Phenylethylamine derivatives

Details Phenylethylamine derivatives Phenylethylamine derivatives

1999-06-18

2001-06-26

Lee, Howard C. (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

N-c doai

C514S490000, C558S234000, C560S115000, C560S136000

Reexamination Certificate

active

06251938

ABSTRACT:

FIELD OF INVENTION
The present invention relates to novel compounds, pharmaceutical compositions containing said compounds and their use in the treatment of various CNS disorders.
BACKGROUND TO THE INVENTION
Dementia may take several forms including static dementia, Alzheimer's-type dementia, senile dementia, presenile dementia and progressive dementia. One of the common pathological features of several types of dementia is the lack of the neurotransmitter acetylcholine. This has led to the development of acetylcholine esterase inhibitors for use in the treatment of dementia's such as the compound tacrine.
Recently, compounds that in addition to inhibiting acetylcholine esterase, have inhibitory activity against monoamine oxidase type A (MAO-A) have been developed. The perceived benefit of having the anti-MAO-A activity is stated to be an anti-depressant effect (European Patent Applications Publication Nos. 614,888 and 664,291) Fink et al., (Bioorg & Med Chem Letts (1996) 6 625-630) also disclose compounds having both acetylcholine esterase and monoamine oxidase inhibitory moieties.
International Patent Application Publication No. WO96/02524 relates to alkylamino substituted phenylcarbamate derivatives having acetylcholinesterase inhibitory activity and their use in the treatment of Alzheimer's Disease.
SUMMARY OF THE INVENTION
The present invention compounds of formula I having the following formula:
wherein m is from 0-4; X is O or S; Y is halogeno; R, is hydrogen or C
1-4
alkyl; R
2
is hydrogen, C
1-4
alkyl or optionally substituted propargyl; R
3
and R
4
are each independently hydrogen, C
1-8
alkyl, C
6-12
aryl, C
6-12
cycloalkyl or C
6-12
aralkyl; and R
5
is hydrogen or C
1-4
alkyl, with the proviso that when X is O, R
2
is optionally substituted propargyl;
As used hereinafter, references to the compounds of formula I include all compounds of formula I without the final proviso.
The invention relates to the compounds themselves, pharmaceutical compositions containing said compounds and their use in the treatment of depression, Attention Deficit Disorder (ADD), Attention Deficit and Hyperactivity Disorder (ADHD), Tourette's Syndrome, Alzheimer's Disease and other dementia's such as senile dementia, dementia of the Parkinson's type, vascular dementia and Lewy body dementia.
A further aspect of the present invention relates to the use of the compounds of formula I wherein m is from 0-4; X is O or S; Y is halogeno; R
1
is hydrogen or C
1-4
alkyl; R
2
is hydrogen, C
1-4
alkyl or optionally substituted propargyl; R
3
and R
4
are each independently hydrogen, C
1-8
alkyl, C
6-12
aryl, C
6-12
cycloalkyl or C
6-12
aralkyl; and R is hydrogen or C
1-4
alkyl, in the treatment of neurotrauma, memory disorder or depression.
As used herein the term “neurotrauma” includes, but is not limited to, damage caused to the nervous system (both central and peripheral) by virtue of ischemic damage such as stroke, hypoxia or anoxia, neurodegenerative diseases, Parkinson's Disease, Alzheimer's Disease, Huntington's Disease, neurotoxic injury, head trauma injury, spinal trauma injury, peripheral neuropathy and any form of nerve damage.
The present invention relates to the racemic compounds themselves and optically active isomers thereof.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention is directed to compounds having the following formula:
wherein
m is from 0-4;
X is O or S;
Y is halogeno;
R
1
is hydrogen or C
1-4
alkyl;
R
2
is hydrogen, C
1-4
alkyl or optionally substituted propargyl; and R
3
and R
4
are each independently hydrogen, C
1-8
alkyl, C
6-12
aryl, C
6-12
cycloalkyl or C
6-12
aralkyl, R
5
is hydrogen or C
1-4
alkyl; and pharmaceutically acceptable salts thereof, provided that when X is O, R
2
is optionally substituted propargyl.
In an embodiment of the present invention, X is O. In a further embodiment of the present invention, X is S.
