Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-06-17
2001-06-05
Seaman, D. Margaret (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S294000, C514S307000, C514S308000, C514S314000, C514S315000, C514S318000, C544S349000, C546S095000, C546S096000, C546S140000, C546S144000, C546S167000, C546S192000, C546S195000, C546S196000, C546S207000
Reexamination Certificate
active
06242450
ABSTRACT:
BACKGROUND OF THE INVENTION
Serotonin (5-HT) exhibits diverse physiological activity mediated by at least four receptor classes, the most heterogeneous of which appears to be 5-HT
1
. A human gene which expresses a fifth 5-HT
1
subtype, named 5-HT
1F
, was isolated by Kao and coworkers (
Proc. Natl. Acad. Sci. USA
, 90, 408-412 (1993)). This 5-HT
1F
receptor exhibits a pharmacological profile distinct from any serotonergic receptor yet described. While 5-HT
1F
agonists have been reported by Audia and Nissen (U.S. Pat. No. 5,521,196) and Audia (U.S. Pat. No. 5,521,197), antagonists of the 5-HT
1F
receptor, and their pharmacological activity, were heretofore unknown. This invention provides novel 5-HT
1F
antagonists which are useful for the treatment of anxiety disorders.
SUMMARY OF THE INVENTION
The present invention provides the substituted piperidines of formula I:
where:
R and R′ are independently hydrogen or hydroxy;
AR
1
is phenyl, naphthyl, quinolinyl, isoquinolinyl, indanyl, 1,2,3,4-tetrahydronaphthyl, indolyl, N-(C
1
-C
4
alkyl)indolyl, benzothiazolyl, benzothienyl, benzofuryl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzofuryl, julolidinyl, or dibenzofuryl, each optionally substituted with one or two substituents independently selected from the group consisting of C
1
-C
6
alkyl, C
1
-C
6
acyl, benzoyl, C
1
-C
6
alkoxy, phenoxy, C
1
-C
6
alkylthio, trifluoromethyl, trifluoromethoxy, or halo;
AR
2
is pyridin-3-yl, quinolin-3-yl, isoquinolin-4-yl, or quinoxalin-2-yl; and pharmaceutically acceptable acid addition salts thereof.
A further embodiment of this invention is a method for decreasing activation of the 5-HT
1F
receptor by administering a compound of Formula I.
Antagonism of the 5-HT
1F
receptor provides a method for treating anxiety disorders. A further embodiment of this invention is a method for the treatment of anxiety disorders, comprising administering to a mammal in need of such treatment an effective dose of a compound of Formula I.
In addition, this invention provides pharmaceutical formulations comprising an effective amount for deactivation of the 5-HT
1F
receptor of a compound of Formula I, in combination with a suitable pharmaceutical carrier, diluent, or excipient.
This invention also provides the use of a compound of Formula I for the manufacture of a medicament for the treatment of anxiety disorders. Additionally, this invention provides a pharmaceutical formulation adapted for the treatment of anxiety disorders containing a compound of Formula I.
DETAILED DESCRIPTION
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, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-pentyl, 2-pent-yl, 3-pentyl, neopentyl, hexyl, and the like. The term “alkoxy” includes methoxy, ethoxy, isopropoxy, butoxy, tert-butoxy, hexyloxy, and the like. The term “alkylthio” includes methylthio, ethylthio, isopropylthio, butylthio, tert-butylthio, hexylthio, and the like. The term “acyl” includes formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, and the like. The term “halo” includes fluoro, chloro, bromo and iodo.
The compounds of the invention where R is hydroxy possess an asymmetric carbon labelled with an asterisk in the following formula:
As such, each of the compounds of the present invention exists not only as the racemate but as individual R- and S-enantiomers as well:
The compounds of the present invention include the individual R- and S-enantiomers, and mixtures thereof, including the racemates.
The compounds of this invention are useful in a method for decreasing activation of the 5-HT
1F
receptor for treating disorders which have been linked to excessive neurotransmission of serotonin in mammals. It is preferred that the mammal to be treated by the administration of compounds of this invention is human.
