Inhibitors of serotonin reuptake

Details Inhibitors of serotonin reuptake Inhibitors of serotonin reuptake

1999-06-03

2001-10-16

Rotman, Alan L. (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S309000, C514S314000, C514S319000, C514S320000, C514S323000, C546S153000, C546S156000, C546S169000, C546S178000, C546S180000, C546S181000, C546S197000, C546S198000, C546S199000, C546S201000

Reexamination Certificate

active

06303627

ABSTRACT:

BACKGROUND OF THE INVENTION
During the past two decades, the relationship between neuronal monoamines in the brain and a variety of diseases and conditions has been appreciated and investigated. The discovery of selective monoamine reuptake inhibitors has provided the medical community with exciting new tools with the potential for treatment of several physiological and psychological disorders. Reuptake inhibitors increase the levels of endogenous monoamines by inhibiting the neuronal mechanism for recovering the monoamine from the synapse without interfering with the neuronal receptors. If the reuptake inhibitor is selective for a particular monoamine, undesirable side-effects from the therapy can be reduced.
Fluoxetine, a selective inhibitor of serotonin reuptake, has gained wide acceptance as a therapy for the treatment of depression and eating disorders, and is under active investigation for the treatment of other disorders. Similarly, tomoxetine hydrochloride [(−)-N-methyl-3-(2-methylphenoxy)propanamine hydrochloride] is a selective inhibitor of norepinephrine uptake being investigated clinically for the treatment of urinary incontinence. These compounds are among many taught in U.S. Pat. Nos. 4,018,895, 4,194,009, 4,314,081 and 5,026,707 as being potent inhibitors of the uptake of various physiologically active monoamines, including serotonin, norepinephrine and dopamine. The present invention provides 4-arylpiperidines useful for the inhibition of serotonin reuptake.
SUMMARY OF THE INVENTION
The present invention provides 4-arylpiperidines of formula I:
where
A—B is —C═CH— or —CHCH
2
—;
n is 0 or 1;
R
1
is H or C
1
-C
4
alkyl;
R
2
is H, or C
1
-C
6
alkyl; and
Aryl is naphthyl or heteroaryl, each optionally monosubstituted with a substitutent selected from the group consisting of halo, hydroxy, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, cyano, nitro, carboxamido, and trifluoromethyl; or pharmaceutically acceptable salts or hydrates thereof.
This invention also provides a pharmaceutical formulation which comprises, in association with pharmaceutically acceptable carriers, diluents or excipients, a compound of Formula I.
This invention further comprises a method for the inhibition of serotonin reuptake comprising administering to a mammal in need of such treatment an effective amount of 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, and the like. The term “alkoxy” includes methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like. The term “halogen” includes fluoro, chloro, bromo and iodo.
The term “naphthyl” is taken to mean naphth-1-yl or naphth-2-yl.
The term “heteroaryl” is taken to mean benzofur-2-yl, benzofur-3-yl, indazol-3-yl, benzimidazol-2-yl, benzothiazol-2-yl, benzoxazol-2-yl, benzoisothiazol-3-yl, benzoisoxazol-3-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, isoquinolin-1-yl, isoquinolin-3-yl, and isoquinolin-4-yl.
While all of the compounds of Formula I are useful for the inhibition of serotonin reuptake, certain classes of the compounds are preferred. The following paragraphs describe such preferred classes.
a) A—B is —C═CH—;
b) A—B is —CH—CH
2
—;
c) R
1
is hydrogen;
d) R
1
is methyl;
e) Aryl is naphthyl;
f) Aryl is heteroaryl;
g) Aryl is selected from benzothiazol-2-yl, benzofur-2-yl, and quinolin-2-yl;
h) Aryl is monosubstituted with halogen;
i) Aryl is monosubstituted with chloro;
j) Aryl is benzothiazol-2-yl;
k) Aryl benzofur-2-yl monosubstituted at the 6-position;
l) R
2
is hydrogen;
m) R
2
is methyl;
n) A—B is —CHCH
2
—, n is 0, R
2
is methyl at the 2-position of the piperidine ring, and the compound exists as the trans-isomer;
o) n is 0;
p) The compound is a salt;
q) The compound is a free base.
It will be understood that the above 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 some of the free 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 salts for ease of handling and administration, since the latter are routinely solid at room temperature. 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, 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.
Certain compounds of the invention where R
2
is methyl or ethyl are chiral. As such, these compounds may exist as single members of specific optical isomer pairs (a)-(f), as mixtures of these optical isomer pairs, or as racemic mixtures of these optical isomer pairs. The skilled artisan will also appreciate that the isomer pairs (a)-(d) exist as diastereomers, since the alkyl moiety creates an element of asymmetry at the 4-position of the piperidine nucleus. All of these diastereomers and enantiomers are contemplated by the present invention.
While all racemates, diastereomers, single enantiomers, and mixtures of enantiomers are useful serotonin reuptake inhibitors, it is preferred that the compound be a single enantiomer or diastereomer.
It is especially preferred that the compound contains a moiety of formula (b).
The skilled artisan will appreciate that the pure isomers may be prepared from chiral starting materials, or by fractional crystallization using chiral acids. Additionally, compounds of the invention where R
1
is H may be used as intermediates by introducing a chiral auxiliary, separating the diastereomers by fractional crystallization or chromatography, and then cleaving the chiral auxiliary. R
1
substituents other than H may then be reintroduced, as desired, by reductive alkylation or alkylation with an appropriate reagent.
The following group is illustrative of the compounds of the present invention:
(+)-trans-2-methyl-4-(benzofur-3-yl)piperidine sulfate;
4-(4-bromobenzofur-2-yl)-1,2,3,6-tetrahydropyridine phosphate;
4-(5-fluorobenzofur-3-yl)piperidine hydrochloride;
4-(6-iodobenzofur-2-yl)piperidine;
(−)-cis-1,2-dimethyl-4-(7-hydroxybenzofur-3-yl)piperidine hydrobromide monohydrate;
4-(4-methylbenzofur-2-ylmethyl)piperidine acetate;
4-(5-isopropylbenzofur-3-yl)piperidine;
trans-1-methyl-3-ethyl-4-(6-isobutylbenzofur-2-yl)piperidine acrylate;
4-(7-ethoxybenzofur-3-yl)piperidine succinate;
4-(4-tert-butoxybenzofur-2-yl)piperidine;
1-isopropyl-4-(5-cyanobenzofur-3-yl)-1,2,3,6-tetrahydropyridine dinitrobenzoate;
4-(6-nitrobenzofur-2-yl)piperidine;
1-butyl-4-(6-carboxamidobenzofur-3-yl)piperidine;
4-(7-trifluoromethybenzofur-2-yl)piperidine citrate;
(+)-trans-2-methyl-4-(indazol-3-yl)piperidine sulfate;
4-(4-bromoindazol-yl)-1,2,3,6-tetrahydropyridine phosphate;
4-(5-fluoroindazol-3-yl)piperidine hydrochloride;
4-(6-iodoindazol-3-ylmethyl)piperidin

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