Aminoindan derivatives

Details Aminoindan derivatives Aminoindan derivatives

2001-08-31

2002-10-08

Barts, Samuel (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C560S025000, C560S134000

Reexamination Certificate

active

06462222

ABSTRACT:

FIELD OF THE 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 exists in 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 dementias such as the compound tacrine. A summary of the different approaches to and progress made in the treatment of Alzheimer's Disease may be found in Drugs of the Future (1995) 20(11): 1145-1162.
Recently, compounds that in addition to inhibiting acetylcholine esterase, possess 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 Publication Nos. 614,888 and 664,291).
U.S. Pat. Nos. 5,387,133, 5,453,446, 5,457,133 and 5,519,061 all disclose that the compound (R)-N-propargyl-1-aminoindan, a highly selective monoamine oxidase type B (MAO-B) inhibitor is effective in the treatment of dementias of the Alzheimer type and memory disorders. There is no indication given therein that the compound might have acetylcholine esterase inhibitory activity. Furthermore, the compound is only very weakly active as a MAO-A inhibitor.
PCT International Publication No. WO95/18617 discloses various aminoindan derivatives that are active in a variety of CNS disorders including dementias of the Alzheimer type. There is no indication given therein that any of the compounds disclosed might have acetylcholine esterase inhibitory activity.
SUMMARY OF THE INVENTION
The present invention relates to compounds of formula I:
wherein when a is 0; b is 1 or 2; when a is 1, b is 1; m is from 0 to 3; X is O or S; Y is halogeno; R
1
is hydrogen or 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
aralkyl or C
6-12
cycloalkyl optionally substituted.
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, Alzheirner's Disease and other dementias such as senile dementia, presenile dementia, progressive 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 in the treatment of neurotraumatic disorder. As used herein the term “neurotraumatic disorder” is meant to include damage caused to the nervous system (both central and peripheral) by virtue of ischemic damage such as that which occurs in 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 or any form of nerve damage.
An additional aspect of the present invention relates to the use of the compounds of formula I in the treatment of memory disorder or depression.
The present invention relates to the racemic compounds themselves and optically active enantiomers thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1
shows the reduction in latency for mice after closed head injury in the Morris Water Maze Test after treatment with compound
1
, compound
10
or Saline (Control). The arrow shows the time of closed head injury.
FIG. 2
shows the reduction in latency for mice after closed head injury in the Morris Water Maze Test after treatment with compound
24
, compound
25
or Saline (Control). The arrow shows the time of closed head injury.
FIG. 3
shows the reduction in latency for mice after closed head injury in the Morris Water Maze Test after treatment with compound
37
, compound
39
or Saline (Control). The arrow shows the time of closed head injury.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to compound of Formula I:
wherein when a is 0, b is 1 or 2; when a is 1, b is 1, m is from 0-3, 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
aralkyl or C
6-12
cycloalkyl each optionally substituted.
In an embodiment of the present invention, a is 0 and b is 1. In another embodiment of the present invention, a is 0, b is 1, and X is O.
In an embodiment of the present invention, X is
0
. In an additional embodiment of the present invention, X is S.
In an embodiment of the present invention, R
2
is selected from the group consisting of hydrogen, methyl, ethyl or optionally substituted propargyl.
In another embodiment of the present invention, R
2
is propargyl.
In a further embodiment of the present invention, the compound is selected from the group consisting of: (rac) 6-(N-methyl, N-ethyl-carbamyloxy)-N′-propargyl-1-aminoindan HCl; (rac) 6-(N,N-dimethyl, carbamyloxy)-N′-methyl-N′-propargyl-1-aminoindan HCl; (rac) 6-(N-methyl,N-ethyl-carbamyloxy)-N′-propargyl-1-aminotetralin HCl; (rac)6-(N,N-dimethyl-thiocarbamoyloxy)-1-aminoindan HCl; (rac)6-(N-propyl-carbamyloxy)-N′-propargyl-1-aminoindan HCl; (rac)5-chloro-6-(N-methyl, N-propyl-carbamyloxy)-N′-propargyl-1-aminoindan HCl; (S)-6-(N-methyl, N-propyl-carbamyloxy)-N′-propargyl-1-aminoindan HCl; and (R)-6-(N-methyl, N-ethyl-carbamyloxy)-N′-propargyl-1-aminoindan hemi-(L)-tartrate.
In a further embodiment of the present invention, R
1
is hydrogen, methyl or ethyl and R
2
is hydrogen, methyl, ethyl or optionally substituted propargyl. In a further embodiment of the present invention, the propargyl group is substituted with a C
1-4
alkyl group on the methylene group (R
6
in Scheme I).
According to the present invention, the term “halogens” 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 an additional embodiment of the present invention, the group OC(X)NR
3
R
4
is on the 4, 6 or 7 position of the indan ring counting from the amino substituted carbon.
In another embodiment of the present invention, at least one of R
3
and R
4
is methyl and the other is hydrogen, methyl, ethyl, propyl, butyl, hexyl, phenyl, benzyl or cyclohexyl.
In the practice of this invention, pharmaceutically acceptable salts include, but are not limited to, the esylate, mesylate, maleate, fumarate, tartrate, hemi-tartarate, hydrochloride, hydrobromide, p-toluenesulfonate, benzoate, acetate, phosphate 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, indications of such amounts are given below.
These compositions 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 1000 mg.
In an alternative embodiment, the pharmaceuticall

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