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(12) United States Patent (10) Patent No.: US 6,627,639 B2 Stack Et Al

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(12) United States Patent (10) Patent No.: US 6,627,639 B2 Stack Et Al USOO6627639B2 (12) United States Patent (10) Patent No.: US 6,627,639 B2 Stack et al. (45) Date of Patent: Sep. 30, 2003 (54) USES FOR INDOLETETRAHYDROPYRIDINE 6,458.802 B1 10/2002 Tran et al. DERIVATIVES OF 2,3-DIHYDRO-7H-14) DIOXINO-2,3-EINDOLE FOREIGN PATENT DOCUMENTS WO WO 91/13872 9/1991 (75) Inventors: Gary P. Stack, Ambler, PA (US); WO WO 97/23485 7/1997 Megan Tran, Hoboken, NJ (US); WO WO 98/294.15 7/1998 Byron A. Bravo, Eagleville, PA (US) WO WO 98/40386 9/1998 (73) Assignee: Wyeth, Madison, NJ (US) OTHER PUBLICATIONS (*) Notice: Subject to any disclaimer, the term of this CA 10:16, Gary P. 1999. patent is extended or adjusted under 35 CA 128: 308493, Gary P. Stack, 1998. U.S.C. 154(b) by 0 days. Primary Examiner Jane Fan (74) Attorney, Agent, or Firm-Rebecca R. Barrett (21) Appl. No.: 10/339,511 (57) ABSTRACT (22) Filed: Jan. 9, 2003 O O Compounds of the formula (65) Prior Publication Data US 2003/0134870 A1 Jul. 17, 2003 Related U.S. Application Data R1 O (63) Continuation-in-part of application No. 10/131,339, filed on X N Apr. 24, 2002. (60) Provisional application No. 60/286,575, filed on Apr. 26, 2 N 2001. HN O (51) Int. Cl. ............................................ A61K 31/4433 elease (52) U.S. Cl. ........................................ 514/300; 514/338 R2 (58) Field of Search .................................. 514/338,300 (56) References Cited are useful in the treatment of central nervous System disor ders including depression, obsessive compulsive disorder, U.S. PATENT DOCUMENTS panic attacks, generalized anxiety disorder, Sexual dysfunction, eating disorders and addictive disorders caused 5,318,988 A 6/1994 Schohe-Loop et al. 5,371,094. A 12/1994 Heine et al. by ethanol or cocaine abuse. 5,741,789 A 4/1998 Hibschman et al. 5,869,490 A 2/1999 Stack 2 Claims, No Drawings US 6,627,639 B2 1 2 USES FOR INDOLETETRAHYDROPYRIDNE wherein DERIVATIVES OF 2,3-DIHYDRO-7H-14) R", R, R", Rand R7 are, independently, hydrogen, halo, DIOXINO-2,3-EINDOLE cyano, carboxamido, carboalkoxy of two to Six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 BACKGROUND OF THE INVENTION carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido This application is a continuation-in-part of co-pending of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 application Ser. No. 10/131,339, filed on Apr. 24, 2002, carbon atoms, which claims priority from provisional application Serial No. 1O R is hydrogen, halogen, alkyl of 1 to 6 carbon atoms or 60/286,575, filed on Apr. 26, 2001, the entire disclosure of trifluoromethyl; which is hereby incorporated by reference. R is hydrogen or alkyl of 1 to 6 carbon atoms; Major depression is a Serious health problem affecting Z is CR7 or N; more than 5% of the population, with a life-time prevalence and pharmaceutically acceptable Salts thereof. of 15-20%. 15 In some preferred embodiments of the invention R is Selective Serotonin reuptake inhibitors have produced hydrogen, halo, cyano, trifluoromethyl, alkyl of 1 to 6 Significant Success in treating depression and related ill carbon atoms, or alkoxy of 1 to 6 carbon atoms. In Still more neSSes and have become among the most prescribed drugs. preferred embodiments of the invention R is hydrogen or They nonetheless have a slow onset of action, often taking alkyl of 1 to 6 carbon atoms. R' is still more preferably Several weeks to produce their full therapeutic effect. hydrogen. Furthermore, they are effective in fewer than two-thirds of In other embodiments of the invention R is hydrogen, patients. trifluoromethyl, or alkyl of one to six carbon atoms. In still Serotonin selective reuptake inhibitors (SSRIs) are well more preferred embodiments of the present invention, R is known for the treatment of depression and other conditions. hydrogen or lower alkyl. SSRIs work by blocking the neuronal, reuptake of serotonin, 25 R. R" and Rare independently selected from hydrogen, thereby increasing the concentration of Serotonin in the halo, cyano, carboxamido, alkyl of 1 to 6 carbon atoms, and Synaptic space, and thus increasing the activation of alkoxy of 1 to 6 carbon atoms in some embodiments of the postsynaptic Serotonin receptors. invention. More preferably R. R' and Rare independently However, although a single dose of an SSRI can inhibit Selected from halogen, cyano and hydrogen. Still more the neuronal Serotonin transporter which would be expected preferably, R, R and R are independently selected from to increase Synaptic Serotonin, long-term treatment is halogen and hydrogen. required before clinical improvement is achieved. Where