Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-28
2003-07-15
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S311000, C514S357000, C514S646000, C546S139000, C546S152000, C546S329000, C564S305000
Reexamination Certificate
active
06593340
ABSTRACT:
FIELD OF THE INVENTION
This present invention relates to N-propargylphentermine and certain of its substituted analogues and their salts. The present invention relates to such compounds as they have neuroprotectant and/or antidepressant activities. The present invention also relates to pharmaceutical compositions including such compounds as an active ingredient. The present invention further relates to the therapeutic use of such compounds.
BACKGROUND OF THE INVENTION
No references have been noted in the prior art regarding N-propargylphentermine and its use as a neuroprotective compound.
While references to N-propargyl-N-methylalkylamines as selective monoamine exidase-B inhibiting and neuroprotective compounds are noted, such compounds are tertiary amines. Birkmayer et al., Journal of Neurotransmission 64:113-127 (1985); Yu et al., Journal of Medicinal Chemistry 35:3705-3713 (1992); Yu et al., Journal of Neurochemistry 63:1820-1828(1994). The present invention is primarily related to secondary amines.
SUMMARY OF THE INVENTION
It has now been discovered that N-propargylphentermine-related compounds having the following general formula:
where
R
1
and/or R
2
and/or R
3
=one or more phenyl, pyridinyl, pyrryl, furanyl, quinoline, isoquinoline, indolyl, naphthyl, thienyl or similar arylalkyl (where arylalkyl is defined as an aromatic structure such as a phenyl, pyridinyl, pyrryl, furanyl, quinoline, isoquinoline, indolyl, naphthyl, thienyl or similar aryl group combined with a linear or branched or cyclic alkyl chain consisting of between 1 and 10 carbons), substituted arylakyl, (where substituted arylalkyl is defined as an aromatic structure such as a phenyl, pyridinyl, pyrryl, furanyl, quinoline, isoquinoline, indolyl, naphthyl, thienyl or similar aryl group combined with a linear or branched or cyclic alkyl chain consisting of between 1 and 10 carbons and substituted with one or more groups consisting of Cl, F, Br, OH, CF
3
, NH
3
, NO
2
, alkoxy, alkythiol, thiol or similar substitution), CH
3
, Cl, F, Br, OH, CF
3
NH
3
NO
2
, alkoxy, alkylthiol, thiol or similar C
1
-C
8
alkyl, substituted alkyl, alkenyl, alkynyl groups,.
X when present is a salt-forming acid; have useful therapeutic activity as neuroprotective, antidepressant and/or anorexia agents.
The present invention includes methods of protecting the nervous system, treating neurodegenerative diseases or depression, suppressing appetite or controlling weight gain by administering, enterally or parenterally or as an injection, the compounds of the present invention in an animal or human at a dose of 0.01 mg/kg per day to 100 mg/kg per day. The compounds are usually but not necessarily isolated in the form of their mono- or di-salt, the salt-forming acids preferably being selected from hydrochloric acid, hydrobromic acid and oxalic acid.
The compounds of the present invention have been found to have neuroprotectant and/or potential antidepressant activity.
The present invention also includes use of established animal models for testing for neuroprotectant and/or potential antidepressant activity of N-propargyphentermine or derivatives having the following general formula:
where
R
1
and/or R
2
and/or R
3
one or more phenyl, pyridinyl, pyrryl, furanyl, quinoline, isoquinoline, indolyl, naphthyl, thienyl or similar aryalkyl (where arylalkyl is defined as an aromatic structure such as a phenyl, pyridinyl, pyrryl, furanyl, quinoline, isoquinoline, indolyl, naphthyl, thienyl or similar aryl group combined with linear or branched or cyclic alkyl chain consisting of between 1 and 10 carbons), substituted arylalkyl, (where substituted arylalkyl is defined as an aromatic structure such as a phenyl, pyridinyl, pyrryl, furanyl, quinoline, isoquinoline, indolyl, naphthyl, thienyhl or similar aryl group combined with a linear or branched or cyclic alkyl chain consisting of between 1 and 10 carbons and substituted with one or more groups consisting of Cl, F, Br, OH, CF
3
, NH
3
, NO
2
, alkoxy, alkylthiol, thiol or similar C
1
-C
8
alkyl, substituted alkyl, alkenyl, alkynyl groups,
X when present is a salt-forming acid,
The compound can be administered in sufficient amounts to bestow neuroprotectant and/or antidepressant activity.
Synthesis of N-propargyphentermine
The N-propargylphentermine compounds of the present invention have been prepared as set forth below. N-propargyl derivatives of phentermine which possesses the characteristics of formula (I) can also be synthesized. The structure of phentermine is provided below. N-propargylphentermine can also be evaluated for monoamine oxidase-A- and monoamine oxidase-B-inhibiting properties, neuroprotective activity and for properties indicative of inhibition of amine uptake.
Phentermine
N-Propargylphentermine (I) can be prepared directly from phentermine by reaction with propargyl bromide. Phentermine is reacted with a molar equivalent of propargyl bromide in acetonitrile with excess potassium carbonate at room temperature for 24 hours. A mixture of products (N-substituted and N,N-distributed) is obtained, although this reaction favors the production of N-propargylphentermine. The resulting material is then filtered and dried, and chromatography on silica gel is used to purify the desired product.
The following typical compounds (CVT-PP019 and CVT-PP022) selected from the CVT-PP series were prepared as described above as examples.
CODE# CVT-PP019
Chemical Name: N-propargylphentermine
Formula: C
13
H
17
N
Molecular Weight: 187
Structure:
CODE # CVT-PP022
Chemical Name: p-chloro-N-propargylphentermine
Formula: C
13
H
16
NCl
Molecular Weight: 221.5
Structure:
Biological Activity of Typical Compounds
The typical compounds PP019 and PP022 were tested in biochemical assays and in animals as follows.
The activity of the compound was initially determined in vitro at doses of 1×10
−4
and 1×10
−5
M for its ability to inhibit monoamine oxidase-A and monoamine oxidase-B. If the substance was active at these doses, a dose response relation was constructed and the effective dose (ED
50
) determined. Each compound was also tested ex vivo for monoamine oxidase-inhibiting activity; ex vivo for serotonin-, dopamine- and noradrenaline-elevating activity; ex vivo for 5-hydroxyindoleacetic acid-reducing activity; ex vivo for protection against SDP-4-induced depletion of noradrenaline and in vitro for noradrenaline or serotonin uptake-inhibiting activity. If toxicity was encountered with the initial dose, the dose was reduced until one was reached which was tolerated by the animals being tested.
Compounds of the general formula I have been found to possess at least one of monoamine oxidase-inhibiting, amine-elevating, 5-hydroxytryptamine uptake-inhibiting and neuroprotectant activity in animals.
REFERENCES:
patent: 3067101 (1962-12-01), Easton et al.
Baker Glen
Coutts Ronald
Ling Lei
Shan Jacqueline
Sloley Brian D.
CV Technologies Inc.
Davis Zinna Northington
Rothwell Figg Ernst & Manbeck
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