While all of the compounds of the present invention are useful as 5-HT
1F
antagonists, certain classes are preferred. The following paragraphs describe such preferred classes.
aa) R is hydroxy;
ab) R′ is hydroxy;
ac) R and R′ are both hydroxy;
ad) AR
1
is phenyl;
ae) AR
1
is indolyl;
af) AR
1
is indol-4-yl;
ag) AR
1
is indol-5-yl;
ah) AR
1
is N-(C
1
-C
4
alkyl)indolyl;
ai) AR
1
is substituted phenyl;
aj) AR
1
is monosubstituted phenyl;
ak) AR
1
is phenyl monosubstituted with trifluoromethyl, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
1
-C
6
alkylthio, or halo;
al) AR
1
is phenyl monosubstituted with trifluoromethyl;
am) AR
1
is phenyl monosubstituted with C
1
-C
6
alkoxy;
an) AR
1
is phenyl monosubstituted with methoxy;
ao) AR
1
is 4-methoxyphenyl;
ap) AR
1
is 4-benzyloxyphenyl;
aq) AR
1
is phenyl monosubstituted with C
1
-C
6
alkyl;
ar) AR
1
is phenyl monosubstituted with methyl, ethyl, isopropyl, or tert-butyl;
as) AR
1
is phenyl monosubstituted in the 4-position with methyl, ethyl, isopropyl, or tert-butyl;
at) AR
1
is 2-tert-butylphenyl;
au) AR
1
is phenyl monosubstituted with halo;
av) AR
1
is phenyl monosubstituted in the 4-position with halo;
aw) AR
1
is 4-chlorophenyl;
ax) AR
1
is 4-iodophenyl;
ay) AR
1
is disubstituted phenyl;
az) AR
1
is 2,4-disubstituted phenyl;
ba) AR
1
is phenyl disubstituted with C
1
-C
6
alkyl;
bb) AR
1
is phenyl disubstituted with methyl;
bc) AR
1
is 2,4-dimethylphenyl;
bd) AR
1
is 2-methoxy-4-methylphenyl;
be) AR
1
is 2-methyl-4-methylthiophenyl;
bf) AR
1
is 2-methyl-4-acetylphenyl;
bg) AR
1
is naphthyl;
bh) AR
1
is naphth-2-yl;
bi) AR
1
is 6-methoxynaphth-2-yl;
bj) AR
1
is indanyl;
bk) AR
1
is substituted indanyl;
bl) AR
1
is 7-methylindan-4-yl;
bm) AR
1
is 1,2,3,4-tetrahydronaphth-6-yl;
bn) AR
1
is quinolinyl;
bo) AR
1
is quinolin-6-yl;
bp) AR
1
is quinolin-7-yl;
bq) AR
1
is dibenzofur-3-yl;
br) AR
2
is quinolin-3-yl;
bs) AR
2
is quinoxalin-2-yl;
bt) AR
2
is pyridin-3-yl;
bu) The compound is a racemate;
bv) The compound is the R-enantiomer;
bw) The compound is the S-enantiomer;
bx) The compound is the free base;
by) The compound is a salt;
bz) The compound is the oxalate salt.
It will be understand that the above preferred classes may be combined to form additional preferred classes.
Since the compounds of this invention are amines, they are basic in nature and accordingly react with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Since many of the free amines of the compounds of this invention are oils or low melting amorphous solids, it is preferable to convert the free amines to their pharmaceutically acceptable acid addition salts 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, methane-sulfonic 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, bisulf-ate, sulfite, bisulfite, phosphate, monohydrogenphosphate, 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 oxalic acid.
The following group is illustrative of compounds contemplated within the scope of this invention:
1-(3-phenoxyprop-1-yl)-4-hydroxy-4-(isoquinolin-4-yl)piperidine oxalate;
1-(3-(
Koch Daniel James
Phebus Lee Alan
Rocco Vincent Patrick
Sajdyk Tammy Joy
Eli Lilly and Company
Seaman D. Margaret
Titus Robert D.
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