Z is CR, R is preferably hydrogen, halo, cyano, It has been suggested that the SSRIs increase the seroto carboxamido, alkyl of 1 to 6 carbon atoms, or alkoxy of 1 to nin levels in the vicinity of the Serotonergic cell bodies and 6 carbon atoms, more preferably R' is halogen, cyano or that the excess Serotonin activates Somatodendritic 35 hydrogen. Still more preferably R' is halogen or hydrogen. autoreceptors, 5-HT1A receptors, causing a decrease in Sero R is preferably hydrogen or lower alkyl. tonin release in major forebrain areas. This negative feed Most preferred are compounds where R' is hydrogen, back limits the increment of Synaptic Serotonin that can be halo, cyano, trifluoromethyl, alkyl of 1 to 6 carbon atoms or induced by antidepressants. alkoxy of 1 to 6 carbon atoms, R is hydrogen, trifluorom 40 ethyl or alkyl of 1 to 6 carbon atoms, R, R' and R are A 5-HT1A antagonist would limit the negative feedback independently Selected from hydrogen, halo and cyano and and should improve the efficacy of the Serotonin reuptake R is hydrogen. mechanism. (Perez, V., et al., The Lancet, 349:1594–1597 Still more preferred compounds of the present invention (1997)). Such a combination therapy would be expected to are compounds where R' is hydrogen, R is hydrogen or Speed up the effect of the Serotonin reuptake inhibitor. 45 lower alkyl, R, R' and Rare independently selected from Thus, it is highly desirable to provide improved com hydrogen and halogen, Z is CR, R is hydrogen, and R is pounds which both inhibit serotonin reuptake and which are hydrogen or halogen. antagonists of the 5-HT1A receptor. This invention relates to both the R and S Stereoisomers of the 2,3-dihydro-7H-1,4-dioxino 2,3-eindole derivatives DESCRIPTION OF THE INVENTION 50 as well as to mixtures of the R and S stereoisomers. In accordance with this invention, there is provided a Throughout this application, the name of the product of this group of novel compounds of the formula: invention, where the absolute configuration of the 2,3- dihydro-7H-1,4-dioxino 2,3-eindole derivative is not indicated, is intended to embrace the individual R and S 55 enantiomers as well as mixtures of the two. In Some pre ferred embodiments of the present invention the S stereoi Somer is preferred. Where a Stereoisomer is preferred, it may in Some embodiments, be provided substantially free of the corre 60 sponding enantiomer. Thus, an enantiomer Substantially free of the corresponding enantiomer refers to a compound which is isolated or Separated via Separation techniqueS or prepared free of the corresponding enantiomer. Substantially free, as used herein means that the compound is made up of 65 a Significantly greater proportion of one Stereoisomer. In preferred embodiments the compound is made up of at least about 90% by weight of a preferred stereoisomer. In other US 6,627,639 B2 3 4 embodiments of the invention, the compound is made up of an epihalohydrin in the presence of a base Such as Sodium at least about 99% by weight of a preferred stereoisomer. hydride to produce (4) and heated in a high boiling Solvent Preferred StereoisomerS may be isolated from racemic mix Such as mesitylene or Xylene to effect both Claisen rear tures by any method known to those skilled in the art, including high performance liquid chromatography (HPLC) rangement of the allyl group and cyclization of the dioxan and the formation and crystallization of chiral Salts or by ring. The resulting primary alcohol (5) is converted to the methods described herein. See, for example, Jacques, et al., tosylate (6) by reaction with p-toluenesulfonyl chloride in Enantiomers, Racemates and Resolutions (Wiley the presence of a tertiary amine or pyridine, or alternatively Interscience, New York, 1981); Wilen, S. H., et al., Tetra to a halide by reaction with carbon tetrabromide or carbon hedron 33:2725 (1977); Eliel, E. L. Stereochemistry of tetrachloride in combination with triphenylphosphine. The Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H. allyl side chain is then cleaved to the aldehyde (7) by Tables of Resolving Agents and Optical Resolutions p. 268 treatment with ozone at low temperature, followed by work (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, up with a tertiary base Such as diisopropylethylamine or Ind. 1972). triethylamine, or by treatment with catalytic osmium tetroX Alkyl as used herein refers to an aliphatic hydrocarbon 15 ide and Sodium periodate. Reduction of the nitro group with chain and includes Straight and branched chains Such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Sec hydrogen over platinum oxide leads directly to formation of butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, and the indole (8) in which R is hydrogen.
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