In an embodiment of the present invention, the compound is selected from the group consisting of: (rac)-3-(N-methyl,N-propyl-carbamyloxy)-&agr;-methyl-N′-propargyl phenethylamine HCl; (rac)-3-(N,N-dimetlhyl-carbamyloxy)-&agr;-methyl-N′-methyl,N′-propargyl phenethylamine HCl; (rac)-3-(N-methyl,N-hexyl-carbamyloxy)-&agr;-methyl-N′-methyl, N′-propargyl phenethylamine mesylate; (rac)-3-(N-methyl,N-cyclohexyl-carbamyloxy)-&agr;-methyl-N′-methyl,N′-methyl,N′-propargyl phenethylamine HCl; and (S)-3-(N-methyl, N-hexyl-carbamyloxy)-&agr;-methyl-N′-methyl,N′-propargyl phenethylamine ethanesulfonate.
A first object of the present invention relates to the compounds of formula I and their use in the treatment of Alzheimer's Disease and related dementias.
In an embodiment of the present invention R
1
is hydrogen., methyl or ethyl. When R
2
is propargyl then it may optionally be substituted. Such substitution is preferably on the methylene group (see R
6
in Scheme I) and is selected from the group consisting of C
1-4
alkyl.
According to the present invention, “halogeno” is used to refer to fluoro, chloro, bromo or iodo.
In an embodiment of the present invention, when m is greater than 1, each Y may be the same or different.
In a further embodiment of the present invention, at least one of R
3
and R
4
is methyl and the other is hydrogen, methyl, ethyl propyl, hexyl or cyclohexyl. In an additional embodiment of the present invention, R
5
is hydrogen or methyl.
The subject invention further provides pharmaceutically acceptable salts of the compounds of formula I. Examples of pharmaceutically acceptable salts include, but are not limited to, esylate salts, mesylate salts, maleate salts, fumarate salts, tartrate salts, hydrochloride salts, hydrobromide salts, p-toluenesulfonate salts, benzoate salts, acetate salts, phosphate salts and sulfate salts.
The subject invention further provides a pharmaceutical composition which comprises a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The “therapeutically effective amount” of a compound of formula I or a pharmaceutically acceptable salt thereof may be determined according to methods well known to those skilled in the art.
The compositions of the present invention may be prepared as medicaments to be administered orally, parenterally, rectally, or transdermally.
Suitable forms for oral administration include tablets, compressed or coated pills, dragees, sachets, hard or soft gelatin capsules, sublingual tablets, syrups and suspensions. In one embodiment, the pharmaceutically acceptable carrier is a solid and the pharmaceutical composition is a tablet.
The therapeutically effective amount may be an amount from about 0.5 mg to about 2000 mg, preferably, from about 1 mg to about 100 mg.
In an alternative embodiment, the pharmaceutically acceptable carrier is a liquid and the pharmaceutical composition is an injectable solution. The therapeutically effective amount may be an amount from about 0.5 mg to about 2000 mg, preferably from 1 mg to about 1000 mg. The volume administered may bean amount between 0.5 and 10 ml.
In a further alternative embodiment, the carrier is a gel and the pharmaceutical composition is a suppository. For parenteral administration the invention provides ampoules or vials that include an aqueous or non-aqueous solution or emulsion. For rectal administration there are provided suppositories with hydrophilic or hydrophobic vehicles. For topical application as ointments and transdermal delivery there are provided suitable delivery systems as known in the. art. For oral or suppository formulations, 0.5-2000 mg per unit dosage, and preferably 1-1000 mg per dosage unit is taken daily.
These compositions may be used alone to treat the above-listed disorders, or alternatively, as in the case of Alzheimer's Disease, for example, they may be used as an adjunct to the conventional treatments such as haloperidol, tacrine or deprenyl.
The invention w

Affiliated with

Also associated with

Rating

Phenylethylamine derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Phenylethylamine derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Phenylethylamine derivatives will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2528593