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(12) United States Patent (10) Patent N0.: US 6,967,201 B1 Briner Et Al

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(12) United States Patent (10) Patent N0.: US 6,967,201 B1 Briner Et Al US006967201B1 (12) United States Patent (10) Patent N0.: US 6,967,201 B1 Briner et al. (45) Date of Patent: *Nov. 22, 2005 (54) BENZOFURYLPIPERAZINES AND (56) References Cited BENZOFURYLHOMOPIPERAZINES: SEROTONIN AGONISTS U.S. PATENT DOCUMENTS 5,698,766 A 12/1997 Julius et 211. (75) Inventors: Karin Briner, Indianapolis, IN (US); 6,638,936 B1 * 10/2003 Briner et a1. Joseph Paul Burkhart, Plain?eld, IN (US); Timothy Paul Burkholder, FOREIGN PATENT DOCUMENTS Carmel, IN (US); Brian Eugene EP 0 006 524 A 1/1980 Cunningham, Martinsville, IN (US); EP 0 189 612 A 8/1986 Matthew Joseph Fisher, Mooresville, W0 W0 95 11243 A 4/1995 IN (US); William Harlan Gritton, W0 W0 97 08167 A 3/1997 Zionsville, IN (US); Shawn W0 W0 97 36893 A 10/1997 Christopher Miller, Noblesville, IN (US); J e?'rey Thomas Mullaney, OTHER PUBLICATIONS Indianapolis, IN (US); Matthew Robert Kuipers W. et al: “N4-unsubstituted 1-6 nl-arylpiperaZines Reinhard, Indianapolis, IN (US); as high-affinity 5 -HT1A recept r ligands” Journal of Medici Dennis Charles Thompson, nal Chemistry., vol. 38, No. 11, May 26, 1995, pp. 1942 Indianapolis, IN (US); Leonard Larry 1954, XP002153536 American Chemical Society. Washing Winneroski, Greenwood, IN (US); ton., US ISSN: 0022-2623. Yanping Xu, Fishers, IN (US) * cited by examiner (73) Assignee: Eli Lilly and Company, Indianapolis, Primary Examiner—Emily Bernhardt IN (US) (74) Attorney, Agent, or Firm—R. Craig Tucker (57) ABSTRACT (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. The present invention provides serotonergic benZofurylpip eraZines of Formula I: This patent is subject to a terminal dis claimer. (21) Appl. No.: 10/031,312 / R4 '\/ / R1 (22) PCT Filed: Jul. 21, 2000 R3 / O R (86) PCT No.: PCT/ US00/ 19543 § 371 (6X1), Where: (2), (4) Date: May 6, 2002 A is a piperaZine of formula: (87) PCT Pub. No.2 wo01/09111 H (i) PCT Pub. Date: Feb. 8, 2001 R7 | R6’ N R7’ R6 Related US. Application Data R8 R5’ Provisional application No. 60/146,270, ?led on Jul. (60) R8’ N R5 29, 1999. (51) Int. Cl.7 .................. .. A61K 31/496; C07D 405/10 and R, R1, R2, R3, R4, R5, R5’, R6, R6’, R7, R7’, R8, and R8' (52) US. Cl. ................. .. 514/254.11; 544/376; 544/231 are as described in the speci?cation. (58) Field of Search .............................. .. 544/376, 231; 514/254.11 9 Claims, No Drawings US 6,967,201 B1 1 2 BENZOFURYLPIPERAZINES AND R6’ is hydrogen or methyl, provided that R6 may be BENZOFURYLHOMOPIPERAZINES: methyl only When R6 is other than hydrogen; or R6 and SEROTONIN AGONISTS R6’, together With the carbon atom to Which they are attached, form a cyclopropyl moiety; This US. national stage application of International R7’ is hydrogen or methyl, provided that R7 may be Application PCT/US00/19543, ?led Jul. 21, 2000, claims methyl only When R7 is other than hydrogen; or R7 and R7’, together With the carbon atom to Which they are priority to US. provisional application Ser. No. 60/146,270, attached, form a cyclopropyl moiety; ?led Jul. 29, 1999. R8’ is hydrogen or methyl, provided that R8 may be The neurotransmitter serotonin (5-hydroXytryptamine, 1O methyl only When R8 is other than hydrogen; or R8 and 5-HT) has a rich pharmacology arising from a heteroge R8’, together With the carbon atom to Which they are neous population of at least seven receptor classes. The attached, form a cyclopropyl moiety; serotonin 5 -HT2 class is further subdivided into at least three R9 is C1—C8 alkyl Where the alkyl chain is optionally subtypes, designated 5-HT2a, 5-HT2b, and 5-HT2C. The substituted With a substituent selected from the group 5-HT2C receptor has been isolated and characterized (Julius, 15 consisting of phenyl and pyridyl; et al., US. Pat. No. 4,985,352), and transgenic mice lacking or pharmaceutically acceptable acid addition salts thereof the 5-HT2C receptor have been reported to exhibit seiZures subject to the folloWing provisos: and an eating disorder resulting in increased consumption of a) When R2, R3, and R4 are all selected from the group food (Julius, et al., US. Pat. No. 5,698,766). Compounds consisting of hydrogen, tri?uoromethyl, cyano, C1—C4 selective for the 5-HT2C receptor Would provide useful alkoXy, or C1—C4 alkyl, neither R6 nor R7 may be therapies for the treatment of seiZure and eating disorders selected from the group consisting of hydrogen and Without the side effects associated With current therapies. C1—C6 alkyl unless: 1. R is halo; The present invention provides compounds of Formula I: 2. R1 is halo or phenyl 25 3. R6’ or R7’ is methyl; or 4. R5 or R8 are other than hydrogen, b) When R, R1, and tWo of R2, R3, and R4 are hydrogen and one of R2, R3, or R4 is selected