Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-06
2003-10-28
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S376000
Reexamination Certificate
active
06638936
ABSTRACT:
The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has a rich pharmacology arising from a heterogeneous population of at least seven receptor classes. The serotonin 5-HT
2
class is further subdivided into at least three subtypes, designated 5-HT
2a
, 5-HT
2b
, and 5-HT
2c
. The 5-HT
2c
receptor has been isolated and characterized (Julius, et al., U.S. Pat. No. 4,985,352), and transgenic mice lacking the 5-HT
2c
receptor have been reported to exhibit seizures and an eating disorder resulting in increased consumption of food (Julius, et al., U.S. Pat. No. 5,698,766). Compounds selective for the 5-HT
2c
receptor would provide useful therapies for the treatment of seizure and eating disorders without the side effects associated with current therapies.
Hartog (Hartog, et al., U.S. Pat. No. 5,424,313) generically describes a number of benzofurylpiperazines which are taught to be useful as psychotropics, central analgetics, and thrombolytics. The use of benzofuryl-piperazines as selective 5-HT
2c
agonists has heretofore not been appreciated. The present invention provides compounds selective for the 5-HT
2c
receptor.
The present invention provides compounds of Formula I:
where R is methyl or ethyl, or pharmaceutically acceptable acid addition salts thereof.
This invention also provides a pharmaceutical formulation which comprises, in association with a pharmaceutically acceptable carrier, diluent or excipient, a compound of Formula I.
The present invention provides a method for increasing activation of the 5-HT
2C
receptor in mammals comprising administering to a mammal in need of such activation a pharmaceutically effective amount of a compound of Formula I.
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-HT
2C
receptor for treating a variety of disorders which have been linked to decreased neurotransmission of serotonin in mammals. Included among these disorders are obesity, obsessive compulsive disorder, and depression. Any of these methods employ a compound of Formula I.
This invention also provides the use of a compound of Formula I for the manufacture of a medicament for the treatment of obesity. Additionally, this invention provides a pharmaceutical formulation adapted for the treatment of obesity containing a compound of Formula I. Furthermore, this invention includes a method for the treatment of obesity which comprises administering an effective amount of a compound of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of Formula I are generally referred to as 1-(4-trifluoromethylbenzofur-7-yl)-3(S) -methylpiperazine when R is methyl, and 1-(4-trifluoromethylbenzofur-7-yl)-3(S)-ethylpiperazine when R is ethyl. Since this compound is an amine, it is basic in nature and accordingly reacts with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. It is preferable to convert the free amine to a pharmaceutically acceptable acid addition salt for ease of handling and administration. Acids commonly employed to form such salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids, such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like. Examples of such pharmaceutically acceptable salts thus are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen-phosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, &bgr;-hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable salts are those formed with hydrochloric acid and fumaric acid.
The compounds of Formula I may be prepared by chiral chromatography of the racemic or enantiomerically enriched free amines, or fractional crystallization of salts prepared from racemic or enantiomerically enriched free amines and a chiral acid. Alternatively, the free amines may be reacted with a chiral auxiliary and the enantiomers separated by chromatography followed by removal of the chiral auxiliary to regenerate the free amines. Furthermore, separation of enantiomers may be performed at any convenient point in the synthesis of the compound of the invention. Preferably, the compounds of the invention are prepared beginning with chiral starting materials.
The present invention also provides a method for increasing activation of the 5-HT
2C
receptor in mammals by administering to a mammal in need of such activation a pharmaceutically effective amount of a compound of Formula I. The preferred mammal is human.
Compounds of Formula I may be prepared as described in the following scheme, beginning with 4-trifluorometh-yl-7-(substituted)-benzofuran and 2(S)-methyl- or ethylpiperazine.
The 4-trifluoromethylbenzofur-7-yl bromide, iodide, or triflate is reacted with 2(S)-methyl- or ethylpiperazine in the presence of an appropriate catalyst and base. The coupling is catalyzed with an appropriate metal catalyst, such as nickel or palladium. Palladium catalysts are preferred and are either commercially available or may be generated in situ by combining trisdibenzylideneacetone dipalladium or palladium chloride with a phosphine ligand such as racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, tri-o-tolylphosphine, or bis(diphenylphosphino)ferrocene. The ratio of palladium to phosphine ligand is typically between 1:1 and 1:5. Typically 0.01 to 0.1 equivalents of catalyst are used relative to starting benzofuran. Useful bases include sodium tert-butoxide, lithium tert-butoxide, and potassium tert-butoxide. Typically 1-5 equivalents of base are used relative to starting benzofuran.
The benzofuran, piperazine, catalyst, and base are combined in a suitable solvent. Suitable solvents include toluene, benzene, dioxane, and tetrahydrofuran. The mixture is stirred at 20-200° C. under an inert atmosphere, typically nitrogen or argon, until the reaction is complete. Additional portions of any reagent may be added during the course of the reaction as necessary or desired. Typically, 1-1.2 equivalents of the piperazine are reacted with the benzofuran.
Alternatively, the compounds of Formula I may be prepared as described in the following scheme.
The piperazine ring may be constructed onto the benzofuryl moiety by coupling 4-trifluoromethyl-7-bromo-benzofuran with benzophenone imine under the coupling conditions previously described. The resulting adduct is treated with aqueous acid to provide the corresponding amine. This aminobenzofuran is coupled with an appropriately nitrogen-protected (S)-alanine (when R=methyl) or (S)-2-aminobutyric acid (when R=ethyl) under standard peptide coupling conditions. The resulting amide is reduced with a hydride reducing agent such as lithium aluminum hydride, and the corresponding amine deprotected to provide a diamine. The diamine is treated with an appropriate reagent, for example bromoacetyl bromide, to prepare the corresponding lactam. Reduction of this lactam under standard hydride reducing conditions, for example by treatment with borane or lithium aluminum hydride, provide the desired compound.
The requisite benzofuran is either commercially available or may be prepared from an appropriate
Briner Karin
Burkholder Timothy Paul
Heiman Mark Louis
Nelson David Lloyd Garver
Bernhardt Emily
Eli Lilly and Company
Tucker R. Craig
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