expression "pharmaceutically acceptable acid addition salts" is intended to apply to any non-toxic organic or inorganic acid addition salt of the base compounds represented by Formula I or any of its intermediates. Illus- trative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulphuric, and phosphoric acid and 15 acid metal salts such as sodium monohydrogen orthophosphate, and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include the mono-, di-, and tricarboxylic acids. Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxy-benzoic, phenylacetic, cinnamic, salicyclic, 2-phenoxy-benzoic, p-toluenesulfonic acid, and sulfonic acids such as methanesulfonic acid and 2-hydroxyethane sulfonic acid. Such salts can exist in either a hydrated or sub- 20 stantially anhydrous form. In general, the acid addition salts of these compounds are soluble in water and various hydrophilic organic solvents, and in comparison to their free base forms, generally demonstrate higher melting points. [0011] The expression "pharmaceutically acceptable basic addition salts" is intended to apply to any non-toxic organic or inorganic basic addition salts of the compounds represented by Formula I or any of its intermediates. Illus- trative bases which form suitable salts include alkali metal or alkaline-earth metal hydroxides such as sodium, potas- 25 sium, calcium, magnesium, or barium hydroxides; ammonia, and aliphatic, alicyclic, or aromatic organic amines such as methylamine, dimethylamine, trimethylamine, and picoline. Either the mono- or di-basic salts can be formed with those compounds. [0012] Some of the compounds of Formula I contain one or more asymmetric centers and will therefore exist as enantiomers and diastereomers. Any reference in this application to one of the compounds represented by Formula I, 30 or any intermediate thereof, should be construed as covering a specific optical isomer, a racemic mixture or a diaster- eomeric mixture. The specific optical isomers can be synthesized or can be separated and recovered by techniques known in the art such as chromatography on chiral stationary phases, resolution via chiral salt formation and subse- quent separation by selective crystallization, or enzymatic hydrolysis using stereoselective esterases as is known in the art. Alternatively, a chirally pure starting material may be utilized. 35 [0013] All of the compounds of Formula Ia contain an indole. This indole may be optionally substituted as is indi- cated by the presence of the R substituent. When R is represented by a substituent other than hydrogen, these substit- uents may appear at any of the positions 2, 4, 5, 6, or 7. [0014] All of the compounds represented by Formula Ib contain a benzodioxan. [0015] All of the compounds of Formula I contain a phenyl ring adjacent to the amide substituent. This phenyl ring 40 may also be substituted as is indicated by the R1 substituent. This substituent can be located at any of the ortho, meta, or para positions. [0016] The amino-alkylene chain connecting the benzodioxan or indole with the terminal phenyl ring may be further substituted as indicated by the X and Y, substituents. X and Y, may be represented by the same substituents or differing substituents. 45 [0017] Examples of compounds encompassed by the present invention include: a) 6-[[2-(5-hydroxy-1H-indol-3-yl)ethyl]amino]-N-[4-(trifluoromethyl)phenyl]-heptanamide; b) 7-[[2-(5-hydroxy-1H-indol-3-yl)ethyl]amino]-N-(4-methoxyphenyl)-octanamide; c) 6-[[2-(5-hydroxy-1H-indol-3-yl)ethyl]amino]-N-phenyl-heptanamide; 50 d) 5-[[2-(5-hydroxy-1H-indol-3-yl)ethyl]amino]-N-[4-(trifluoromethyl)phenyl]-hexanamide; e) 6-[[2-(5-hydroxy-1H-indol-3-yl)ethyl]amino]-N-(4-methoxyphenyl)-heptanamide; f) 4-[[2-(5-hydroxy-1H-indol-3-yl)ethyl]amino]-N-[4-(trifluoromethyl)phenyl]-pentanamide; g) 6-[[2-(5-methoxy-1H-indol-3-yl)ethyl]amino]-N-[4-(trifluoromethyl)phenyl]-heptanamide; h) 6-[[2-(5-hydroxy-1H-indol-3-yl)ethyl]methylamino]-N-[4-(trifluoromethyl)phenyl]-heptanamide; 55 i) 6-[[2-(5-hydroxy-1H-indol-3-yl)ethyl]amino]-N-(2-methoxyphenyl)-heptanamide; j) 6-[[2-(5-carboxamido-1H-indol-3-yl)ethyl]amino]-N-(4-methoxyphenyl)-heptanamide; k) 6-[[2-(1H-indol-3-yl)ethyl]amino]-N-[4-(trifluoro-methyl)phenyl]-hexanamide; l) 6-[[2-(5-hydroxy-1H-indol-3-yl)ethyl]amino]-N-[4-(1-propyl)phenyl]-hexanamide; 4 EP 0 478 954 B1 m) 5-[[2-(5-hydroxy-1H-indol-3-yl)ethyl]amino]-N-[4-(1-propyloxy)phenyl]-hexanamide; n) 6-[2-[(2,3-dihydro-1,4-benzodioxin-2-yl)ethyl]amino]-N-phenyl-hexanamide; o) 6-[(2,3-dihydro-1,4-benzodioxin-2-yl)methylamino]-N-[4-(trifluoromethyl)phenyl]-heptanamide; p) 6-[(2,3-dihydro-1,4-benzodioxin-2-yl)methylamino]-N-(4-methoxyphenyl)-heptanamide;