from the group consisting of ?uoro, chloro, bromo, methyl, or meth oXy, at least one of R5, R6, R7, or R8 must be other than R1 hydrogen; R3 / c) When R1 is bromo or R is methyl, at least one of R2, R3, o and R4 must be other than hydrogen; and R d) no more than tWo of R5, R6, R7, and R8 may be other 35 than hydrogen. This invention also provides a pharmaceutical formula Where: tion Which comprises, in association With a pharmaceuti A is homopiperaZine or a piperaZine of formula: cally acceptable carrier, diluent or eXcipient, a compound of Formula I. 40 The present invention provides a method for increasing activation of the 5-HT2C receptor in mammals comprising administering to a mammal in need of such activation a pharmaceutically effective amount of a compound of For mula I. 45 The present invention also provides a method for treating obesity in mammals comprising administering to a mammal in need of such treatment a pharmaceutically effective amount of a compound of Formula I. A further embodiment of this invention is a method for increasing activation of the 5-HT2C receptor for treating a R is hydrogen, halo, tri?uoromethyl or C1—C6 alkyl; variety of disorders Which have been linked to decreased R1 is hydrogen, halo, tri?uoromethyl, phenyl, or C1—C6 neurotransmission of serotonin in mammals. Included alkyl; among these disorders are depression, obesity, bulimia, R2, R3, and R4 are independently hydrogen, halo, diha premenstrual syndrome or late luteal phase syndrome, alco lomethyl, tri?uoromethyl, 1,1-di?uoroethy-1-yl, 55 holism, tobacco abuse, panic disorder, anXiety, post-trau cyano, C1—C4 alkoXy, C1—C4 alkoXycarbonyl, C1—C6 matic syndrome, memory loss, dementia of aging, social alkyl, —C(O)NHR9, or C1—C6 alkyl substituted With a phobia, attention de?cit hyperactivity disorder, disruptive substituent selected from the group consisting of halo, behavior disorders, impulse control disorders, borderline personality disorder, obsessive compulsive disorder, chronic C1—C4 alkoXy and hydroXy. fatigue syndrome, premature ejaculation, erectile dif?culty, R5, R6, R7, and R8 are independently hydrogen, C1—C6 anorexia nervosa, disorders of sleep, autism, anXiety, seiZure alkyl, phenyl, benZyl, hydroXymethyl, halomethyl, disorders, and mutism. Any of these methods employ a dihalomethyl, trihalomethyl, or benZyloXymethyl; compound of Formula I. R5’ is hydrogen or methyl, provided that R5v may be This invention also provides the use of a compound of methyl only When R5 is other than hydrogen; or R5 and 65 Formula I for the manufacture of a medicament for the R5’, together With the carbon atom to Which they are treatment of obesity. Additionally, this invention provides a attached, form a cyclopropyl moiety; pharmaceutical formulation adapted for the treatment of US 6,967,201 B1 3 4 obesity containing a compound of Formula I. Furthermore, substituent on the piperaZine ring is other than hydrogen are this invention includes a method for the treatment of obesity illustrated by the folloWing structures: Which comprises administering an effective amount of a compound of Formula I. The general chemical terms used in the formulae above have their usual meanings. For example, the term “alkyl” includes such groups as methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and the like. The term “alkoxy” includes methoxy, ethoxy, propoxy, isopropoxy, 10 butoxy and the like. The term “acyl” includes such groups as R3_ R2 R3_ R2 formyl, acetyl, propionyl, butyryl, 2-methylpropionyl, and m/ / R1 l/ / R1 the like. The term “halo” includes ?uoro, chloro, bromo and R4 R4 iodo. O / O / 15 The term “C1—C6 alkyl substituted With a substituent R R selected from the group consisting of C1—C4 alkoxy and hydroxy” means a branched or linear alkyl group substituted in the carbon chain With one or tWo substituents indepen H E1 6 H 56 dently selected from hydroxy or C1—C4 alkoxy. \ R \ H The term “C1—C8 alkyl Where the alkyl chain is optionally N N substituted With a substituent selected from the group con sisting of phenyl and pyridyl” means a branched or linear alkyl group Which may be substituted in the carbon chain N\ \ N\ \ With a phenyl or pyridinyl ring. Since the compounds of this invention are amines, they PEER./ / R1 PEER./ / R1 are basic in nature and accordingly react With any of a R4 / R4 / number of inorganic and organic acids to form pharmaceu O O 3O tically acceptable acid addition salts. Since some of the free R R amines of the compounds of this invention are typically oils at room temperature, it is preferable to convert the free amines to their pharmaceutically acceptable acid addition Individual diastereomers, for example those compounds of salts for ease of handling and administration, since the latter the present invention Where tWo substituents on the pipera are routinely solid at room temperature.
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