Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1998-07-06
2001-06-26
Barts, Samuel (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C564S504000
Reexamination Certificate
active
06251950
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a class of propargylamines, their salts and to pharmaceutical compositions containing such compounds. The compounds have cellular rescue properties which make them useful in the treatment and prevention of diseases in which cell death occurs by apoptosis.
BACKGROUND OF THE INVENTION
Neurodegenerative disorders of both acute types (e.g. stroke, head trauma, Bell's palsy, spinal cord and other nerve crush injuries) and chronic types (e.g. Alzheimer's disease, Parkinson's disease, Picks's disease, amyotrophic lateral sclerosis, Huntington's disease, glaucoma, as well as idiopathic neuropathies) are responsible for enormous human suffering, are a burden on health care systems and result in significant economic loss. A drug or treatment which could prevent, delay or alleviate one or more of these conditions would be of immense value.
R-Deprenyl hydrochloride (selegiline, L-deprenyl) has been demonstrated to be an effective adjuvant to L-dopa in the treatment of Parkinson's disease and, in early otherwise untreated cases, it has more recently been reported to delay onset of symptoms when administered alone. It has also been claimed that the use of deprenyl improved the clinical condition of some Alzheimer patients and the symptoms of attention deficit disorder in Tourette's syndrome patients. In addition, it has been observed to prolong life span and sexual activity in rodents and humans.
Initially, the improvement in Parkinson's and other patients was ascribed to the protection of neurons by the MAO-B inhibitory properties of deprenyl. However, studies of the effect of deprenyl on neuronal survival in N-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP)-induced Parkinsonism, axotomized immature facial motoneurons in rats, and hippocampal neuron death following ischemia or excitotoxin insult have shown that survival is increased by a mechanism which is independent of monoamine oxidase type B (MAO-B) inhibition. Studies with PC12 cells have shown that deprenyl can prevent apoptosis by a mechanism which involves selective alterations in gene expression to block the loss of mitochondrial function which in turn would commit these cells to apoptosis. Deprenyl has also been shown to prevent N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4)-induced degeneration of rat brain noradrenergic axons and terminals. The concentrations of deprenyl required to prevent apoptosis are at least an order of magnitude lower than the minimum necessary for MAO-B inhibition in some of these models. Furthermore, not all MAO-B inhibitors are effective in rescuing damaged neurons.
Deprenyl is metabolized to amphetamine and methamphetamine which have been observed to be neurotoxic even at quite low concentrations, which creates a possible problem with deprenyl as a neuronal rescue drug. Similarly deprenyl has been shown to enhance the cytotoxicity of dopamine towards catecholaminergic neuroblastoma SH-SY5Y cells. Deprenyl has been demonstrated to be a substrate for cytochrome P450 enzymes, which mediate the dealkylation process leading to the observed metabolites, methamphetamine and desmethyldeprenyl. Desmethyldeprenyl is active as an anti-apoptotic drug and studies involving the inhibition of P450 enzymes have shown that desmethyldeprenyl is the active component when deprenyl is given since pretreatment with a P450 inhibitor such as proadifen eliminates the neurorescue properties of deprenyl. It has also been reported that the desmethyldeprenyl-like compound, N-propargyl-1-aminoindan, is effective in enhancing the in vitro neuronal survival after glutamate toxicity.
Recently, some aliphatic analogues of deprenyl have proven to be as effective MAO-B inhibitors as deprenyl. As with deprenyl, it is the R-enantiomers which are active. They have also been shown to protect and rescue damaged neurons in the same models of neurodegeneration described above for deprenyl.
The aliphatic propargylamines identified in this application are active as antiapoptotic compounds.
DESCRIPTION OF THE INVENTION
The present invention relates to a group of propargylamines of general formula (I)
wherein R
1
in hydrogen or CH
3
and R
2
is (CH
2
)
n
CH
3
and n is 0 or an integer from 1 to 16, preferably 1 to 10, more preferably 1 to 5, and the salts thereof, particularly pharmaceutically acceptable salts.
