Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-10-02
2004-09-28
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S331000, C514S020800, C562S560000, C562S562000
Reexamination Certificate
active
06797699
ABSTRACT:
The present invention relates to neuroprotective agents.
In events such as prolonged hypoxia and ischaemia, which may or may not be associated with hypoglycaemia, neuronal damage, to varying degrees, is encountered.
Ischaemia typically occurs during heart attacks, but the damage incurred at these times is substantially limited to the heart tissues, and certain treatments have been developed. With regard to the present invention, we are concerned with the effects of more long term ischaemia on the brain, such as occurs with stroke patients or as a result of head injury. The severity of the ischaemia depends on the nature of the stroke or injury, but, invariably, there is brain damages and it is this which the present invention addresses.
Various neuroprotective agents are known in the art which attempt to alleviate the problem of brain damage, but all of those currently known tend to be associated with adverse side effects. For example, MK801 (dizocilpine maleate) is a fairly simple molecule and is known to provide a level of neuroprotection to ischaemic patients. However, MK801 is also associated with “alarming psychotropic effects” (Martindale), as well as adverse motor effects. The neuroprotective effects are detailed in Brain Research 755 (1997) 36-46 (Pringle, A. K., et al), incorporated herein by reference. These same authors also described the neuroprotective effects of conotoxin in an earlier paper but, despite the neuroprotective effects of this compound, adverse side effects, in vivo, are observed.
Recently, research has been performed on a series of polyamine compounds related to spermidine, and these compounds are disclosed in WO93/12777, with specific reference to their use as cationic channel regulating agents. These compounds are disclosed in connection with methods for regulating cation transport across cellular membranes possessing cation channels, the compounds being polyamine compounds having a lysine or arginine-based moiety (or a guanidine moiety) coupled to a straight chain polyamine. Mention of their effect on NMDA
N
-methyl-
D
-aspartate) receptors is also made. These compounds were unpredictable in their effect on cationic channels, various compounds having an effect on P-type calcium channels, whilst other compounds had effects on potassium and sodium channels. Although these compounds have subsequently been used in research for their effects on calcium channels, research effectively finished with the publication in Proc. Natl. Acad. Sci. USA [86, 1689-1693 (1989), Llinàs, R, et al], which disclosed that a substance known as FTX from funnel-web spider toxin was toxic to mice in extremely small doses.
The present inventors were not aware of the research by Llinàs and his colleagues, and were pursuing similar compounds, as they were known to have some calcium channel blocking activity. In fact, what was discovered was that, not only is the calcium channel blocking activity not very significant, but also there is little or no effect on NMDA receptors. Further, it was also established that these compounds are, despite the earlier research, non-toxic, and they also have a substantial neuroprotective effect.
It is believed that the reason for the discrepancy between the earlier results and the present results lies in the preparation of the compounds. In particular, the FTX component of funnel-web spider toxin was specifically isolated from the toxin in the prior art, rather than being prepared separately. This compound is currently thought to have the following formula (1)
Related compounds have been manufactured synthetically, using the approaches described herein, which result in little or no detectable contamination of the end product. The results in the various assays have, therefore, been exceedingly surprising in that the compounds have proven non-toxic, as well as to have little effect on calcium channels. Indeed, if there were a substantial effect on P-type calcium channels and/or the compounds were toxic, then there would be no use for them in the clinical field. Instead, we find that the compounds, in their purified form, have use as neuroprotective agents.
Thus, in a first aspect, the present invention provides a substantially pure compound having the general formula (I)
wherein:
Q represents an amidino group, a cyano group or a group of formula XYN—, where
X and Y are the same or different, and each may represent a hydrogen atom, a lower alkyl group, or a simple hetero-atom containing group or, together with the nitrogen atom to which they are attached, form a nitrogen-containing heterocyclic group;
R
a
represents a straight or branched chain alkylene or alkenylene group having from 1 to 6 carbon atoms and each optionally being substituted by from 1 to 4 alkyl groups each having from 1 to 3 carbon atoms;
R
b
and R
c
each represents an alkylene or alkenylene group having 3 or 4 carbon atoms in a straight chain, each being optionally substituted by 1 or 2 alkyl groups each having from 1 to 3 carbon atoms, the total number of carbon atoms in said
straight chains of R
b
and R
c
being 7;
R
2
and R
3
are the same as or different from each other and each represents a hydrogen atom, or a group of formula R, RCO, ROCO—, or RNHCO—, where
R represents a lower alkyl group or an aryl group, said alkyl or aryl group being optionally substituted by one or more of the substituents &agr;, defined below;
the chiral carbon atom indicated by the asterisk is in the L configuration;
Z is an aromatic amino acid residue;
n is 0 or 1;
R
1
represents a hydrogen atom or a lower alkyl group or an aryl group, said alkyl or aryl group being optionally substituted by one or more of the substituents &agr;, defined below; and
W represents a hydrogen atom or an alkyl or aryl group;
and pharmaceutically acceptable salts thereof.
A preferred class of compounds of the present invention are those compounds of formula (Ia):
(wherein Q, R
a
, R
b
, R
c
, R
2
, R
3
, Z, n, and R
1
are as defined above) and pharmaceutically acceptable salts thereof.
A still more preferred class of compounds of the present invention are those compounds of formula (Ib):
wherein:
X, Y, Z, n and R
1
are as defined above;
x is an integer from 1 to 5;
y is 3 or 4
R
4
, R
5
, R
6
and R
7
may be the same or different and each represents a hydrogen atom or a lower alkyl group; and
the chiral carbon atom indicated by the asterisk is in the L configuration;
and pharmaceutically acceptable salts thereof.
Substituents &agr; are selected from: halogen atoms, amino groups, alkylamino groups, dialkylamino groups, cyano groups, hydroxy groups, alkyl groups (except when the substituted group is alkyl), aryl groups, carbamoyl groups, alkylcarbamoyl groups, dialkylcarbamoyl groups and carboxy groups and esters thereof.
The present invention further provides non-toxic compounds of formula (I), (Ia) or (Ib) as defined above. There is still further provided a neuroprotective composition comprising a compound as defined above, as well as use of a compound as defined above in the manufacture of a medicament for the retardation of neuronal damage before, after or during an ischaemic event. The invention also provides a method of treating a mammal, which may be human, to protect said mammal from the neuronal damage caused by an ischaemic event by administering to said mammal before, after or during an ischaemic event an effective amount of a non-toxic compound of formula (I), (Ia) or (Ib) as defined above.
By substantially pure is meant a compound which, under conditions of HPLC (high performance liquid chromatography) is not shown to have any or any significant amount of contaminants detectable thereby. Trace levels of contaminants may be acceptable in certain circumstances and such circumstances may be determined by the skilled person at the time. In general, levels of contaminant should be less than 1%, and preferably substantially less than 1%, for example less than 0.1%, possibly as low as 0.001%.
In the alternative, it is preferred that the compounds are non-toxic, by which is meant that the compo
Bradley Mark
Iannotti Fausto
Pringle Ashley Ker
Sundstrom Lars Eric
Low Christopher S. F.
Lukton David
Price Heneveld Cooper DeWitt & Litton
University of Southampton
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