Compounds of the general formula (I) in which R
1
differs from R
2
are chiral. It has been found that the R-enantiomers are useful as cellular rescue agents for the treatment and prevention of diseases in which cell death occurs by apoptosis, such as those mentioned above. This effect is observed at doses much lower than those required for MAO-B inhibition. The S-enantiomers do not prevent apoptosis but can antagonise the anti-apoptotic actions of the R-enantiomers, and are useful as research tools. The achiral compounds display cellular rescue properties.
The racemates are useful as intermediates in the preparation of R- and S-enantiomers. Methods of separating racemates are known. Suitable methods include fractional crystallization of a suitable salt, chromatography and preparation of for example N-acetyl derivatives, followed by deacetylation of one enantiomer with a stereospecific enzyme. It is preferred, however, to make chiral compounds of formula (I) from chiral reactants, using reactions that do not destroy the stereochemistry. When referring to enantiomers, it is preferred that an enantiomer shall not contain more than about 3% of the enantiomer of the opposite configuration. It is particularly preferred that an enantiomer contain less than about 1% of the enantiomer of the opposite configuration.
The invention relates as well to the use of compounds of the general formula I, as defined above, and salts thereof, as cellular rescue agents for the treatment and prevention of diseases in which cell death occurs by apoptosis including stroke, head trauma, Bell's palsy, spinal cord and other nerve crush injuries, Alzheimer's disease, Parkinson's disease, Pick's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, cardiac myopathies, nephropathy, retinopathy, diabetic complications, glaucoma, as well as idiopathic neuropathies.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The present invention relates to a group of propargylamines of general formula (I),
wherein R
1
is hydrogen or CH
3
and R
2
is (CH
2
)
n
CH
3
where n is an integer from 0 to 16, and salts thereof, and their use as cellular rescue agents for the treatment and prevention of diseases in which cell death occurs by apoptosis, as mentioned above.
Preferred compounds of the invention include:
N-(ethyl)propargylamine;
N-(1-Propyl)propargylamine;
N-(2-Propyl)propargylamine;
N-(1-Butyl)propargylamine;
N-(1-Pentyl)propargylamine;
N-(1-Hexyl)propargylamine;
N-(1-Heptyl)propargylamine;
N-(1-Octyl)propargylamine;
N-(1-Nonyl)propargylamine;
N-(1-Decyl)propargylamine;
N-(1-Undecyl)propargylamine;
N-(1-Dodecyl)propargylamine;
(R)-N-(2-Butyl)propargylamine;
(R)-N-(2-Pentyl)propargylamine;
(R)-N-(2-Hexyl)propargylamine;
(R)-N-(2-Heptyl)propargylamine;
(R)-N-(2-Octyl)propargylamine;
(R)-N-(2-Nonyl)propargylamine;
(R)-N-(2-Decyl)propargylamine;
(R)-N-(2-Undecyl)propargylamine;
(R)-N-(2-Dodecyl)propargylamine;
The S-enantiomers antagonize the effect of the R-enantiomers, and are useful as research tools. Preferred compounds of the S-configuration are:
(S)-N-(2-Butyl)propargylamine;
(S)-N-(2-Pentyl)propargylamine;
(S)-N-(2-Hexyl)propargylamine;
(S)-N-(2-Heptyl)propargylamine;
(S)-N-(2-Octyl)propargylamine;
(S)-N-(2-Nonyl)propargylamine;
(S)-N-(2-Decyl)propargylamine;
(S)-N-(2-Undecyl)propargylamine;
(S)-N-(2-Dodecyl)propargylamine;
Compounds of formula (I) in which R
1
is hydrogen and n is 0 or 1 to 4, and the compound in which R
1
is CH
3
and n is 0 are known. The racemates of compounds of formula (I) in which R
1
is CH
3
and n is 1 or 4 are also known. It is believed that the other compounds of formula (I) including the enant
Boulton Alan
Davis Bruce
Durden David
Dyck Lillian
Li Xinmin
Barts Samuel
Synnestvedt & Lechner LLP
University of Saskatchewan
LandOfFree
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